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Shi, Yu, Zihao Liu, Qun Lin, Qing Luo, Yinghuan Cen, Juanmei Li, Xiaolin Fang e Chang Gong. "MiRNAs and Cancer: Key Link in Diagnosis and Therapy". Genes 12, n. 8 (23 agosto 2021): 1289. http://dx.doi.org/10.3390/genes12081289.
Abstract (sommario):
Since the discovery of the first microRNA (miRNA), the exploration of miRNA biology has come to a new era in recent decades. Monumental studies have proven that miRNAs can be dysregulated in different types of cancers and the roles of miRNAs turn out to function to either tumor promoters or tumor suppressors. The interplay between miRNAs and the development of cancers has grabbed attention of miRNAs as novel tools and targets for therapeutic attempts. Moreover, the development of miRNA delivery system accelerates miRNA preclinical implications. In this review, we depict recent advances of miRNAs in cancer and discuss the potential diagnostic or therapeutic approaches of miRNAs.
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Chou, Li-Der, Chien-Chang Liu, Meng-Sheng Lai, Kai-Cheng Chiu, Hsuan-Hao Tu, Sen Su, Chun-Lin Lai, Chia-Kuan Yen e Wei-Hsiang Tsai. "Behavior Anomaly Detection in SDN Control Plane: A Case Study of Topology Discovery Attacks". Wireless Communications and Mobile Computing 2020 (20 novembre 2020): 1–16. http://dx.doi.org/10.1155/2020/8898949.
Abstract (sommario):
Software-defined networking controllers use the OpenFlow discovery protocol (OFDP) to collect network topology status. The OFDP detects the link between switches by generating link layer discovery protocol (LLDP) packets. However, OFDP is not a security protocol. Attackers can use it to perform topology discovery via injection, man-in-the-middle, and flooding attacks to confuse the network topology. This study proposes a correlation-based topology anomaly detection mechanism. Spearman’s rank correlation is used to analyze the network traffic between links and measure the round-trip time of each LLDP frame to determine whether a topology discovery via man-in-the-middle attack exists. This study also adds a dynamic authentication key and counting mechanism in the LLDP frame to prevent attackers from using topology discovery via injection attack to generate fake links and topology discovery via flooding attack to cause network routing or switching abnormalities.
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Li, Yan, Weiguo Li, Xin Chen, Hong Jiang, Jiatong Sun, Huan Chen e Sali Lv. "Integrated Analysis Identifies Interaction Patterns between Small Molecules and Pathways". BioMed Research International 2014 (13 luglio 2014): 1–10. http://dx.doi.org/10.1155/2014/931825.
Abstract (sommario):
Previous studies have indicated that the downstream proteins in a key pathway can be potential drug targets and that the pathway can play an important role in the action of drugs. So pathways could be considered as targets of small molecules. A link map between small molecules and pathways was constructed using gene expression profile, pathways, and gene expression of cancer cell line intervened by small molecules and then we analysed the topological characteristics of the link map. Three link patterns were identified based on different drug discovery implications for breast, liver, and lung cancer. Furthermore, molecules that significantly targeted the same pathways tended to treat the same diseases. These results can provide a valuable reference for identifying drug candidates and targets in molecularly targeted therapy.
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Landi, Sofia M., Pooja Viswanathan, Stephen Serene e Winrich A. Freiwald. "A fast link between face perception and memory in the temporal pole". Science 373, n. 6554 (1 luglio 2021): 581–85. http://dx.doi.org/10.1126/science.abi6671.
Abstract (sommario):
The question of how the brain recognizes the faces of familiar individuals has been important throughout the history of neuroscience. Cells linking visual processing to person memory have been proposed but not found. Here, we report the discovery of such cells through recordings from an area in the macaque temporal pole identified with functional magnetic resonance imaging. These cells responded to faces that were personally familiar. They responded nonlinearly to stepwise changes in face visibility and detail and holistically to face parts, reflecting key signatures of familiar face recognition. They discriminated between familiar identities, as fast as a general face identity area. The discovery of these cells establishes a new pathway for the fast recognition of familiar individuals.
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Kellner, Franziska, Fernando Geu-Flores, Nathaniel H. Sherden, Stephanie Brown, Emilien Foureau, Vincent Courdavault e Sarah E. O'Connor. "Discovery of a P450-catalyzed step in vindoline biosynthesis: a link between the aspidosperma and eburnamine alkaloids". Chemical Communications 51, n. 36 (2015): 7626–28. http://dx.doi.org/10.1039/c5cc01309g.
