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1
Telemala, Joseph P., and Hussein Suleman. "Exploring Topic-language Preferences in Multilingual Swahili Information Retrieval in Tanzania." ACM Transactions on Asian and Low-Resource Language Information Processing 20, no. 6 (November 30, 2021): 1–30. http://dx.doi.org/10.1145/3458671.
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Habitual switching of languages is a common behaviour among polyglots when searching for information on the Web. Studies in information retrieval (IR) and multilingual information retrieval (MLIR) suggest that part of the reason for such regular switching of languages is the topic of search. Unlike survey-based studies, this study uses query and click-through logs. It exploits the querying and results selection behaviour of Swahili MLIR system users to explore how topic of search (query) is associated with language preferences—topic-language preferences. This article is based on a carefully controlled study using Swahili-speaking Web users in Tanzania who interacted with a guided multilingual search engine. From the statistical analysis of queries and click-through logs, it was revealed that language preferences may be associated with the topics of search. The results also suggest that language preferences are not static; they vary along the course of Web search from query to results selection. In most of the topics, users either had significantly no language preference or preferred to query in Kiswahili and changed their preference to either English or no preference for language when selecting/clicking on the results. The findings of this study might provide researchers with more insights in developing better MLIR systems that support certain types of users and in certain scenarios.
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Jungmair, Michael, André Kohn, and Jana Giceva. "Designing an open framework for query optimization and compilation." Proceedings of the VLDB Endowment 15, no. 11 (July 2022): 2389–401. http://dx.doi.org/10.14778/3551793.3551801.
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Since its invention, data-centric code generation has been adopted for query compilation by various database systems in academia and industry. These database systems are fast but maximize performance at the expense of developer friendliness, flexibility, and extensibility. Recent advances in the field of compiler construction identified similar issues for domain-specific compilers and introduced a solution with MLIR, a generic infrastructure for domain-specific dialects. We propose a layered query compilation stack based on MLIR with open intermediate representations that can be combined at each layer. We further propose moving query optimization into the query compiler to benefit from the existing optimization infrastructure and make cross-domain optimization viable. With LingoDB, we demonstrate that the used approach significantly decreases the implementation effort and is highly flexible and extensible. At the same time, LingoDB achieves high performance and low compilation latencies.
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Manchala, Sadanandam. "STATISTICAL SIGNIFICANCE IN MULTILINGUAL INFORMATION RETRIEVAL (MLIR) SYSTEM." IOSR Journal of Engineering 02, no. 04 (April 2012): 794–802. http://dx.doi.org/10.9790/3021-0204794802.
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Sujatha, Pothula, Prasad Koti T, and Dhavachelvan P. "Appraisal of MLIR systems using Weight Based Precision Metrics." International Journal of Computer Sciences and Engineering 6, no. 9 (September 30, 2018): 896–904. http://dx.doi.org/10.26438/ijcse/v6i9.896904.
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Zhang, Nathan, Kevin Canini, Sean Silva, and Maya Gupta. "Fast Linear Interpolation." ACM Journal on Emerging Technologies in Computing Systems 17, no. 2 (April 2021): 1–15. http://dx.doi.org/10.1145/3423184.
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We present fast implementations of linear interpolation operators for piecewise linear functions and multi-dimensional look-up tables. These operators are common for efficient transformations in image processing and are the core operations needed for lattice models like deep lattice networks, a popular machine learning function class for interpretable, shape-constrained machine learning. We present new strategies for an efficient compiler-based solution using MLIR to accelerate linear interpolation. For real-world machine-learned multi-layer lattice models that use multidimensional linear interpolation, we show these strategies run 5-10× faster on a standard CPU compared to an optimized C++ interpreter implementation.
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Korra, Raju, Pothula Sujatha, Author P.Dhavachelvan, Madarapu Naresh Kumar, and Sidige Chetana. "Performance Assessment of AMRR and ADCG Metrics in MLIR and IR Systems." International Journal of Computer Applications 24, no. 2 (June 30, 2011): 43–48. http://dx.doi.org/10.5120/2919-3851.
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Pompougnac, Hugo, Ulysse Beaugnon, Albert Cohen, and Dumitru Potop Butucaru. "Weaving Synchronous Reactions into the Fabric of SSA-form Compilers." ACM Transactions on Architecture and Code Optimization 19, no. 2 (June 30, 2022): 1–25. http://dx.doi.org/10.1145/3506706.
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We investigate the programming of reactive systems combining closed-loop control with performance-intensive components such as Machine Learning (ML). Reactive control systems are often safety-critical and associated with real-time execution requirements, a domain of predilection for synchronous programming languages. Extending the high levels of assurance found in reactive control systems to computationally intensive code remains an open issue. We tackle it by unifying concepts and algorithms from synchronous languages with abstractions commonly found in general-purpose and ML compilers. This unification across embedded and high-performance computing enables a high degree of reuse of compiler abstractions and code. We first recall commonalities between dataflow synchronous languages and the static single assignment (SSA) form of general-purpose/ML compilers. We highlight the key mechanisms of synchronous languages that SSA does not cover—denotational concepts such as synchronizing computations with an external time base, cyclic and reactive I/O, as well as the operational notions of relaxing control flow dominance and the modeling of absent values. We discover that initialization-related static analyses and code generation aspects can be fully decoupled from other aspects of synchronous semantics such as memory management and causality analysis, the latter being covered by existing dominance-based algorithms of SSA-form compilers. We show how the SSA form can be seamlessly extended to enable all SSA-based transformations and optimizations on reactive programs with synchronous concurrency. We derive a compilation flow suitable for both high-performance and reactive aspects of a control application, by embedding the Lustre dataflow synchronous language into the SSA-based MLIR/LLVM compiler infrastructure. This allows the modeling of signal processing and deep neural network inference in the (closed) loop of feedback-directed control systems. With only minor efforts leveraging the MLIR infrastructure, the generated code matches or outperforms state-of-the-art synchronous language compilers on computationally intensive ML applications.
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Patel, Aryan. "Mojo: A Python-based Language for High-Performance AI Models and Deployment." INTERANTIONAL JOURNAL OF SCIENTIFIC RESEARCH IN ENGINEERING AND MANAGEMENT 07, no. 10 (October 1, 2023): 1–11. http://dx.doi.org/10.55041/ijsrem26529.
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Python has become a popular language for AI model development due to its elegant and flexible programming capabilities, extensive tool ecosystem, and high-performance libraries like Numpy and PyTorch. However, Python's execution speed remains a challenge, especially for performance-critical inner loops. To address this, Python programmers often rely on wrappers for C, FORTRAN, or Rust code, leading to a "two-language" approach that introduces complexities in deployment and debugging. This research paper introduces Mojo, a promising solution to the Python performance issue, which is essentially Python++ and built on top of MLIR (Multi-Level Intermediate Representation). Mojo is a rigorously designed superset of Python that allows seamless integration of high-performance implementations by switching to a faster "mode." This paper discusses the key features of Mojo, its deployment advantages, and its comparison with other alternatives in the AI and ML development landscape.
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Gysi, Tobias, Christoph Müller, Oleksandr Zinenko, Stephan Herhut, Eddie Davis, Tobias Wicky, Oliver Fuhrer, Torsten Hoefler, and Tobias Grosser. "Domain-Specific Multi-Level IR Rewriting for GPU." ACM Transactions on Architecture and Code Optimization 18, no. 4 (December 31, 2021): 1–23. http://dx.doi.org/10.1145/3469030.
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Most compilers have a single core intermediate representation (IR) (e.g., LLVM) sometimes complemented with vaguely defined IR-like data structures. This IR is commonly low-level and close to machine instructions. As a result, optimizations relying on domain-specific information are either not possible or require complex analysis to recover the missing information. In contrast, multi-level rewriting instantiates a hierarchy of dialects (IRs), lowers programs level-by-level, and performs code transformations at the most suitable level. We demonstrate the effectiveness of this approach for the weather and climate domain. In particular, we develop a prototype compiler and design stencil- and GPU-specific dialects based on a set of newly introduced design principles. We find that two domain-specific optimizations (500 lines of code) realized on top of LLVM’s extensible MLIR compiler infrastructure suffice to outperform state-of-the-art solutions. In essence, multi-level rewriting promises to herald the age of specialized compilers composed from domain- and target-specific dialects implemented on top of a shared infrastructure.
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Liu, Jie, Zhongyuan Zhao, Zijian Ding, Benjamin Brock, Hongbo Rong, and Zhiru Zhang. "UniSparse: An Intermediate Language for General Sparse Format Customization." Proceedings of the ACM on Programming Languages 8, OOPSLA1 (April 29, 2024): 137–65. http://dx.doi.org/10.1145/3649816.
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The ongoing trend of hardware specialization has led to a growing use of custom data formats when processing sparse workloads, which are typically memory-bound. These formats facilitate optimized software/hardware implementations by utilizing sparsity pattern- or target-aware data structures and layouts to enhance memory access latency and bandwidth utilization. However, existing sparse tensor programming models and compilers offer little or no support for productively customizing the sparse formats. Additionally, because these frameworks represent formats using a limited set of per-dimension attributes, they lack the flexibility to accommodate numerous new variations of custom sparse data structures and layouts. To overcome this deficiency, we propose UniSparse, an intermediate language that provides a unified abstraction for representing and customizing sparse formats. Unlike the existing attribute-based frameworks, UniSparse decouples the logical representation of the sparse tensor (i.e., the data structure) from its low-level memory layout, enabling the customization of both. As a result, a rich set of format customizations can be succinctly expressed in a small set of well-defined query, mutation, and layout primitives. We also develop a compiler leveraging the MLIR infrastructure, which supports adaptive customization of formats, and automatic code generation of format conversion and compute operations for heterogeneous architectures. We demonstrate the efficacy of our approach through experiments running commonly-used sparse linear algebra operations with specialized formats on multiple different hardware targets, including an Intel CPU, an NVIDIA GPU, an AMD Xilinx FPGA, and a simulated processing-in-memory (PIM) device.
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Reshitaj, Albena, Krenar Reshitaj, Erik Musliu, and Kanita Hoxha. "Association between Hypodontia of the Permanent Lateral Incisors and other Dental Anomalies in School Children Aged 12-16 Years in Kosovo." International Journal of Biomedicine 12, no. 2 (June 5, 2022): 273–78. http://dx.doi.org/10.21103/article12(2)_oa13.
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Background: Hypodontia of lateral incisors (LI) is frequently associated with other dental anomalies. The objective of this study was to determine the association of LI with other dental anomalies by comparing the two groups: Group 1 with hypodontia of the maxillary LI (MLI1) and Group 2 with hypodontia of the mandibular LI (MLI2), in secondary school education students in Kosovo. Methods and Results: A total of 3306 secondary school students aged 12-16 years, regardless of gender, were included in this prospective study. The abnormalities investigated were recorded by RTG-panoramic and dental charts. The teeth were recorded as a congenital absence when the mineralization of the crown, identified by panoramic tomography, was absent. The prevalence of LI hypodontia was as follows: MLI1 (Group 1) included 36 cases (92.3%) and MLI2 (Group 2) included only 3 cases (7.6%), which indicates a much higher percentage of cases with hypodontia of MLI1. In Group 1, 21(58.3%) cases of LI hypodontia were bilateral and 15(41.7%) unilateral; in Group 2, 2(66.7%) cases were unilateral and 1(33.3%) case – bilateral. Among dental anomalies, the occurrence of rotation was found in 19(48.7%) cases with LI hypodontia: 47.2% cases in Group 1 and 66.7% cases in Group 2. The prevalence of dental inclination anomaly was 30.77% of all cases with hypodontia of LI: 27.8% of cases in Group 1 and 66.7% of cases in Group 2. The prevalence of ectopy was in 17.9% of cases of all hypodontia cases of LI: 16.7% of cases in Group 1 and 33.3% of cases in Group 2. Crown anomalies were evident in 7(17.9%) patients of all hypodontia cases of LI, all of which were in Group 1. Other anomalies such as microdontia were evident in two patients in Group 1. Transposition, bodily movement, and superposition were present in one patient in Group 1; in Group 2, one patient had transposition. At the same time, the frequency of dental transposition was significantly higher in Group 2 than in Group 1 (P=0.02088). Other dental anomalies of crown and root and infraposition were not present in both groups. There were no significant differences in the other dental anomalies between the two groups. Conclusion: The consequences of hypodontia in dental arches are obvious. Knowing the prevalence of hypodontia and its association with other dental anomalies helps classify the need for further treatment for the patients, whether orthodontic, prosthetic, or surgical.
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Straight, Samuel W., David Karnak, Jean-Paul Borg, Emmanuel Kamberov, Heidi Dare, Ben Margolis, and James B. Wade. "mLin-7 is localized to the basolateral surface of renal epithelia via its NH2 terminus." American Journal of Physiology-Renal Physiology 278, no. 3 (March 1, 2000): F464—F475. http://dx.doi.org/10.1152/ajprenal.2000.278.3.f464.
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In Caenorhabditis elegans, the basolateral localization of the Let-23 growth factor receptor tyrosine kinase requires the expression of three genes: lin-2, lin-7, and lin-10. Mammalian homologs of these three genes have been identified, and a complex of their protein products exists in mammalian neurons. In this paper, we examine the interaction of these mammalian proteins in renal epithelia. Coprecipitation experiments demonstrated that mLin-2/CASK binds to mLin-7, and immunofluorescent labeling showed that these proteins colocalized at the basolateral surface of Madin-Darby canine kidney cells and renal epithelia. Although labeling intensity varied markedly among different renal epithelial cells, those cells strongly expressing mLin-7 also showed intense mLin-2/CASK labeling. We have also demonstrated that mLin-2/CASK binding requires amino acids 12–32 of mLin-7 and have shown that this region of mLin-7 is also necessary for the targeting of mLin-7 to the basolateral surface. Furthermore, the overexpression of mLin-2/CASK mutants in Madin-Darby canine kidney cells caused endogenous mLin-7 to mislocalize. In summary, the NH2 terminus of mLin-7 is crucial for its basolateral localization, likely through its interaction with mLin-2/CASK.
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Lee, Seonok, Shuling Fan, Olya Makarova, Samuel Straight, and Ben Margolis. "A Novel and Conserved Protein-Protein Interaction Domain of Mammalian Lin-2/CASK Binds and Recruits SAP97 to the Lateral Surface of Epithelia." Molecular and Cellular Biology 22, no. 6 (March 15, 2002): 1778–91. http://dx.doi.org/10.1128/mcb.22.6.1778-1791.2002.
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ABSTRACT Mammalian Lin-2 (mLin-2)/CASK is a membrane-associated guanylate kinase (MAGUK) and contains multidomain modules that mediate protein-protein interactions important for the establishment and maintenance of neuronal and epithelial cell polarization. The importance of mLin-2/CASK in mammalian development is demonstrated by the fact that mutations in mLin-2/CASK or SAP97, another MAGUK protein, lead to cleft palate in mice. We recently identified a new protein-protein interaction domain, called the L27 domain, which is present twice in mLin-2/CASK. In this report, we further define the binding of the L27C domain of mLin-2/CASK to the L27 domain of mLin-7 and identify the binding partner for L27N of mLin-2/CASK. Biochemical analysis reveals that this L27N domain binds to the N terminus of SAP97, a region that was previously reported to be essential for the lateral membrane recruitment of SAP97 in epithelia. Our colocalization studies, using dominant-negative mLin-2/CASK, show that the association with mLin-2/CASK is crucial for lateral localization of SAP97 in MDCK cells. We also report the identification of a novel isoform of Discs Large, a Drosophila melanogaster orthologue of SAP97, which contains a region highly related to the SAP97 N terminus and which binds Camguk, a Drosophila orthologue of mLin-2/CASK. Our data identify evolutionarily conserved protein-protein interaction domains that link mLin-2/CASK to SAP97 and account for their common phenotype when mutated in mice.
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Ahmady, Elmira, Shelley A. Deeke, Seham Rabaa, Lara Kouri, Laura Kenney, Alexandre F. R. Stewart, and Patrick G. Burgon. "Identification of a Novel Muscle A-type Lamin-interacting Protein (MLIP)." Journal of Biological Chemistry 286, no. 22 (April 15, 2011): 19702–13. http://dx.doi.org/10.1074/jbc.m110.165548.
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Mutations in the A-type lamin (LMNA) gene are associated with age-associated degenerative disorders of mesenchymal tissues, such as dilated cardiomyopathy, Emery-Dreifuss muscular dystrophy, and limb-girdle muscular dystrophy. The molecular mechanisms that connect mutations in LMNA with different human diseases are poorly understood. Here, we report the identification of a Muscle-enriched A-type Lamin-interacting Protein, MLIP (C6orf142 and 2310046A06rik), a unique single copy gene that is an innovation of amniotes (reptiles, birds, and mammals). MLIP encodes alternatively spliced variants (23–57 kDa) and possesses several novel structural motifs not found in other proteins. MLIP is expressed ubiquitously and most abundantly in heart, skeletal, and smooth muscle. MLIP interacts directly and co-localizes with lamin A and C in the nuclear envelope. MLIP also co-localizes with promyelocytic leukemia (PML) bodies within the nucleus. PML, like MLIP, is only found in amniotes, suggesting that a functional link between the nuclear envelope and PML bodies may exist through MLIP. Down-regulation of lamin A/C expression by shRNA results in the up-regulation and mislocalization of MLIP. Given that MLIP is expressed most highly in striated and smooth muscle, it is likely to contribute to the mesenchymal phenotypes of laminopathies.
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Misko, Albert L., Laura D. Weinstock, Sitara B. Sankar, Amanda Furness, Yulia Grishchuk, and Levi B. Wood. "Peripheral Inflammatory Cytokine Signature Mirrors Motor Deficits in Mucolipidosis IV." Cells 11, no. 3 (February 4, 2022): 546. http://dx.doi.org/10.3390/cells11030546.
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Background: Mucolipidosis IV (MLIV) is an autosomal recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by a loss of function of the lysosomal channel transient receptor potential mucolipin-1 and is associated with an early pro-inflammatory brain phenotype, including increased cytokine expression. The goal of the current study was to determine whether blood cytokines are linked to motor dysfunction in patients with MLIV and reflect brain inflammatory changes observed in an MLIV mouse model. Methods: To determine the relationship between blood cytokines and motor function, we collected plasma from MLIV patients and parental controls concomitantly with assessment of motor function using the Brief Assessment of Motor Function and Modified Ashworth scales. We then compared these profiles with cytokine profiles in brain and plasma samples collected from the Mcoln1−/− mouse model of MLIV. Results: We found that MLIV patients had prominently increased cytokine levels compared to familial controls and identified profiles of cytokines correlated with motor dysfunction, including IFN-γ, IFN-α2, and IP-10. We found that IP-10 was a key differentiating factor separating MLIV cases from controls based on data from human plasma, mouse plasma, and mouse brain. Conclusions: Our data indicate that MLIV is characterized by increased blood cytokines, which are strongly related to underlying neurological and functional deficits in MLIV patients. Moreover, our data identify the interferon pro-inflammatory axis in both human and mouse signatures, suggesting that interferon signaling is an important aspect of MLIV pathology.
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Ling, Qing. "Repressing HIF-1α-Induced HDAC9 Contributes to the Synergistic Effect of Venetoclax and Menin Inhibitor in KMT2A r AML." Blood 142, Supplement 1 (November 28, 2023): 7123. http://dx.doi.org/10.1182/blood-2023-183070.
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Background: MLL-rearranged acute myeloid leukemia (MLLr-AML) is one aggressive subtype of AML, and is conferred one extremely poor prognosis under the current therapeutic strategy. Up to now, it still lacked one effective treatment to maintain the long-term survival for patients with MLLr-AML, while the developments of targeted therapy brought hopes. At present, the star drug BCL-2 inhibitor Venetoclax combined with Azacitidine (AZA) or low-dose Cytarabine (LDAC) has become the first-line scheme for elderly AML, which is not beneficial for MLLr-AML patients. So we are committed to finding a more suitable partner for VEN because MLLr-AML is very sensitive to VEN in vitro studies. The MLL-menin complex is crucial for maintaining MLLr-AML, and the research and application of MLL-menin inhibitors (MEN1i) is currently one of the hotspots in the AML field. Therefore in this study, we aimed to uncover the synergistic effect and mechanism of MEN1i combined with Venetoclax in treating MLLr-AML. Methods: Cell culture and transfection, Cell proliferation, apoptosis and Cell cycle assay, Quantitative RT-PCR, and Western blotting analysis were used to explore biological phenotypes. RNA-seq profiling was performed for DMSO, VEN, MEN1i, and combination of VEN and MEN1i groups in three MLLr-AML cell lines MV4-11, MOLM13, THP-1. Bioinformatic tools were used for differential analysis. Results: MLLr-AML cells were sensitive to VEN or MEN1i monotherapy, and the combination of two drugs had a strong synergistic effect in vitro and in vivo. Furthermore, we found that combination of VEN and MEN1i significantly enhanced apoptotic induction to influence the MLLr-AML survival. To uncover the synergetic mechanism of VEN and MEN1i, we displayed RNA-Sequencing for DMSO, VEN, MEN1i, and combination of VEN and MEN1i groups in three MLLr-AML cell lines MV4-11, MOLM13, THP-1. Finally we found that repressing HIF-1α-induced HDAC9 contributes to the synergistic effect of Venetoclax and MEN1i in MLLr-AML. Conclusion: VEN combined with MEN1i had a strong synergistic effect in the treatment of MLLr-AML. Repressing HIF-1α-induced HDAC9 contributes to the synergistic effect of Venetoclax and MEN1i in MLLr-AML.
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Ahmady, Elmira, Alexandre Blais, and Patrick G. Burgon. "Muscle Enriched Lamin Interacting Protein (Mlip) Binds Chromatin and Is Required for Myoblast Differentiation." Cells 10, no. 3 (March 10, 2021): 615. http://dx.doi.org/10.3390/cells10030615.
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Muscle-enriched A-type lamin-interacting protein (Mlip) is a recently discovered Amniota gene that encodes proteins of unknown biological function. Here we report Mlip’s direct interaction with chromatin, and it may function as a transcriptional co-factor. Chromatin immunoprecipitations with microarray analysis demonstrated a propensity for Mlip to associate with genomic regions in close proximity to genes that control tissue-specific differentiation. Gel mobility shift assays confirmed that Mlip protein complexes with genomic DNA. Blocking Mlip expression in C2C12 myoblasts down-regulates myogenic regulatory factors (MyoD and MyoG) and subsequently significantly inhibits myogenic differentiation and the formation of myotubes. Collectively our data demonstrate that Mlip is required for C2C12 myoblast differentiation into myotubes. Mlip may exert this role as a transcriptional regulator of a myogenic program that is unique to amniotes.
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Zhou, Yutong, Yu Qian, and Jie Jin. "Targeting HDAC9 Contributes to Degradation of MLL Fusion Oncoproteins in KMT2A-Rearranged Acute Myeloid Leukemia." Blood 142, Supplement 1 (November 28, 2023): 1578. http://dx.doi.org/10.1182/blood-2023-185947.