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Jumiati, Rinda, Boy Chandra e Dan Ridho Asra. "Drug Discovery of Griseofulvin : A Review". Asian Journal of Pharmaceutical Research and Development 9, n. 4 (14 agosto 2021): 101–7. http://dx.doi.org/10.22270/ajprd.v9i4.993.
Abstract (sommario):
Background: Griseofulvin is a fungistatic antifungal drug used to treat dermatophytosis. Dermatophytes that are often found include Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum canis, Microsporum gypseum, Epidermophyton floccosum.
Purpose: This review article aims to discuss the drug discovery review of griseofulvin.
Data Source: The author created this review article using the literature study method relevant to the purpose of the review. Sources of information from national journals and international journals that are accessed through online sites such as Google Scholar, Research Gate, Science Direct, Springer Link, and NCBI. Key words were used to find the journals, namely griseofulvin, dermatophyte, toxicity.
Conclusion: The conclusion of this article is that griseofulvin is used as an antifungal drug containing chlorine from Penicillium griseofulvum isolated against mycelium fungus. This drug is non-toxic, so it is effective and safe to fight various types of fungal infections of the skin such as tinea capitis and remains the drug of choice for dermatophytes.
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O’Mahony, Mairin. "Self-discovered breast cancer symptoms and women's help seeking behaviour: key findings from phase one of a two-phase study". Boolean: Snapshots of Doctoral Research at University College Cork, n. 2010 (1 gennaio 2010): 133–32. http://dx.doi.org/10.33178/boolean.2010.29.
Abstract (sommario):
Breast cancer is the most common cancer among women in the western world. In Ireland, breast cancer was the most common cancer diagnosed amongst women during 2000-2004 with approximately 3,095 cases reported annually and an average of 947 deaths. It is well known that the earlier the diagnosis of breast cancer is made the more likely it is that women will have a better health outcome. However, 20-30% of women wait for one month or more before presenting to a Health Care Professional with a self discovered breast symptom. This is a worrying situation given the increased emphasis on prompt presentation of symptoms and the associated link with better health care outcomes for women diagnosed with breast cancer. Therefore, more work on help-seeking behaviour from the woman’s perspective will help Health Care Professionals to understand women’s needs and concerns surrounding symptom discovery and highlight the key issues linked to delayed ...
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El Ksimi, Ali, e Cherkaoui Leghris. "Towards a New Algorithm to Optimize IPv6 Neighbor Discovery Security for Small Objects Networks". Security and Communication Networks 2018 (6 giugno 2018): 1–11. http://dx.doi.org/10.1155/2018/1816462.
Abstract (sommario):
In order to verify the uniqueness of link-local or unicast addresses, nodes must perform a Duplicate Address Detection process before using them. However, this process is subject to many attacks and the security is willing to be the most important issues in Small Object Networks with IPv6. In this paper, we developed a new algorithm to optimize the security in IPv6-DAD process; this method is based on SHA-512 to verify the identity of the Neighbor Discovery messages transmitted in the link local. First, before sending the NS message, the new node uses the function SHA-512 to hash to the target address and use the last 64 bits in a new field and then encrypt the result with its private key. When receiving the secure message, the existing nodes decrypt it. Our algorithm is going to secure the DAD process by using a digital signature. Overall, this algorithm showed a significant effect in terms of the Address Configuration Success Probability (ACSP).
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Septifani, Eza Azhara, Rina Desni Yetti e Ridho Asra. "Review: The Discovery and Development of Sildenafil Citrate". Asian Journal of Pharmaceutical Research and Development 9, n. 4 (14 agosto 2021): 108–17. http://dx.doi.org/10.22270/ajprd.v9i4.1018.
Abstract (sommario):
Background: Griseofulvin is a fungistatic antifungal drug used to treat dermatophytosis. Dermatophytes that are often found include Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum canis, Microsporum gypseum, Epidermophyton floccosum. Purpose: This review article aims to discuss the drug discovery review of griseofulvin. Data Source: The author created this review article using the literature study method relevant to the purpose of the review. Sources of information from national journals and international journals that are accessed through online sites such as Google Scholar, Research Gate, Science Direct, Springer Link, and NCBI. Key words were used to find the journals, namely griseofulvin, dermatophyte, toxicity. Conclusion: The conclusion of this article is that griseofulvin is used as an antifungal drug containing chlorine from Penicillium griseofulvum isolated against mycelium fungus. This drug is non-toxic, so it is effective and safe to fight various types of fungal infections of the skin such as tinea capitis and remains the drug of choice for dermatophytes.