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Acute myeloid leukemia with MLL rearrangement (MLLr-AML) is a highly aggressive subtype of AML. Existing treatment strategies are nonspecific and ineffective. The MLL fusion gene is one of the driver oncogenes in leukemia and is central to the pathogenesis of MLLr-AML, and more research has recently begun to focus on targeting MLL fusion proteins. Targeting MLL fusion proteins has been shown to have a tumor suppressor effect, demonstrating efficacy in preclinical models of MLLr-AML, and in 2022 Scott A Armstrong ‘s team suggested that degradation of MLL-AF9 can cause an increase in cell differentiation and apoptosis, confirming the efficacy of targeting MLL fusions. However, specific targets that degrade MLL fusion proteins as well as clinically translatable targeted therapies are still lacking and need to be further explored. Study confirmed that MLL-rearranged ALL cells are highly sensitive to the broad-spectrum HDAC inhibitor panobinostat. A recent clinical study by Mireia Camós’ team proposed that HDAC9 has a significantly high expression in childhood MLL-rearranged B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and AML, but that article did not address any mechanistic studies. The potential value of HDAC9 in adult lymphoid hematologic diseases has been gradually revealed, however, the expression profile and precise molecular mechanisms of HDAC9 in adult myeloid hematologic tumors, have not been reported, which deserves to be further explored. In order to investigate the expression and role of HDAC9 in MLLr-AML, we analyzed the second-generation sequencing data from the Beat AML dataset and found that HDAC9 has a significantly high expression in MLLr-AML, while only HDAC9 is characterized by this feature in HDAC family molecules. Further we analyzed the data of 300 adult AML specimens in our hospital (including 20 MLLr-AML patients), and the results further confirmed that only HDAC9 among the HDAC family had a significantly higher expression level in the MLLr-AML patient group than that in the Non-MLLr-AML patient group (P<0.001), and the high expression of HDAC9 in the MLLr-AML patient group was a common phenomenon and not limited to a particular class of MLL chaperone molecules. Further studies revealed that overexpression of MLL fusion proteins in HEK293T could cause up-regulation of HDAC9 protein levels, and this experiment clarified the direct correlation between the MLL fusion genes and the high expression of HDAC9. The HDAC IIa inhibitor (TMP-269), which can target HDAC9, was significantly more sensitive in MLLr-AML cell lines than in Non-MLLr-AML cell lines, and also that MLLr-AML cell survival was dependent on HDAC9, and that knockdown of HDAC9 induced an increase in apoptosis and a slowdown in proliferation in MLLr-AML cells. We subsequently demonstrated that knockdown of HDAC9 downregulates the expression of MLL fusion proteins through degradation of MLL proteins. Furthermore, when exploring therapeutic options for targeting MLLr-AML, we found that combining the BCL-2 inhibitor Venetoclax (VEN) with an MLL-Menin specific inhibitor (MEN1i) specifically downregulated the expression of HDAC9 and had a favorable synergistic killing effect on MLLr-AML in both in vitro and in vivo models, further suggesting an important role of HDAC9 in the treatment of MLLr-AML. To sum up, through this study, we can shed light on the role of specific HDAC molecules in MLLr-AML and provide a new potential target for the degradation of MLL fusion protein to eradicate MLLr-AML.
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Alewine, Christine, Bo-young Kim, Vandana Hegde, and Paul A. Welling. "Lin-7 targets the Kir 2.3 channel on the basolateral membrane via a L27 domain interaction with CASK." American Journal of Physiology-Cell Physiology 293, no. 6 (December 2007): C1733—C1741. http://dx.doi.org/10.1152/ajpcell.00323.2007.
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Polarized expression of the Kir 2.3 channel in renal epithelial cells is influenced by the opposing activities of two different PDZ proteins. Mammalian Lin-7 (mLin-7) directly interacts with Kir 2.3 to coordinate basolateral membrane expression, whereas the tax interacting protein 1 (TIP-1), composed of a single PDZ domain, competes for interaction with mLin-7 and drives Kir 2.3 into the endocytic pathway. Here we show that the basolateral targeting function of mLin-7 depends on its L27 domain, which directs interaction with a cognate L27 domain in the basolateral membrane-anchoring protein, calcium/calmodulin-dependent serine protein kinase (CASK). In MDCK cells, the expression of an mLin-7 mutant that lacks the L27 domain displaced Kir 2.3 from the mLin-7/CASK complex and caused the channel to accumulate into large intracellular vesicles that partially colocalized with Rab-11. Conversely, transplantation of the mLin-7 L27 domain to TIP-1 conferred CASK interaction and basolateral targeting of Kir 2.3. Expression of the CASK L27 domain redistributed endogenous mLin-7 to an intracellular compartment and caused Kir 2.3 to accumulate in subapical endosomes. Taken together, these data support a model whereby mLin-7 acts as a PDZ-to-L27 adapter, mediating indirect association of Kir 2.3 with a basolateral membrane scaffold and thereby stabilizing Kir 2.3 at the basolateral membrane.
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Kim, Hwa Young, Choong Ho Shin, Chang Ho Shin, and Jung Min Ko. "Uncovering the phenotypic consequences of multi-locus imprinting disturbances using genome-wide methylation analysis in genomic imprinting disorders." PLOS ONE 18, no. 8 (August 18, 2023): e0290450. http://dx.doi.org/10.1371/journal.pone.0290450.
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Imprinted genes are regulated by DNA methylation of imprinted differentially methylated regions (iDMRs). An increasing number of patients with congenital imprinting disorders (IDs) exhibit aberrant methylation at multiple imprinted loci, multi-locus imprinting disturbance (MLID). We examined MLID and its possible impact on clinical features in patients with IDs. Genome-wide DNA methylation analysis (GWMA) using blood leukocyte DNA was performed on 13 patients with Beckwith–Wiedemann syndrome (BWS), two patients with Silver–Russell syndrome (SRS), and four controls. HumanMethylation850 BeadChip analysis for 77 iDMRs (809 CpG sites) identified three patients with BWS and one patient with SRS showing additional hypomethylation, other than the disease-related iDMRs, suggestive of MLID. Two regions were aberrantly methylated in at least two patients with BWS showing MLID: PPIEL locus (chromosome 1: 39559298 to 39559744), and FAM50B locus (chromosome 6: 3849096 to 3849469). All patients with BWS- and SRS-MLID did not show any other clinical characteristics associated with additional involved iDMRs. Exome analysis in three patients with BWS who exhibited multiple hypomethylation did not identify any causative variant related to MLID. This study indicates that a genome-wide approach can unravel MLID in patients with an apparently isolated ID. Patients with MLID showed only clinical features related to the original IDs. Long-term follow-up studies in larger cohorts are warranted to evaluate any possible phenotypic consequences of other disturbed imprinted loci.
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Pyo, Jung-Soo, Nae Yu Kim, Byoung Kwan Son, and Kwang Hyun Chung. "Prognostic Implication of pN Stage Subdivision Using Metastatic Lymph Node Ratio in Resected Pancreatic Ductal Adenocarcinoma." International Journal of Surgical Pathology 28, no. 3 (November 5, 2019): 245–51. http://dx.doi.org/10.1177/1066896919886057.
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In this meta-analysis, we aimed to evaluate the prognostic implication of the metastatic lymph node ratio (mLNR) and its optimal criterion in pancreatic ductal adenocarcinoma (PDAC) with lymph node metastasis (LNM). The present study included 3735 patients with PDAC who had LNM, from 11 eligible studies. We carried out a meta-analysis to determine the correlation between a high mLNR and PDAC prognosis. The estimated mean numbers of examined and metastatic lymph nodes were 22.396 (95% confidence interval [CI] = 19.681-25.111) and 6.496 (95% CI = 4.646-8.345), respectively. A high mLNR was significantly correlated with worse overall survival (hazard ratio = 1.344, 95% CI = 1.276-1.416). In 3 subgroups based on high mLNR criteria (>0 and <0.2, ≥0.2 and <0.4, and ≥0.4), there were significant correlations between a high mLNR and worse survival. A cutoff of 0.200 showed the highest hazard ratio (1.391, 95% CI = 1.268-1.525), which was statistically significant. Our results showed that mLNR is a useful prognostic factor for PDAC with LNM. Although the optimal criterion of high mLNR may be 0.200, further cumulative studies are required before this can be applied in daily practice.
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Jeong, Min Jin, Yeo Nyeong Yoon, Yeon Kyung Kang, Chan Joo Kim, Hae Seong Nam, and Yong Seok Lee. "A Novel Score Using Lymphocyte-to-Monocyte Ratio in Blood and Malignant Body Fluid for Predicting Prognosis of Patients with Advanced Ovarian Cancer." Cancers 15, no. 8 (April 17, 2023): 2328. http://dx.doi.org/10.3390/cancers15082328.
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(1) Background: The lymphocyte-to-monocyte ratio (LMR), one of the systemic inflammatory markers, has been shown to be associated with prognosis of various solid tumors. However, no study has reported clinical utility of the LMR of malignant body fluid (mLMR) (2) Methods: We retrospectively analyzed clinical data of the final 92 patients of a total of 197 patients with advanced ovarian cancer newly diagnosed from November 2015 and December 2021 using our institute big data. (3) Results: Patients were divided into three groups according to their combined bLMR and mLMR scores (bmLMR score): 2, both bLMR and mLMR were elevated; 1, bLMR or mLMR was elevated; and 0, neither bLMR nor mLMR was elevated. A multivariable analysis confirmed that the histologic grade (p = 0.001), status of residual disease (p < 0.001), and bmLMR score (p < 0.001) were independent predictors of disease progression. A low combined value of bLMR and mLMR was strongly associated with a poor prognosis in patients with ovarian cancer. (4) Conclusions: Although further studies are required to apply our results clinically, this is the first study to validate the clinical value of mLMR for predicting prognosis of patients with advanced ovarian cancer.
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Garrido Castro, Patricia, Clara Bueno, Eddy HJ van Roon, Sandra S. Mimoso Pinhancos, Pauline Schneider, Merel Willekes, Pablo Menendez, Rob Pieters, and Ronald Stam. "Unravelling the Mirnome of MLL-Rearranged Acute Lymphoblastic Leukemia." Blood 124, no. 21 (December 6, 2014): 878. http://dx.doi.org/10.1182/blood.v124.21.878.878.
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Abstract BACKGROUND: MLL-rearranged acute lymphoblastic leukemia (MLLr-ALL) in infants (<1 year of age) represents an aggressive malignancy associated with highly unfavorable outcome. It is characterized by chromosomal translocations involving the MLL gene, with the majority (~80%) of these translocations resulting in the fusion of MLL to either AF4 in t(4;11)(q21;22), ENL in t(11;19)(q23;p13.3) or AF9 in t(9;11)(p22;q23). The respective MLL fusion genes, MLL/AF4, MLL/ENL and MLL/AF9, code for strong oncogenic drivers which rewrite the epigenetic landscape of the cell and profoundly alter gene expression. In recent years, several groups, including ours, have defined MLLr-ALL associated gene expression, DNA methylation and histone modification signatures, and these results have laid important corner stones for novel treatment rationales. However, a relevant regulatory mechanism of the cell, microRNAs (miRNA), has only been sparsely investigated in MLLr-ALL. Hence, in order to gain insight of the molecular pathobiology of this disease in all its aspects, elucidation of the MLLr-ALL associated miRNome is pivotal. AIMS: This study aims at defining MLLr-associated miRNA expression patterns using high-throughput miRNA profiling of a comprehensive MLLr- and non-MLL B-cell precursor-ALL patient panel. Furthermore, in order to identify driver miRNAs directly regulated by MLL fusions, we use a gain-of-function model where the most common MLL fusion, MLL/AF4, is ectopically expressed in hematopoietic progenitor cells (HPC) derived from human embryonic stem cells (ESC). High-throughput miRNA profiling of these modulated cells and comparison with patient-derived miRNA signatures will allow to discern which miRNAs are directly involved in MLLr-driven ALL. METHODS: In order to define MLLr-ALL miRNA patterns, we have used the Agilent miRNA microarray platform, which covers 1344 miRNAs. High-throughput profiling of primary patients samples (n=80) and healthy bone marrow (BM) controls (n=5) was performed. The patient cohort comprised 56 MLLr infant ALL patient samples, including the most common translocations MLL/AF4 (n=28), MLL/ENL (n=19) and MLL/AF9 (n=9). As a reference, non-MLL infant (n=12) and non-MLL pediatric B-cell precursor ALL patient samples (n=12) were assayed. Additionally, we also profiled ESC-derived HPCs transduced to express MLL/AF4 and corresponding backbone controls (n=3 independent pools). Statistically significant differential expression was defined as FDR-adjusted p<0.05. RESULTS: We found expression of 344 miRNAs within the patient cohort. Unsupervised principle component analysis was able to separate MLLr-ALL from non-MLL ALL patients and healthy BM. Expression analysis between MLLr-ALL and non-MLL ALL identified 69 significantly differentially expressed miRNAs. Similarly, comparison of MLLr-ALL to healthy BM resulted in 97 differentials. Analysing each MLLr-ALL subtype separately against age-matched infant non-MLL ALL revealed n=44 differentially expressed miRNAs for t(4;11)+ and n=29 differentials for t(11;19)+ MLLr-ALL. Interestingly, comparing t(9;11)+ MLLr-ALL vs non-MLL ALL did not identify any significantly differential expression. Equally, patients with t(9;11) clustered away from the other MLLr-ALL patients and showed greater similarity to non-MLL infant ALL samples. This observation corroborates previous findings, suggesting t(9;11) to be an entity distinct from the other MLLr-ALL subtypes. Conversely, t(4;11)- and t(11;19)-specific miRNA signatures showed an overlap of 45%, indicating a more related pathobiology. In addition to the patient panel, we profiled ESC-derived HPCs expressing MLL/AF4 and controls; 213 miRNAs were found to be differentially expressed. Comparison of this MLL/AF4+ HPC miRNA signature with patient MLLr - and MLL/AF4-specific patterns showed an overlap of >42% for each of the separate analyses, identifying a MLLr-specific miRNA core signature. CONCLUSIONS: We have defined an MLLr-ALL core miRNA signature directly driven by MLL fusions, and are currently validating this link using RNA interference against MLL fusion transcripts. Moreover, ongoing functional analysis of these core miRNAs by overexpression or inhibition will identify which miRNAs play a role in MLL leukemogenesis, unravelling associated pathways and thereby providing rationales for urgently needed novel treatment strategies. Disclosures No relevant conflicts of interest to declare.
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Pyo, Kim, Lee, Baek, and Kang. "Metastatic Lymph Node Ratio (mLNR) is a Useful Parameter in the Prognosis of Colorectal Cancer; A Meta-Analysis for the Prognostic Role of mLNR." Medicina 55, no. 10 (October 4, 2019): 673. http://dx.doi.org/10.3390/medicina55100673.
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Background and objectives: The presenting study aimed to elucidate the prognostic role of the metastatic lymph node ratio (mLNR) in patients with colorectal cancer (CRC), using a meta-analysis. Materials and Methods: Using data from 90,274 patients from 14 eligible studies, we performed a meta-analysis for the correlation between mLNR and survival rate. Besides, subgroup analyses were performed, based on tumor stage, tumor location, and mLNR. Results: A high mLNR showed significant correlation with worse overall survival and disease-free survival rates in CRC patients (hazard ratio (HR), 1.617, 95% confidence interval (CI) 1.393–1.877, and HR 2.345, 95% CI 1.879–2.926, respectively). In patients with stage III, who had regional LN metastasis, the HRs were 1.730 (95% CI 1.266–2.362) and 2.451 (95% CI 1.719–3.494) for overall and disease-free survival, respectively. According to tumor location, rectal cancer showed a worse survival rate when compared to colon cancer. In the analysis for overall survival, when mLNR was 0.2, HR was the highest across the different subgroups (HR 5.040, 95% CI 1.780–14.270). However, in the analysis for disease-free survival, the subgroup with an mLNR < 0.2 had a higher HR than the other subgroups (HR 2.878, 95% CI 1.401–5.912). Conclusions: The mLNR may be a useful prognostic factor for patients with CRC, regardless of the tumor stage or tumor location. Further studies are necessary for the detailed criteria of mLNR before its application in daily practice.
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Secker, Kathy-Ann, Bianca Bloechl, Hildegard Keppeler, Silke Duerr-Stoerzer, Hannes Schmid, Dominik Schneidawind, Johan Jeong, Thomas Hentrich, Julia M. Schulze-Hentrich, and Corina Schneidawind. "MAT2A as Key Regulator and Therapeutic Target in MLLr Leukemogenesis." Cancers 12, no. 5 (May 24, 2020): 1342. http://dx.doi.org/10.3390/cancers12051342.
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Epigenetic dysregulation plays a pivotal role in mixed-lineage leukemia (MLL) pathogenesis, therefore serving as a suitable therapeutic target. S-adenosylmethionine (SAM) is the universal methyl donor in human cells and is synthesized by methionine adenosyltransferase 2A (MAT2A), which is deregulated in different cancer types. Here, we used our human CRISPR/Cas9-MLL-rearranged (CRISPR/Cas9-MLLr) leukemia model, faithfully mimicking MLLr patients’ pathology with indefinite growth potential in vitro, to evaluate the unknown role of MAT2A. Comparable to publicly available patient data, we detected MAT2A to be significantly overexpressed in our CRISPR/Cas9-MLLr model compared to healthy controls. By using non-MLLr and MLLr cell lines and our model, we detected an MLLr-specific enhanced response to PF-9366, a new MAT2A inhibitor, and small interfering (si) RNA-mediated knockdown of MAT2A, by alteration of the proliferation, viability, differentiation, apoptosis, cell cycling, and histone methylation. Moreover, the combinational treatment of PF-9366 with chemotherapy or targeted therapies against the SAM-dependent methyltransferases, disruptor of telomeric silencing 1 like (DOT1L) and protein arginine methyltransferase 5 (PRMT5), revealed even more pronounced effects. In summary, we uncovered MAT2A as a key regulator in MLL leukemogenesis and its inhibition led to significant anti-leukemic effects. Therefore, our study paves the avenue for clinical application of PF-9366 to improve the treatment of poor prognosis MLLr leukemia.
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Ulya, Millatul, Nur Chamidah, and Toha Saifudin. "Mango quality prediction based on near-infrared spectroscopy using multi-predictor local polynomial regression modeling." F1000Research 12 (June 13, 2023): 656. http://dx.doi.org/10.12688/f1000research.130015.1.
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Background: pH and total soluble solids (TSS) are important quality parameters of mangoes; they represent the acidity and sweetness of the fruit, respectively. This study predicts the pH and TSS of intact mangoes based on near-infrared (NIR) spectroscopy using multi-predictor local polynomial regression (MLPR) modeling. Herein, the prediction performance of kernel partial least square regression (KPLSR), support vector machine regression (SVMR), and MLPR is compared. Methods: For this purpose, 186 intact mango samples at three different maturity stages are used. Prediction models are built using MLPR, KPLSR, and SVMR based on untreated and treated spectra. The best regression model for predicting pH is MLPR based on Gaussian filter smoothing spectra. Moreover, the TSS value is more accurately predicted using MLPR based on Savitzky–Golay smoothing. Results: The findings reveal that MLPR is highly accurate in estimating the pH and TSS of mangoes, with mean absolute percentage error (MAPE) values less than 10 %. In addition, the MLPR model has the best predictive performance with the lowest Mean Squared error (MSE) and root mean squared error (RMSE) values and the highest R2 value. Conclusions: The use of NIR spectroscopy in combination with multi-predictor local polynomial regression could provide a quick and non-destructive technique for predicting mango quality. Thus, the results of this study help support sustainable production as a sustainable development goal.
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Ulya, Millatul, Nur Chamidah, and Toha Saifudin. "Mango quality prediction based on near-infrared spectroscopy using multi-predictor local polynomial regression modeling." F1000Research 12 (March 18, 2024): 656. http://dx.doi.org/10.12688/f1000research.130015.2.
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Background pH and total soluble solids (TSS) are important quality parameters of mangoes; they represent the acidity and sweetness of the fruit, respectively. This study predicts the pH and TSS of intact mangoes based on near-infrared (NIR) spectroscopy using multi-predictor local polynomial regression (MLPR) modeling. Herein, the prediction performance of kernel partial least square regression (KPLSR), support vector machine regression (SVMR), and MLPR is compared. Methods For this purpose, 186 intact mango samples at three different maturity stages are used. Prediction models are built using MLPR, KPLSR, and SVMR based on untreated and treated spectra. The best regression model for predicting pH is MLPR based on Gaussian filter smoothing spectra. Moreover, the TSS value is more accurately predicted using MLPR based on Savitzky–Golay smoothing. Results The findings reveal that MLPR is highly accurate in estimating the pH and TSS of mangoes, with mean absolute percentage error (MAPE) values less than 10 %. In addition, the MLPR model has the best predictive performance with the lowest Mean Squared error (MSE) and root mean squared error (RMSE) values and the highest R2 value. Conclusions The use of NIR spectroscopy in combination with multi-predictor local polynomial regression could provide a quick and non-destructive technique for predicting mango quality. Thus, the results of this study help support sustainable production as a sustainable development goal.
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Панченко, Е. Г., О. А. Симонова, and В. В. Стрельников. "Multilocus imprinting disturbances." Nauchno-prakticheskii zhurnal «Medicinskaia genetika 22, no. 12 (December 21, 2023): 33–44. http://dx.doi.org/10.25557/2073-7998.2023.12.33-44.
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Геномный импринтинг – эпигенетический механизм, определяющий и регулирующий экспрессию гомологичных аллелей генов различного родительского происхождения. Нарушения этого механизма приводят к болезням геномного импринтинга (БГИ). Регуляция импринтинга осуществляется не только в пределах близко расположенных кластеров генов, но и посредством взаимодействий в импринтированных генных сетях (ИГС). Эти взаимодействия могут объяснить некоторые наблюдаемые различия в фенотипах различных БГИ и MLID (multilocus imprinting disturbances – мультилокусных нарушений импринтинга, при которых наблюдаются множественные аномалии метилирования импринтированных районов и генов), корреляции между эпигенотипом и фенотипом которых не всегда очевидна. На сегодняшний день описано не менее 20 БГИ у человека, как с самостоятельными, так и с перекрывающимися клиническими признаками, включая малые аномалии развития, врожденные пороки развития, нарушения метаболизма, особенности интеллектуального, моторного, физического развития. Чаще у пациента с определенной БГИ поражается один специфический импринтированный локус, но появляется все больше сообщений о пациентах с MLID. Причинами MLID являются патогенные варианты в генах, кодирующих ооцитарные и зиготические факторы развития эмбриона, такие как NLRP2, NLRP5, NLRP7, KHDC3L, OOEP, PADI6, TLE6, UHRF1, ZFP57, ARID4A, ZAR1, ZNF445, TRIM28. Патогенные варианты этих генов демонстрируют особый способ наследования, поскольку они становятся функционально значимыми только у женщин-носительниц. Они влияют не на здоровье самой носительницы, а на ее репродуктивный прогноз. При генетическом консультировании следует учитывать, что фенотип, обусловленный нарушениями в генах ооцитарных и зиготических факторов развития эмбриона, проявляется только тогда, когда носителями являются женщины. Таким образом, вариант может передаваться по отцовской линии, не вызывая при этом репродуктивных проблем. MLID являются актуальной и активно изучаемой проблемой клинической и молекулярной генетики. Ввиду возможной схожести клинической картины классических БГИ и MLID, пациентам с подозрением на БГИ целесообразно проводить анализ на MLID для установления дополнительных паттернов метилирования импринтированных дифференциально метилированных районов (ДМР). В семьях пациентов с MLID необходимо проводить поиск генетических вариантов в MLID-ассоциированных генах для установления риска повторного рождения детей с БГИ. Исследование MLID-ассоциированных генов может быть актуально для пациенток с привычным невынашиванием беременности, рецидивирующим пузырным заносом и при исследовании абортивного материала без хромосомных аномалий для определения причин прерывания и планирования последующей беременности. Genomic imprinting is an epigenetic mechanism that determines and regulates expression of homologous alleles of genes of different parental origin. Disturbances in this mechanism lead to imprinting disorders (IDs). Imprinting is regulated not only within closely located gene clusters, but also through interactions in imprinted gene networks (IGNs). These interactions may explain some of the observed differences in the phenotypes of various ImpDis and MLID (multilocus imprinting disturbances, in which multiple methylation abnormalities of imprinted regions and genes are observed), where the correlation between the epigenotype and the phenotype is not always obvious. To date, at least 20 IDs have been described in humans, both with independent and with overlapping clinical signs, including minor developmental anomalies, congenital malformations, metabolic disorders, features of intellectual, motor, and physical development. More often, in an individual with a specific ID, one specific imprinted locus is affected, but there are increasing reports of patients with MLID. The causes of MLID are pathogenic variants in genes encoding oocyte and zygotic embryo development factors, such as NLRP2, NLRP5, NLRP7, KHDC3L, OOEP, PADI6, TLE6, UHRF1, ZFP57, ARID4A, ZAR1, ZNF445, TRIM28. Pathogenic variants of these genes exhibit a distinct mode of inheritance in that they become functionally significant only in female carriers. They do not affect the health of the carrier herself, but her reproductive prognosis. When providing genetic counseling, it should be taken into account that the phenotype caused by disturbances in the genes for oocyte and zygotic factors of embryo development appears only when the carriers are women. Thus, the variant can be passed on through the father’s side without causing reproductive problems. MLID is an actively studied problem in clinical and molecular genetics. Due to the possible similarity of the clinical picture of classical ID and MLID, it is advisable for patients with suspected ID to undergo analysis for MLID to establish additional methylation patterns of imprinted DMRs, since in families of patients with MLID it is necessary to conduct medical genetic counseling with a further search for genetic variants in MLID-associated genes, to establish the risk of recurrent birth of children with ID. Also, the study of MLID-associated genes may be relevant for patients with recurrent miscarriage, recurrent hydatidiform mole, and for the study of abortive material, in the absence of chromosomal abnormalities identified in it, to determine the causes of termination and competent planning of a subsequent pregnancy.