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Song, Yifei, Liang Zeng, Zeyu Liu, Zhe Song, Jie Zeng e Jianping An. "Cross-Layer Optimization Spatial Multi-Channel Directional Neighbor Discovery with Random Reply in mmWave FANET". Electronics 11, n. 10 (13 maggio 2022): 1566. http://dx.doi.org/10.3390/electronics11101566.
Abstract (sommario):
MmWave FANETs play an increasingly important role in the development of UAVs technology. Fast neighbor discovery is a key bottleneck in mmWave FANETs. In this paper, we propose a two-way neighbor discovery algorithm based on a spatial multi-channel through cross-layer optimization. Firstly, we give two boundary conditions of the physical (PHY) layer and media access control (MAC) layer for successful link establishment of mmWave neighbor discovery and give the optimal pairing of antenna beamwidth in different stages and scenarios using cross-layer optimization. Then, a mmWave neighbor discovery algorithm based on a spatial multi-channel is proposed, which greatly reduces the convergence time by increasing the discovery probability of nodes in the network. Finally, a random reply algorithm is proposed based on dynamic reserved time slots. By adjusting the probability of reply and the number of reserved time slots, the neighbor discovery time can be further reduced when the number of nodes is larger. Simulations show that as the network scale is 100 to 500 nodes, the convergence time is 10 times higher than that of the single channel algorithm.
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Ronco, Alvaro L., e Eduardo De Stéfani. "Squalene: a multi-task link in the crossroads of cancer and aging". Functional Foods in Health and Disease 3, n. 12 (20 dicembre 2013): 462. http://dx.doi.org/10.31989/ffhd.v3i12.30.
Abstract (sommario):
Since its discovery in the beginning of the XXth century, squalene has been recognized as an important link in metabolic pathways. More recently, it has been further recognized as an intermediate step in the biosynthesis of cholesterol. Its well known antioxidant capability, together with its ability to protect skin, improve the immune system, and modulate the lipid profile, confer a high potential to this natural substance, which is spread all across the body structure, though mainly in the epithelial tissues, and in particular the skin sebum. This review will focus mainly on its major properties, which are related to anticancer properties, the maintenance of the oxidation/antioxidation balance, and its antiaging capabilities. Although the substance was originally obtained from shark liver oil, it is currently possible to obtain useful amounts from vegetable sources like extra virgin olive oil, therefore avoiding the dependence on capturing the aforementioned animal species. Recognized as one of the key components of the Mediterranean dietary style, squalene is necessary to adequately manage oxygen and its derivatives in every cell of the body. Key words: aging, antioxidants, cancer, cholesterol, diet, olive oil, squalene
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KRUMOVA, Milena, e Evgeniy PETROV. "Sub-suppliers model 4.0 and knowledge discovery in industry supply chain". Smart Cities and Regional Development (SCRD) Journal 8, n. 1 (20 gennaio 2024): 119–30. http://dx.doi.org/10.25019/3kxnym42.
Abstract (sommario):
Web 4.0 revolution and the abundance of industrial data in the current business environment allow each industrial company to innovate in a diversity of ways. The novelty approaches for the industry are often related to Industry 4.0, where data plays a key role. This research paper aims to develop a new model of the Sub-Supplier process description „Sub-Suppliers Model 4.0“. The model presents the role of knowledge management and Web 4.0 as having a key impact on the processes for business value creation for the industrial organisation. The paper is structured into three chapters. The introduction presents the methods used along with the research question. Chapter one starts with the theoretical bases and state of the art of the Industrial Sub-Supplier Process (ISSP). Chapter two makes a link between the ISSP, knowledge management and knowledge discovery process using data from Supply Chain Management Software for management decision-making. Chapter three of the research starts with web 4.0 tools and proposes a Sub-Suppliers Model 4.0, while trying to explain how the ISSP can be optimized based on the KPIs used. The main research contribution is the novelty integration of the knowledge discovery concept and the implementation of web 4.0 tools into the ISSP.
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Cao, Jing, Hui Gan, Han Xiao, Hui Chen, Dan Jian, Ning Jiang e Xuan Zhai. "Key protein-coding genes related to microglia in immune regulation and inflammatory response induced by epilepsy". Mathematical Biosciences and Engineering 18, n. 6 (2021): 9563–78. http://dx.doi.org/10.3934/mbe.2021469.