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Lamas, Cátia, Asela Lavall, and Teresa Pinho. "Position and Eruption of Permanent Maxillary Canines in Cases of Maxillary Lateral Incisor Agenesis in Mixed Dentition." Journal of Clinical Pediatric Dentistry 42, no. 3 (January 1, 2018): 240–46. http://dx.doi.org/10.17796/1053-4628-42.3.14.
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Objective: Assess whether the permanent maxillary canine (MC) has a natural tendency to erupt mesially in children with maxillary lateral incisors agenesis (MLIA), compared to children without agenesis. Study design: This retrospective, observational, cross-sectional study consisted of children between 5 and 12 years old divided into three groups: the first group with unilateral MLIA, in which an intraindividual analysis was performed, the second group presented bilateral MLIA, and the third group with patients without agenesis. These last two groups were matched for comparison interindividual, being pared by sex and maturation of the MC. Results: The canine position in the horizontal sector showed a clear mesial positioning of the MC on the agenesis side in individuals with unilateral MLIA (group 1) when compared with the counter lateral side; and in individuals with bilateral MLIA (Group 2) compared with control Individuals without agenesis (group 3). Even with the maintenance of this deciduous tooth in the dental arch, the MC keeps its tendency to mesial eruption. Conclusion: There is a greater tendency for mesial angulation of the maxillary canine in patients with MLIA, regardless of the presence or absence of deciduous lateral incisor.
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Ho, Kevin K. W., Patrick Lo, Dickson K. W. Chiu, Elaine Wei San Kong, Joyce Chao-chen Chen, Qingshan Zhou, Yang Xu, and Søren Dalsgard. "Intrinsic vs. extrinsic motivations of Master of Library and Information Science students: A cross-cultural comparative study." Journal of Librarianship and Information Science 50, no. 2 (September 1, 2016): 141–56. http://dx.doi.org/10.1177/0961000616664564.
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This study examined the career and learning motivation of students studying a Master of Library and Information Science (MLIS) degree programs at universities located in four different countries, namely the University of Hong Kong, National Taiwan Normal University, Peking University, and the University of Copenhagen. The MLIS students from these four universities were invited to take part in a self-completion online questionnaire survey, and 200 responses were collected in total. We discovered that their prior working experience in the library had an impact on their decision to pursue the MLIS program. We also categorized the career and learning motivation factors of MLIS learners into intrinsic and extrinsic factors, and discovered that the participants were motivated by both intrinsic and extrinsic factors to pursue their graduate studies in the Library and Information Science (LIS) field. We found that intrinsic factors influenced the students of University of Copenhagen significantly more than the other student groups, and this could be explained by Hofstede’s cultural dimensions. Our findings can assist with the formulation of development strategies for MLIS programs through a review of the LIS curriculum and help MLIS programs in different countries attract more people to pursue a career in LIS.
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Tee, Trisha, Titine Ruiter, Ahmed Dahaoui, Dorette van Ingen Schenau, Rico Hagelaar, Laurens van der Meer, and Frank van Leeuwen. "Methionine Restriction As a Novel Therapeutic Strategy for MLL (KMT2A)-Rearranged Acute Lymphoblastic Leukemia." Blood 138, Supplement 1 (November 5, 2021): 2269. http://dx.doi.org/10.1182/blood-2021-145308.
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Abstract Background: MLL (KMT2A)-rearranged acute lymphoblastic leukemia (MLLr ALL) is a rare but aggressive subset that represents 5% of childhood ALL cases, and accounts for about 70% of infant leukemias. While overall survival in these young children is around 50%, after relapse, MLLr ALL becomes an almost incurable disease, highlighting the urgent clinical need for new strategies for this patient group. The histone methyl transferase function of the MLL fusion protein complex requires the methionine metabolite s-adenosylmethionine (SAM) as methyl donor, suggesting a selective sensitivity of MLL-r ALL for perturbations in methionine availability. Recent studies in solid tumor models suggest clinical utility of methionine restricted diets or oral administration of methionine depleting enzyme Methionine Gamma Lyase (MGL) to be safe and effective. Therefore, we explored the effect of methionine restriction (MR) as a potential, new therapy for MLLr ALL. Methods: We compared the effects of MR on metabolic activity and viability between MLLr and non-MLLr pre-BCP ALL cell lines using enzymatic depletion, small molecule inhibitors targeting methionine metabolism, and restrictive culture conditions. To identify intrinsic metabolic differences between MLLr and non-MLLr cells and explore how MR impinges on their metabolic state, we performed global metabolomics on MLLr SEM cells and non-MLLr NALM6 cells cultured with complete depletion of methionine. Additionally, we used RNA sequencing to assess the global effects of MR on gene expression, and a CRISPR/Cas9-based reverse genetic screen to identify sensitizers towards MR. Results were validated in vitro using targeted knockouts and small-molecule inhibitors, as well as in vivo using a 95% methionine restricted diet. Immunocompromised mice were engrafted with MLLr SEM cells and 7 days after transplantation, mice were randomized to control or 95% MR diet. Leukemia progression was monitored by flowcytometric detection of human lymphocytes in the blood. Results: We observed that depletion of methionine reduces metabolic activity in almost all BCP-ALL (B-ALL) cell lines, however, only in MLLr B-ALL cell lines was rapid apoptosis induced (Figure 1A). Global metabolic profiling revealed significant basal metabolic differences, of note being SAM, whose levels were approximately 5-fold higher in MLLr SEM cells compared to non-MLLr NALM6 cells. Consistent with this, addition of SAM completely rescued MLLr cell lines from methionine depletion induced apoptosis, an effect not observed in non-MLLr cells (Figure 1A). Metabolomic profiling also highlighted different salvage mechanisms at play in NALM6 cells, with the folate cycle and polyamine synthesis pathway being activated upon MR. Together, these results indicate that MLLr B-ALL cells are selectively sensitive to MR. In line with this, RNASeq data showed significant decreased expression of several known MLL fusion target genes such as PROM1, HOXA10, and MEIS1 in response to MR. To obtain further insight into the pathways involved in the response to MR and to identify potential therapeutic targets that further sensitize cells to MR, we performed a CRISPR/Cas9-based screen. This identified three members of the Bromodomain- and extra-terminal domain (BET) family as potential modifiers of the response to MR in SEM cells. Indeed, RNAseq analysis showed that Myc activity as a proxy of BRD4 function, was strongly suppressed by MR. Finally, preliminary results show the efficacy of dietary intervention alone on leukemia progression. We observe with 95% MR diet, significant delays on leukemic growth (Figure 1B). Moreover, the MR diet was well tolerated, as indicated by minimal weight loss after two months. Although further studies are needed, we anticipate that targeting epigenetic regulators or use of conventional therapies in combination with MR would further potentiate this effect. Conclusions: MLLr leukemic cells have an increased dependency on S-adenosylmethionine and therefore show increased vulnerability to methionine depletion. Limiting methionine availability, either by enzymatic methionine depletion or dietary restriction could provide a novel therapeutic option for this patient group, particularly when combined with other therapies. The availability of an FDA approved methionine-free formula facilitates rapid translation to clinical practice, particularly in infants. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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McNiff, Lindsay, and Lauren Hays. "How Master of Library Studies Students Learn to Search for Information: A Pilot Study." Journal of Education for Library and Information Science 61, no. 4 (December 2020): 463–80. http://dx.doi.org/10.3138/jelis.61.4.2019-0056.
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Master of Library and Information Studies (MLIS) students represent a population for whom literature searching is a core practice and a learning outcome for an entry-level course on information searching. How LIS students learn to find information, though, is not completely clear. Many studies have explored undergraduate searching behavior, but few recent studies have investigated the search behaviors of MLIS students. The purpose of this Scholarship of Teaching and Learning study was to explore the following research questions: (1) How do MLIS students describe learning to search?; (2) What works in helping MLIS students see themselves as better searchers of information?; and (3) What works in helping MLIS students become better searchers of information? Participants articulated that course sequence was important in their development of searching skills, that demonstrable skills and engagement with research improved their view of themselves as searchers, and that course structure, content, and active learning were important factors in their improvement.
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Kuttner, Samuel, Kristoffer Knutsen Wickstrøm, Mark Lubberink, Andreas Tolf, Joachim Burman, Rune Sundset, Robert Jenssen, Lieuwe Appel, and Jan Axelsson. "Cerebral blood flow measurements with 15O-water PET using a non-invasive machine-learning-derived arterial input function." Journal of Cerebral Blood Flow & Metabolism 41, no. 9 (February 8, 2021): 2229–41. http://dx.doi.org/10.1177/0271678x21991393.
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Cerebral blood flow (CBF) can be measured with dynamic positron emission tomography (PET) of 15O-labeled water by using tracer kinetic modelling. However, for quantification of regional CBF, an arterial input function (AIF), obtained from arterial blood sampling, is required. In this work we evaluated a novel, non-invasive approach for input function prediction based on machine learning (MLIF), against AIF for CBF PET measurements in human subjects. Twenty-five subjects underwent two 10 min dynamic 15O-water brain PET scans with continuous arterial blood sampling, before (baseline) and following acetazolamide medication. Three different image-derived time-activity curves were automatically segmented from the carotid arteries and used as input into a Gaussian process-based AIF prediction model, considering both baseline and acetazolamide scans as training data. The MLIF approach was evaluated by comparing AIF and MLIF curves, as well as whole-brain grey matter CBF values estimated by kinetic modelling derived with either AIF or MLIF. The results showed that AIF and MLIF curves were similar and that corresponding CBF values were highly correlated and successfully differentiated before and after acetazolamide medication. In conclusion, our non-invasive MLIF method shows potential to replace the AIF obtained from blood sampling for CBF measurements using 15O-water PET and kinetic modelling.
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Bermeo, Gabriela, Antonio Ibarra, Elisa García, Adrian Flores-Romero, Guadalupe Rico-Rosillo, Rubén Marroquín, Humberto Mestre, Carmina Flores, Francisco Blanco-Favela, and Raúl Silva-García. "Monocyte Locomotion Inhibitory Factor Produced byE. histolyticaImproves Motor Recovery and Develops Neuroprotection after Traumatic Injury to the Spinal Cord." BioMed Research International 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/340727.
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Monocyte locomotion inhibitory factor (MLIF) is a pentapeptide produced byEntamoeba histolyticathat has a potent anti-inflammatory effect. Either MLIF or phosphate buffered saline (PBS) was administered directly onto the spinal cord (SC) immediately after injury. Motor recovery was evaluated. We also analyzed neuroprotection by quantifying the number of surviving ventral horn motor neurons and the persistence of rubrospinal tract neurons. To evaluate the mechanism through which MLIF improved the outcome of SC injury, we quantified the expression of inducible nitric oxide synthase (iNOS), interleukin-10 (IL-10), and transforming growth factor-β(TGF-β) genes at the site of injury. Finally, the levels of nitric oxide and of lipid peroxidation were also determined in peripheral blood. Results showed that MLIF improved the rate of motor recovery and this correlated with an increased survival of ventral horn and rubrospinal neurons. These beneficial effects were in turn associated with a reduction in iNOS gene products and a significant upregulation of IL-10 and TGF-βexpression. In the same way, MLIF reduced the concentration of nitric oxide and the levels of lipid peroxidation in systemic circulation. The present results demonstrate for the first time the neuroprotective effects endowed by MLIF after SC injury.
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Crumpton, Breanne Erin, and Emily Porter-Fyke. "The special library: applicability and usefulness of the MLIS in non-traditional library settings." Bottom Line 29, no. 3 (November 14, 2016): 151–65. http://dx.doi.org/10.1108/bl-04-2016-0017.
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Purpose The aim of this paper is to examine the versatility of the MLIS degree through the lens of special libraries in terms of education, core competencies and benefits. Special libraries show the value of the Master of Library and Information Science (MLIS) degree in preparing professionals to work across institutional boundaries in non-library and non-educational organizations and bring their services to the populace in sometimes unexpected places. Design/methodology/approach The authors first conducted a literature review of special librarians and their skillsets, as well as how to properly define “special library”. They then examined different MLIS programs geared toward special libraries and how library schools prepare special librarians to benefit their organizations. Findings The conclusion drawn is that possession of an MLIS degree lends a special librarian more credence in the execution of their duties because they have been educated in how to best benefit their institution. While additional subject expertise is an advantage to the special librarian, the skills learned in MLIS degree programs provide an essential foundation. Originality/value This is a collaborative view that brings together outside research regarding various types of special libraries and the librarians that work in them in an effort to illustrate the value of the MLIS degree in an original way.
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Beal, Shannon H., Steven L. Chen, Philip D. Schneider, and Steve R. Martinez. "An Evaluation of Lymph Node Yield and Lymph Node Ratio in Well-Differentiated Thyroid Carcinoma." American Surgeon 76, no. 1 (January 2010): 28–32. http://dx.doi.org/10.1177/000313481007600107.
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It is unknown whether the number of lymph nodes harvested (lymph node yield, LNY) or the proportion of metastatic lymph nodes resected (metastatic lymph node ratio, MLNR) influence survival in well-differentiated thyroid carcinoma (WDTC). We hypothesized that overall survival in WDTC is influenced by the LNY and MLNR. We used the Surveillance, Epidemiology, and End Results database to identify all patients with primary, nonmetastatic WDTC who underwent thyroidectomy with at least one lymph node removed between 1988 and 2004. Kaplan-Meier survival curves for LNY and MLNR were compared using the log rank test. Multivariate Cox proportional hazards models included tumor and patient-specific factors. WDTC patients that met entry criteria totaled 9926. In the univariate model, LNY and MLNR had a significant impact on survival ( P < 0.001). In multivariate analysis, increasing LNY was associated with poorer survival in all patients ( P = 0.001) and node-negative patients ( P = 0.03), but not for node-positive patients ( P = 0.27). MLNR did not influence survival in node-positive patients ( P = 0.84). Among patients with WDTC treated with thyroidectomy and lymphadenectomy, increasing LNY and MLNR were associated with decreased survival. The decrease in survival associated with increasing LNY, even in node-negative patients, indicates that nodal understaging is inconsequential to WDTC survival.
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Fischer, Jacqueline, Estelle Erkner, Rahel Fitzel, Pia Radszuweit, Hildegard Keppeler, Fulya Korkmaz, Giovanni Roti, Claudia Lengerke, Dominik Schneidawind, and Corina Schneidawind. "Uncovering NOTCH1 as a Promising Target in the Treatment of MLL-Rearranged Leukemia." International Journal of Molecular Sciences 24, no. 19 (September 23, 2023): 14466. http://dx.doi.org/10.3390/ijms241914466.
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MLL rearrangement (MLLr) is responsible for the development of acute leukemias with poor outcomes. Therefore, new therapeutic approaches are urgently needed. The NOTCH1 pathway plays a critical role in the pathogenesis of many cancers including acute leukemia. Using a CRISPR/Cas9 MLL-AF4/-AF9 translocation model, the newly developed NOTCH1 inhibitor CAD204520 with less toxic side effects allowed us to unravel the impact of NOTCH1 as a pathogenic driver and potential therapeutic target in MLLr leukemia. RNA sequencing (RNA-seq) and RT-qPCR of our MLLr model and MLLr cell lines showed the NOTCH1 pathway was overexpressed and activated. Strikingly, we confirmed this elevated expression level in leukemia patients. We also demonstrated that CAD204520 treatment of MLLr cells significantly reduces NOTCH1 and its target genes as well as NOTCH1 receptor expression. This was not observed with a comparable cytarabine treatment, indicating the specificity of the small molecule. Accordingly, treatment with CAD204520 resulted in dose-dependent reduced proliferation and viability, increased apoptosis, and the induction of cell cycle arrest via the downregulation of MLL and NOTCH1 target genes. In conclusion, our findings uncover the oncogenic relevance of the NOTCH1 pathway in MLLr leukemia. Its inhibition leads to specific anti-leukemic effects and paves the way for further evaluation in clinical settings.
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Aljebreen, Mohammed, Manal Abdullah Alohali, Muhammad Kashif Saeed, Heba Mohsen, Mesfer Al Duhayyim, Amgad Atta Abdelmageed, Suhanda Drar, and Sitelbanat Abdelbagi. "Binary Chimp Optimization Algorithm with ML Based Intrusion Detection for Secure IoT-Assisted Wireless Sensor Networks." Sensors 23, no. 8 (April 18, 2023): 4073. http://dx.doi.org/10.3390/s23084073.
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An Internet of Things (IoT)-assisted Wireless Sensor Network (WSNs) is a system where WSN nodes and IoT devices together work to share, collect, and process data. This incorporation aims to enhance the effectiveness and efficiency of data analysis and collection, resulting in automation and improved decision-making. Security in WSN-assisted IoT can be referred to as the measures initiated for protecting WSN linked to the IoT. This article presents a Binary Chimp Optimization Algorithm with Machine Learning based Intrusion Detection (BCOA-MLID) technique for secure IoT-WSN. The presented BCOA-MLID technique intends to effectively discriminate different types of attacks to secure the IoT-WSN. In the presented BCOA-MLID technique, data normalization is initially carried out. The BCOA is designed for the optimal selection of features to improve intrusion detection efficacy. To detect intrusions in the IoT-WSN, the BCOA-MLID technique employs a class-specific cost regulation extreme learning machine classification model with a sine cosine algorithm as a parameter optimization approach. The experimental result of the BCOA-MLID technique is tested on the Kaggle intrusion dataset, and the results showcase the significant outcomes of the BCOA-MLID technique with a maximum accuracy of 99.36%, whereas the XGBoost and KNN-AOA models obtained a reduced accuracy of 96.83% and 97.20%, respectively.
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Mepyans, Molly, Livia Andrzejczuk, Jahree Sosa, Sierra Smith, Shawn Herron, Samantha DeRosa, Susan A. Slaugenhaupt, Albert Misko, Yulia Grishchuk, and Kirill Kiselyov. "Early evidence of delayed oligodendrocyte maturation in the mouse model of mucolipidosis type IV." Disease Models & Mechanisms 13, no. 7 (June 25, 2020): dmm044230. http://dx.doi.org/10.1242/dmm.044230.
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ABSTRACTMucolipidosis type IV (MLIV) is a lysosomal disease caused by mutations in the MCOLN1 gene that encodes the endolysosomal transient receptor potential channel mucolipin-1, or TRPML1. MLIV results in developmental delay, motor and cognitive impairments, and vision loss. Brain abnormalities include thinning and malformation of the corpus callosum, white-matter abnormalities, accumulation of undegraded intracellular ‘storage’ material and cerebellar atrophy in older patients. Identification of the early events in the MLIV course is key to understanding the disease and deploying therapies. The Mcoln1−/− mouse model reproduces all major aspects of the human disease. We have previously reported hypomyelination in the MLIV mouse brain. Here, we investigated the onset of hypomyelination and compared oligodendrocyte maturation between the cortex/forebrain and cerebellum. We found significant delays in expression of mature oligodendrocyte markers Mag, Mbp and Mobp in the Mcoln1−/− cortex, manifesting as early as 10 days after birth and persisting later in life. Such delays were less pronounced in the cerebellum. Despite our previous finding of diminished accumulation of the ferritin-bound iron in the Mcoln1−/− brain, we report no significant changes in expression of the cytosolic iron reporters, suggesting that iron-handling deficits in MLIV occur in the lysosomes and do not involve broad iron deficiency. These data demonstrate very early deficits of oligodendrocyte maturation and critical regional differences in myelination between the forebrain and cerebellum in the mouse model of MLIV. Furthermore, they establish quantitative readouts of the MLIV impact on early brain development, useful to gauge efficacy in pre-clinical trials.
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Xu, Xin, Wilhelm G. Dirks, Hans G. Drexler, and Zhenbo Hu. "Small Molecular Modulators of Histone Demethylases Selectively Inhibits Growth of Hematopoietic Malignancies." Blood 132, Supplement 1 (November 29, 2018): 3941. http://dx.doi.org/10.1182/blood-2018-99-112376.
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Abstract Background: About 10% of acute leukemia (AL) patients harbor MLL-r(earrangements). MLLr acute myeloid leukemia (AML) mainly occurs in young-to-middle-aged adults whereas MLLr acute lymphoblastic leukemia (ALL) mainly occurs in patients younger than 1 year at diagnosis. AML with MLL fusion to MLLT3 via t(9;11)(p22;q23) predicts intermediate prognosis whereas MLL fusion to other partners predicts adverse prognosis. By contrast, in infants with ALL MLLr invariably confers poor prognosis. Much efforts have been made to identify and target proteins required for initiation and maintenance of MLLr AL, with an aim to improve the prognosis of this aggressive AL subtype. Multiple writers, erasers, and readers of histone post-translational modifications (PTMs) have been identified to be fundamental for the initiation and maintenance of MLLr AL. Small molecular inhibitors of some of these chromatin-associated proteins have been identified, such as EPZ004777 against DOT1L, JQ1 and I-BET151 against BRD4, and so on which are also under clinical trials for AL treatment. Among histone modification erasers essential for MLLr AL, JMJD1C and KDM4C that share Jumonji catalytic domain are fundamental for MLLr AL maintenance. Histone H3 lysine 9 (H3K9) demethylase JMJD1C is one of the most promising MLLr AL targets. Multiple independent studies identified JMJD1C as required for MLLr AML, RUNX1(AML1)/RUNX1T1(ETO) AML and even chronic myeloid leukemia and lymphoma cells but not normal hematopoiesis. KDM4C Is essential for Initiation and maintenance of MLLr AL transcriptional profiling of which is dependent on KDM4C. Moreover, pharmacological inhibition of KDM4C blocks leukemia development in syngeneic mouse model and human AML xenograft model. Although a large number of special inhibitors of histone demethylases have been developed, no special inhibitors against KDM3 family member like JMJD1C have been reported. Results: Here we focused on Jumonji domain that is responsible for enzymatic activities of histone demethylases for identifying potential small molecule modulators of histone demethylases. We selected Jumonji domain of histone H3 lysine (H3K9) demethylase JMJD1C with KDM4C as reference to screen for potential small molecular modulators from 149,519 natural products and 33,765 Chinese medicine components through virtual screening method. Although identified independently from each other, compound #4 and #12 both share a common structural backbone and surface plasmon resonance analysis showed that #4 and #12 bind to JMJD1C, KDM3 family member KDM3B, and KDM4 family member KDM4C with modest affinity. In vivo demethylation assay showed that #4 induces global increase of H3K9 methylation. In vitro demethylation assay showed that #4 is able to reverse H3K9 demethylation conferred by KDM3B and KDM4C. We thus named #4 and #12 as JI-4 and JI-12 (JI, Jumonji inhibitor). Cell proliferation and colony formation assays showed that JI-4 and JI-12 predominantly kill MLLr AL. To increase evidence, multiple similar compounds to JI-4 and JI-12 were tested for cell proliferation repression and JI-16 was found to show superior killing activities against hematopoietic malignant cells compared to JI-4 and JI-12. Mechanistically, JI-16 not only induces apoptosis but also differentiation of MLLr AL cells. Transcriptome analysis and quantitative PCR (QPCR) showed that JI-16 induced gene expression profiling is especially enriched in gene sets involved in metabolism. Conclusion: To sum up, we identified potential pan-inhibitors of the Jumonji domain of histone demethylases. Binding in-vivo is followed by selective killing of MLLr AL cells. Disclosures. No relevant conflicts of interest to declare. Disclosures No relevant conflicts of interest to declare.