Abstract (sommario):
<abstract> <p>Several studies have shown a link between immunity, inflammatory processes, and epilepsy. Active neuroinflammation and marked immune cell infiltration occur in epilepsy of diverse etiologies. Microglia, as the first line of defense in the central nervous system, are the main effectors of neuroinflammatory processes. Discovery of new biomarkers associated with microglia activation after epileptogenesis indicates that targeting specific molecules may help control seizures. In this research, we used a combination of several bioinformatics approaches, including RNA sequencing, to explore differentially expressed genes (DEGs) in epileptic lesions and control samples, and to construct a protein-protein interaction (PPI) network for DEGs, which was examined utilizing plug-ins in Cytoscape software. Finally, we aimed to identify 10 hub genes in immune and inflammation-related sub-networks, which were subsequently validated in real-time quantitative polymerase chain reaction analysis in a mouse model of kainic acid-induced epilepsy. The expression patterns of nine genes were consistent with sequencing outcomes. Meanwhile, several genes, including CX3CR1, CX3CL1, GPR183, FPR1, P2RY13, P2RY12 and LPAR5, were associated with microglial activation and migration, providing novel candidate targets for immunotherapy in epilepsy and laying the foundation for further research.</p> </abstract>
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Al-Shareeda, Mahmood A., Selvakumar Manickam, Murtaja Ali Saare e Navaneethan C. Arjuman. "Proposed security mechanism for preventing fake router advertisement attack in IPv6 link-local network". Indonesian Journal of Electrical Engineering and Computer Science 29, n. 1 (1 gennaio 2022): 518. http://dx.doi.org/10.11591/ijeecs.v29.i1.pp518-526.
Abstract (sommario):
The design of router discovery (RD) is a trust mechanism to confirm the legitimacy of the host and router. Fake router advertisement (RA) attacks have been made possible by this RD protocol design defect. Studies show that the standard RD protocol is vulnerable to a fake RA attack where the host will be denied a valid gateway. To cope with this problem, several prevention techniques have been proposed in the past to secure the RD process. Nevertheless, these methods have a significant temporal complexity as well as other flaws, including the bootstrapping issue and hash collision attacks. Thus, the SecMac-secure router discovery (SecMac-SRD) technique, which requires reduced processing time and may thwart fake RA assaults, is proposed in this study as an improved secure RD mechanism. SecMac-SRD is built based on a UMAC hashing algorithm with ElGamal public key distribution cryptosystem that hides the RD message exchange in the IPv6 link-local network. Based on the obtained expected results display that the SecMac-SRD mechanism achieved less processing time compared to the existing secure RD mechanism and can resist fake RA attacks. The outcome of the expected results clearly proves that the SecMac-SRD mechanism effectively copes with the fake RA attacks during the RD process.
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Almasi, Shekoufeh, e Bernard J. Jasmin. "The multifunctional RNA-binding protein Staufen1: an emerging regulator of oncogenesis through its various roles in key cellular events". Cellular and Molecular Life Sciences 78, n. 23 (11 ottobre 2021): 7145–60. http://dx.doi.org/10.1007/s00018-021-03965-w.
Abstract (sommario):
AbstractThe double-stranded multifunctional RNA-binding protein (dsRBP) Staufen was initially discovered in insects as a regulator of mRNA localization. Later, its mammalian orthologs have been described in different organisms, including humans. Two human orthologues of Staufen, named Staufen1 (STAU1) and Staufen2 (STAU2), share some structural and functional similarities. However, given their different spatio-temporal expression patterns, each of these orthologues plays distinct roles in cells. In the current review, we focus on the role of STAU1 in cell functions and cancer development. Since its discovery, STAU1 has mostly been studied for its involvement in various aspects of RNA metabolism. Given the pivotal role of RNA metabolism within cells, recent studies have explored the mechanistic impact of STAU1 in a wide variety of cell functions ranging from cell growth to cell death, as well as in various disease states. In particular, there has been increasing attention on the role of STAU1 in neuromuscular disorders, neurodegeneration, and cancer. Here, we provide an overview of the current knowledge on the role of STAU1 in RNA metabolism and cell functions. We also highlight the link between STAU1-mediated control of cellular functions and cancer development, progression, and treatment. Hence, our review emphasizes the potential of STAU1 as a novel biomarker and therapeutic target for cancer diagnosis and treatment, respectively.
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Sabatini, David M. "Twenty-five years of mTOR: Uncovering the link from nutrients to growth". Proceedings of the National Academy of Sciences 114, n. 45 (25 ottobre 2017): 11818–25. http://dx.doi.org/10.1073/pnas.1716173114.