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Boccaletti, Giulio, Raffaele Ferrari, and Baylor Fox-Kemper. "Mixed Layer Instabilities and Restratification." Journal of Physical Oceanography 37, no. 9 (September 1, 2007): 2228–50. http://dx.doi.org/10.1175/jpo3101.1.
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Abstract The restratification of the oceanic surface mixed layer that results from lateral gradients in the surface density field is studied. The lateral gradients are shown to be unstable to ageostrophic baroclinic instabilities and slump from the horizontal to the vertical. These instabilities, which are referred to as mixed layer instabilities (MLIs), differ from instabilities in the ocean interior because of the weak surface stratification. Spatial scales are O(1–10) km, and growth time scales are on the order of a day. Linear stability analysis and fully nonlinear simulations are used to study MLIs and their impact on mixed layer restratification. The main result is that MLIs are a leading-order process in the ML heat budget acting to constantly restratify the surface ocean. Climate and regional ocean models do not resolve the scales associated with MLIs and are likely to underestimate the rate of ML restratification and consequently suffer from a bias in sea surface temperatures and ML depths. In a forthcoming paper, the authors discuss a parameterization scheme to include the effect of MLIs in ocean models.
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Rehman, Haroon, Mohd Tariq, Adil Sarwar, Waleed Alhosaini, Md Alamgir Hossain, and Salem Mohammed Batiyah. "Single-Phase Fault Tolerant Multilevel Inverter Topologies—Comprehensive Review and Novel Comparative Factors." Energies 15, no. 24 (December 8, 2022): 9319. http://dx.doi.org/10.3390/en15249319.
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Multilevel inverters (MLIs) are used in a variety of industrial applications in high- and medium-voltage systems. The modularity, high-power output from medium voltages, and low harmonic content are some of the advantages of MLIs. The reliability of MLIs is quite important. The reliability is affected by different kinds of faults occurring in the MLIs. In MLI circuits, switching devices are the most vulnerable components and have a major involvement in all types of faults. As an outcome, it is necessary to take proper corrective action in the event of a fault. This work provides a comprehensive review of different fault tolerant (FT) solutions for MLIs in the event of switch fault. Moreover, various single-phase FT MLI topologies are reviewed, along with their constructional features, merits, and demerits. This work also proposes a comparison approach that integrates novel factors to account for fault tolerance quantitatively. A comparison investigation verifies the effectiveness of the proposed method. The FT operation of an existing five-level FT MLI topology is discussed, simulated, and experimentally verified.
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Straight, Samuel W., Liguang Chen, David Karnak, and Ben Margolis. "Interaction with mLin-7 Alters the Targeting of Endocytosed Transmembrane Proteins in Mammalian Epithelial Cells." Molecular Biology of the Cell 12, no. 5 (May 2001): 1329–40. http://dx.doi.org/10.1091/mbc.12.5.1329.
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To investigate the targeting mechanism for proteins bound to the mammalian Lin-7 (mLin-7) PDZ domain, we created receptor protein chimeras composed of the carboxyl-terminal amino acids of LET-23 fused to truncated nerve growth factor receptor/P75. mLin-7 bound to the chimera with a wild-type LET-23 carboxyl-terminal tail (P75t-Let23WT), but not a mutant tail (P75t-Let23MUT). In Madin-Darby canine kidney (MDCK) cells, P75t-Let23WT localized to the basolateral plasma membrane domain, whereas P75t-Let23MUT remained apical. Furthermore, mutant mLin-7 constructs acted as dominant interfering proteins and inhibited the basolateral localization of P75t-Let23WT. The mechanisms for this differential localization were examined further, and, initially, we found that P75t-Let23WT and P75t-Let23MUT were delivered equally to the apical and basolateral plasma membrane domains. Although basolateral retention of P75t-Let23WT, but not P75t-Let23MUT, was observed, the greatest difference in receptor localization was seen in the rapid trafficking of P75t-Let23WT to the basolateral plasma membrane domain after endocytosis, whereas P75t-Let23MUT was degraded in lysosomes, indicating that mLin-7 binding can alter the fate of endocytosed proteins. Altogether, these data support a model for basolateral protein targeting in mammalian epithelial cells dependent on protein–protein interactions with mLin-7, and also suggest a dynamic role for mLin-7 in endosomal sorting.
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Sachs, Wiebke, Marlies Sachs, Elke Krüger, Stephanie Zielinski, Oliver Kretz, Tobias B. Huber, Anke Baranowsky, et al. "Distinct Modes of Balancing Glomerular Cell Proteostasis in Mucolipidosis Type II and III Prevent Proteinuria." Journal of the American Society of Nephrology 31, no. 8 (July 8, 2020): 1796–814. http://dx.doi.org/10.1681/asn.2019090960.
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BackgroundThe mechanisms balancing proteostasis in glomerular cells are unknown. Mucolipidosis (ML) II and III are rare lysosomal storage disorders associated with mutations of the Golgi-resident GlcNAc-1-phosphotransferase, which generates mannose 6-phosphate residues on lysosomal enzymes. Without this modification, lysosomal enzymes are missorted to the extracellular space, which results in lysosomal dysfunction of many cell types. Patients with MLII present with severe skeletal abnormalities, multisystemic symptoms, and early death; the clinical course in MLIII is less progressive. Despite dysfunction of a major degradative pathway, renal and glomerular involvement is rarely reported, suggesting organ-specific compensatory mechanisms.MethodsMLII mice were generated and compared with an established MLIII model to investigate the balance of protein synthesis and degradation, which reflects glomerular integrity. Proteinuria was assessed in patients. High-resolution confocal microscopy and functional assays identified proteins to deduce compensatory modes of balancing proteostasis.ResultsPatients with MLII but not MLIII exhibited microalbuminuria. MLII mice showed lysosomal enzyme missorting and several skeletal alterations, indicating that they are a useful model. In glomeruli, both MLII and MLIII mice exhibited reduced levels of lysosomal enzymes and enlarged lysosomes with abnormal storage material. Nevertheless, neither model had detectable morphologic or functional glomerular alterations. The models rebalance proteostasis in two ways: MLII mice downregulate protein translation and increase the integrated stress response, whereas MLIII mice upregulate the proteasome system in their glomeruli. Both MLII and MLIII downregulate the protein complex mTORC1 (mammalian target of rapamycin complex 1) signaling, which decreases protein synthesis.ConclusionsSevere lysosomal dysfunction leads to microalbuminuria in some patients with mucolipidosis. Mouse models indicate distinct compensatory pathways that balance proteostasis in MLII and MLIII.
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Agrawal, Rekha, and Shailendra Jain. "Suitability of Reduced Part Count Multilevel Inverter Topologies for Grid Interfacing." Journal of Circuits, Systems and Computers 25, no. 07 (April 22, 2016): 1650081. http://dx.doi.org/10.1142/s021812661650081x.
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Reduced part count multilevel inverters (RPC-MLIs), an emerging technology for grid interfacing applications of renewable energy sources. RPC-MLIs overcome the limitations of conventional two-level and classical multilevel inverters (NPC, FC and CHB) by the use of reduced part counts for generation of same number of levels in the output. Focus of this paper is on to present review of the RPC-MLIs for researchers and engineers and classification of all the topologies. RPC-MLIs are compared considering its circuit complexity and performance. The comparison exposes advantages and disadvantages of topologies, as well as a wide spectrum for future research. This paper also draws the most potential topology in the field of grid integrated applications. Promising topology is simulated here under the same load and input source condition using real time simulator.
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Kaeding, Allison J., Daniel Magoon, Yarden Fraiman, Tamekia Jones, Nyla A. Heerema, Andrew J. Carroll, Kathleen W. Rao, et al. "MLL Rearrangement and Age At Diagnosis Are Strongly Associated with High Level Surface FLT3 Expression and Ex Vivo Sensitivity to FLT3 Inhibition: A Prospective Analysis of 54 Consecutive Infants with ALL Enrolled in Children's Oncology Group (COG) Trial AALL0631." Blood 118, no. 21 (November 18, 2011): 568. http://dx.doi.org/10.1182/blood.v118.21.568.568.
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Abstract Abstract 568 Background: Infant acute lymphoblastic leukemia (ALL) is clinically and biologically distinct from ALL in older children. About 80% of infant ALL cases harbor MLL rearrangements (MLLr). MLLr infant ALL is an aggressive disease with poor prognosis, particularly in cases diagnosed at <90 days of age. Infant cases with wild type MLL (MLLwt) are clinically similar to childhood ALL. Retrospective studies of selected banked specimens have suggested that MLLr infant ALL cases express higher levels of FLT3 receptor tyrosine kinase mRNA and protein, and show enhanced in vitro FLT3 inhibitor-induced cytotoxicity compared to MLLwt childhood ALL, leading to an ongoing COG trial to determine if adding lestaurtinib to chemotherapy improves outcome for MLLr infant ALL (AALL0631). Methods: We prospectively characterized 54 consecutive diagnostic leukemia specimens from infants with ALL enrolled on AALL0631 with respect to: 1) Quantitative surface FLT3 protein expression (s-FLT3) using FACS CD135 mean fluorescence index (MFI); 2) FLT3 inhibitor (lestaurtinib: 0 to 100 nM) in vitro sensitivity using 48 hour WST-1 cytotoxicity assays; samples defined as “sensitive” if 100 nM produced ≥40% inhibition of cell viability compared to vehicle controls; 3) Identification and quantification of putative leukemia stem cell (LSC) subpopulation by flow cytometric immunophenotyping (% CD34+, CD38− viable cells). Studies were performed blinded to clinical information and MLL status; data were later correlated with age at diagnosis (<90 days vs. ≥90 days) and MLL-rearrangement status/fusion partner (cytogenetics/FISH). Results: Of 54 cases, 42 (78%) are MLLr and 12 (22%) are MLLwt. For MLLr cases, fusion partners are AF4 (n=13), ENL (n=17), AF9 (n=3), AF1p (n=2), and other (n=7). Of MLLr cases, 10 (24%) were <90d and 32 (76%) were ≥90 days. All MLLwt cases were ≥90 days.We analyzed s-FLT3 according to MLL genotype, MLL fusion partner and age, and found significantly higher s-FLT3 in MLLr than MLLwt cases (mean MFI 34.2 vs. 11.6, p=0.03). According to MLL fusion partner, we found the highest s-FLT3 in AF9, lowest in AF4, and intermediate in ENL and AF1p. The AF9 vs. AF4 comparison was significant (p=0.006). According to age in the MLLr cohort, we found strikingly higher s-FLT3 in infants diagnosed at <90days compared to those >90days (mean MFI 62.6 vs. 22.0, p<0.0001). We analyzed FLT3 inhibitor sensitivity according to MLL genotype and s-FLT3. All 42 of the MLLr samples were evaluable, with 35 (83%) sensitive and 7 (17%) resistant; 11 of 12 MLLwt samples were evaluable (1 had excessively poor viability), with 6 (55%) sensitive and 5 (45%) resistant. We thus found a significant association between MLLr and FLT3 inhibitor sensitivity (Chi square 4.125, p=0.042). In the s-FLT3 analysis, the sensitive samples trended towards higher s-FLT3 than the resistant samples (mean MFI 31.3 vs. 16.7, p=0.17). Finally, we compared s-FLT3 in the putative LSC-like subpopulation fraction (if present) with the “bulk” leukemia population. Of the 54 samples analyzed, 35 (65%) had a clearly identifiable LSC-like population (i.e., comprising >0.5% of the total viable leukemia population). Within these 35 samples, s-FLT3 was significantly higher in the LSC-like fraction than in the bulk leukemia population (mean MFI 40.4 vs. 31.2, p=0.05). Conclusions: We have for the first time prospectively compared FLT3 expression and FLT3 inhibitor sensitivity in unselected representative cohorts of MLLr and MLLwt infants, confirming that MLLr cases express significantly higher levels of surface FLT3 protein and are more sensitive to the cytotoxic effects of FLT3 inhibition. Novel findings include higher surface FLT3 protein expression in MLL-AF9 cases relative to MLL-AF4 cases, and the strikingly higher surface FLT3 protein expression in MLLr cases in the youngest infants. An intriguing finding is the presence of phenotypically-defined subpopulations of “LSC-like” cells in the majority of cases, and that this LSC-like population expresses significantly higher levels of FLT3 protein than the “bulk” population. These findings provide further evidence that FLT3 overexpression plays a role in MLLr leukemogenesis. If these findings correlate with clinical responses in COG AALL0631, they may prove to be useful predictive biomarkers in selecting patients for whom FLT3-targeted therapy is most appropriate. Disclosures: No relevant conflicts of interest to declare.
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Secker, Kathy-Ann, Hildegard Keppeler, Silke Duerr-Stoerzer, Hannes Schmid, Dominik Schneidawind, Thomas Hentrich, Julia Schulze-Hentrich, Lothar Kanz, and Corina Schneidawind. "Myc Drives MLL Leukemogenesis in a Human CRISPR/Cas9 Leukemia Model and Indirect Inhibition with JQ1 Diminishes Leukemia Activity." Blood 132, Supplement 1 (November 29, 2018): 2213. http://dx.doi.org/10.1182/blood-2018-99-114419.
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Abstract Introduction: MLL rearranged leukemias are associated with a poor prognosis and response to conventional therapies is limited. Therefore, identification of new targets resulting in the development of novel compounds are urgently needed. However, the lack of authentic model systems due to retroviral MLL fusion protein overexpression and usage of pure mouse models that do not mimic the nature of the original human disease compromise efficient pharmacological studies. We generated with the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system a human MLL-rearranged (MLLr) leukemia model derived from umbilical cord blood cells, that is based on patient specific complete translocations of the MLL, AF4 or AF9 genes and shares phenotypical, morphological and molecular features of patient leukemic cells. Thus, it allows us to reproduce downstream effects caused by MLL fusion proteins on patient-like pathologic levels. Gene set enrichment analysis (GSEA) and expression analysis identified Myc as a critical target in our indefinite in vitro growing human MLLr model. Here, we report the impact of the indirect Myc inhibitor JQ1 on cell proliferation and apoptosis in our authentic human MLLr leukemia model. Methods: We used CRISPR/Cas9 to induce MLL-AF4 and -AF9 translocations in primary hematopoietic stem and progenitor cells (HSPCs) derived from human cord blood. MLLr cells were characterized via RNA sequencing, compared to primary patient cells and subjected to GSEA and differential gene expression analysis. MLLr cells were used to analyze the consequences of the Myc inhibitor JQ1 on proliferation and apoptosis determined by flow cytometry. Results: Patient-specific MLL-AF4 and -AF9 cells were generated with a translocation efficiency of 100% after a cell culture period of 30 days. In liquid culture MLLr cells displayed a distinct survival advantage with indefinite growth potential whereas control cells (HSPCs nucleofected with Cas9 alone) terminally differentiated and eventually died out after 60 days of culture. Our human MLLr model based on complete translocations of the MLL and AF4 or AF9 genes, respectively, shared molecular oncogenic features of patient leukemic cells determined by RNA sequencing: Analysis of differentially expressed genes revealed a typical MLLr leukemia signature, with upregulation of HOXA cluster and downregulation of HOXB cluster. Interestingly, further analysis of the impact of MLL fusion protein on transcriptional programs revealed Myc as a highly important target. Strikingly, treatment with the indirect Myc inhibitor JQ1 resulted in a dose-dependent reduced proliferation (50 nM: 61-65%) and induction of apoptosis (100 nM: 23-46%) of MLLr cells whereas control cells were not affected. Conclusions: Our genome editing approach to generate indefinite growing MLL-AF4 and -AF9 translocated cells faithfully models MLLr leukemia and provides an experimental platform to identify molecular targets and testing of new therapies. Myc inhibitor JQ1 shows robust antiproliferative capacity and promotes cell death serving as a potential new therapeutic target for the treatment of MLLr leukemia. Disclosures No relevant conflicts of interest to declare.
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Kuiper, Koenraad, Marie-Elaine van Egmond, Gerard Kempen, and Simone Sprenger. "Slipping on superlemmas." Mental Lexicon 2, no. 3 (December 7, 2007): 313–57. http://dx.doi.org/10.1075/ml.2.3.03kui.
Full textAbstract:
Only relatively recently have theories of speech production concerned themselves with the part idioms and other multi-word lexical items (MLIs) play in the processes of speech production. Two theories of speech production which attempt to account for the accessing of idioms in speech production are those of Cutting and Bock (1997) and superlemma theory (Sprenger, 2003; Sprenger, Levelt, & Kempen, 2006). Much of the data supporting theories of speech production comes either from time course experiments or from slips of the tongue (Bock & Levelt, 1994). The latter are of two kinds: experimentally induced (Baars, 1992) or naturally observed (Fromkin, 1980). Cutting and Bock use experimentally induced speech errors while Sprenger et al. use time course experiments. The missing data type that has a bearing on speech production involving MLIs is that of naturally occurring slips. In this study the impact of data taken from naturally observed slips involving English and Dutch MLIs are brought to bear on these theories. The data are taken initially from a corpus of just over 1000 naturally observed English slips involving MLIs (the Tuggy corpus). Our argument proceeds as follows. First we show that slips occur independent of whether or not there are MLIs involved. In other words, speech production proceeds in certain of its aspects as though there were no MLI present. We illustrate these slips from the Tuggy data. Second we investigate the predictions of superlemma theory. Superlemma theory (Sprenger et al., 2006) accounts for the selection of MLIs and how their properties enter processes of speech production. It predicts certain activation patterns dependent on a MLI being selected. Each such pattern might give rise to slips of the tongue. This set of predictions is tested against the Tuggy data. Each of the predicted activation patterns yields a significant number of slips. These findings are therefore compatible with a view of MLIs as single units in so far as their activation by lexical concepts goes. However, the theory also predicts that some slips are likely not to occur. We confirm that such slips are not present in the data. These findings are further corroborated by reference a second smaller dataset of slips involving Dutch MLIs (the Kempen corpus). We then use slips involving irreversible binomials to distinguish between the predictions of superlemma theory which are supported by slips involving irreversible binomials and the Cutting and Bock model’s predictions for slips involving these MLIs which are not.
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Pyo, Jung-Soo, Young-Min Shin, and Dong-Wook Kang. "Prognostic Implication of Metastatic Lymph Node Ratio in Colorectal Cancers: Comparison Depending on Tumor Location." Journal of Clinical Medicine 8, no. 11 (November 1, 2019): 1812. http://dx.doi.org/10.3390/jcm8111812.
Full textAbstract:
Background: The proportion of the number of involved lymph nodes (LNs) to the number of examined LNs—defined as metastatic LN ratio (mLNR)—has been considered as a prognostic parameter. This study aims to elucidate the prognostic implication of the mLNR in colorectal cancer (CRC) according to the tumor location. Methods: We evaluated the correlation between prognoses and the involved and examined LNs as well as mLNR according to the tumor location in 266 surgically resected human CRCs. Besides, to evaluate the optimal cutoff for high and low mLNRs, we investigated the correlation between mLNR and survival according to the various cutoffs. Results: LN metastasis was found in 146 cases (54.9%), and colon and rectal cancers were found in 116 (79.5%) and 30 (20.5%) of the cases, respectively. The mean mLNRs were significantly higher in rectal cancer than in colon cancer (0.38 ± 0.28 vs. 0.21 ± 0.24, P = 0.003). Besides this, the number of involved LNs in rectal cancer was significantly high compared to colon cancer (11.83 ± 10.92 vs. 6.37 ± 7.78, P = 0.014). However, there was no significant difference in the examined LNs between the rectal and colon cancers (31.90 ± 12.28 vs. 36.60 ± 18.11, P = 0.181). In colon cancer, a high mLNR was significantly correlated with worse survival for all cutoffs (0.1, 0.2, 0.3, and 0.4). However, rectal cancer only showed a significant correlation between high mLNR and worse survival in the subgroup with a cutoff of 0.2. Conclusions: Our results showed that high mLNR was significantly correlated with worse survival. The number of involved LNs and mLNRs were significantly higher in rectal cancer than in colon cancer. The cutoff of 0.2 can be useful for the differentiation of prognostic groups, regardless of tumor location.
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Gurunathan, Arun, Lana S. Itskovich, Jason Clark, Matthew Burwinkel, Nathan Salomonis, Meenakshi Venkatasubramanian, Kashish Chetal, Lynn Lee, and Ashish R. Kumar. "MLL-Fusion Leukemia Dependence on MBNL1 Is Associated with Alternative Splicing of Oncogenic Proteins." Blood 132, Supplement 1 (November 29, 2018): 3883. http://dx.doi.org/10.1182/blood-2018-99-112349.
Full textAbstract:
Abstract Leukemia is the most common childhood cancer, and while outcomes for most children have improved significantly, the prognosis in infant leukemia remains dire. The majority of infant leukemia, either acute myeloid (AML) or acute lymphoid (ALL), is caused by reciprocal translocations of the MLL-gene. Prior studies show that one of the most consistently overexpressed genes in these leukemias (compared to all other leukemias) is the RNA binding protein muscleblind-like 1 (MBNL1). We found that MBNL1 knockdown significantly impairs propagation of MLL-rearranged (MLLr) leukemic cells in vitro and in vivo using human cell lines and transformed murine cells. To further characterize the role of MBNL1 in acute leukemia, we performed shRNA knockdown experiments in MLLr and non-MLLr leukemia cell lines and in primary patient samples. While MBNL1 knockdown does also impair growth of non-MLLr leukemic cells, the effect is less pronounced. In a 5-day growth experiment MBNL1-knockdown MLLr cells (THP-1) displayed a median 71% reduced growth compared to controls, whereas non-MLLr cells (HL-60) displayed only a median 32% growth reduction (p=0.0001). Cells from two patients with MLLr AML (one with MLL-AF9 and one with MLL-AF10 fusion) underwent shNT (non-targeting) or shMBNL1 transduction.. Unsorted cells were transplanted into NSGS mice. Mice were observed until showing signs of distress and then analyzed for engraftment of human cells and abundance of transduced cells (venus-positive). In the shNT group there was robust persistence of transduced cells (7%-98% of human cells), whereas shMBNL1-transduced cells were not detected or comprised <1% of human cells in most of the recipient mice. Given that MBNL1 is known to regulate alternative splicing, we used unbiased RNAseq along with a novel analytic splice-junction and intron-quantification toolkit (AltAnalyze) to determine splicing changes induced by knockdown of MBNL1 in the MLLr leukemia cell line MOLM-13. In a parallel analysis, we determined splicing differences between MLLr and cytogenetically-normal (CN) AML patient samples. We then compared these two results to determine the splicing events regulated by MBNL1 and assess the contribution of MBNL1 to splicing events observed in primary MLLr leukemias. Strikingly, this comparative analysis found that 88% of overlapping differentially expressed splicing events (75 out of 85) were concordant between patient MLLr and CN-AML as compared to control versus MBNL1 knockdown. The most common class of splicing event that occurred with MBNL1 knockdown was intron retention. Specifically, our findings suggest that MBNL1 knockdown restores intron retention, and that MBNL1 overexpression promotes expression of protein-coding genes that would otherwise be suppressed through intron retention-introduced premature termination codons. Several genes whose transcripts are alternatively spliced by MBNL1 have prior associations with cancer, most notably DOT1L and SETD1A which are specifically implicated in MLLr leukemia. Splicing validation through RT-PCR confirmed increased intron retention in DOT1L and SETD1A transcripts after MBNL1 knockdown. Interestingly, one target of MBNL1 is the MBNL1 mRNA itself, with resultant exclusion of exon 5. MBNL1 lacking exon 5 has a stronger affinity to RNA. In summary, our data suggests that MBNL1 plays a key role in the pathogenesis of MLL-fusion leukemia, wherein it stabilizes the transcripts of multiple leukemogenic genes including DOT1L and SETD1A. Proteins such as DOT1L are critical for transcriptional activation of downstream targets of the MLL-fusion protein (including activation of MBNL1, creating a positive feedback loop). Additionally, high levels of MBNL1 protein may alter splicing in ways that enhance MBNL1 functionality. Disclosures No relevant conflicts of interest to declare.