Abstract (sommario):
In my PNAS Inaugural Article, I describe the development of the mTOR field, starting with efforts to understand the mechanism of action of the drug rapamycin, which ∼25 y ago led to the discovery of the mTOR protein kinase. I focus on insights that we have contributed and on work that has been particularly influential to me, as well as provide some personal reflections and stories. We now appreciate that, as part of two distinct complexes, mTORC1 and mTORC2, mTOR is the major regulator of growth (mass accumulation) in animals and is the key link between the availability of nutrients in the environment and the control of most anabolic and catabolic processes. Nutrients signal to mTORC1 through the lysosome-associated Rag GTPases and their many regulators and associated cytosolic and lysosomal nutrient sensors. mTOR signaling is deregulated in common diseases, like cancer and epilepsy, and mTORC1 is a well-validated modulator of aging in multiple model organisms. There is significant excitement around using mTORC1 inhibitors to treat cancer and neurological disease and, potentially, to improve healthspan and lifespan.
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Shao, Min Hua, e Yi Ping Lee. "An Adaptive Link-Disjoint Multipath Routing in Ad Hoc Networks". Advanced Materials Research 171-172 (dicembre 2010): 628–31. http://dx.doi.org/10.4028/www.scientific.net/amr.171-172.628.
Abstract (sommario):
Mobile Ad Hoc Networks (MANET) are different from other network features, every mobile node possesses the role of host and router which makes routing mechanism become a key of the influence network stability. Because MANET topology is dynamic and easy-changing, so many scholars provide multipath and backup path routing protocol to solve the problems above. In 2001, Marina and Das proposed AOMDV multipath routing protocol which solves the limit of AODV single path routing protocol and promoted the efficiency of the whole network operation. However, we find out AOMDV has more than one first hop problem that cannot operate the multiple paths in some sparse networks. Thus, this paper uses the idea of common link to solve the problem which is an adaptive and efficient multipath routing protocol. To correspond to different dynamic topology, we need to adjust to route establishing scheme, in order to efficiently increase the number of paths and to decrease the frequency of route discovery which will provide a stable network connection. Finally, through the NS-2 simulation of experimental results shows our scheme the better performance in end to end delay and package delivery rate, compared with AOMDV routing protocol, and our scheme does not cause the additional network overhead.
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Alameri, Ibrahim, Jitka Komarkova, Tawfik Al-Hadhrami e Ahmad Lotfi. "Systematic review on modification to the ad-hoc on-demand distance vector routing discovery mechanics". PeerJ Computer Science 8 (5 settembre 2022): e1079. http://dx.doi.org/10.7717/peerj-cs.1079.
Abstract (sommario):
Mobile ad-hoc networks (MANETs) and wireless mesh networks (WMNs) are used in a variety of research areas, including the military, industry, healthcare, agriculture, the Internet of Things (IoT), transportation, and smart cities. The swift advancement in MANET technology is the driving force behind this rising adoption rate. Routing over MANET is a critical problem due to the dynamic nature of the link qualities, even when nodes are static. A key challenge in MANETs is the need for an efficient routing protocol that establishes a route according to certain performance metrics related to the link quality. The routing protocols utilised by the nodes in WMNs and MANETs are distinct. Nodes in both types of networks exchange data packets through the routing protocols. For this highly mobile network, the ad-hoc On-Demand Distance Vector (AODV) routing protocol has been suggested as a possible solution. Recent years have attracted researchers’ attention to AODV since it is a routing technique for ad-hoc networks that prevents looping. The architecture of this routing protocol considers several factors, including the mobility of nodes, the failure of connection links, and the loss of packets. In this systematic review, one of the key focuses is bringing attention to the classic AODV, which was developed after discussing the recent development of several versions of AODV. The AODV routing protocol performs a path strength check to generate a more reliable and secure route between the source and destination nodes. In AODV, investigations demonstrate advances in both the format protocol approach and the network simulation-2 (NS-2), and these improvements were made in the same scenario used to revitalise AODV. It has been discovered that the AODV is more effective in several aspects, such as throughput, end-to-end delay, packet delivery ratio (PDR), energy consumption, jitter, packet loss ratio, and network overhead. Furthermore, this paper presents this systematic review based on AODV modifications in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). It also provides a methodological framework for the papers’ selection.
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Welborn, V. Vaissier. "Beyond structural analysis of molecular enzyme-inhibitor interactions". Electronic Structure 4, n. 1 (14 febbraio 2022): 014006. http://dx.doi.org/10.1088/2516-1075/ac509f.
Abstract (sommario):
Abstract Fast and effective drug discovery processes rely on rational drug design to circumvent the tedious and expensive trial and error approach. However, accurate predictions of new remedies, which are often enzyme inhibitors, require a clear understanding of the nature and function of the key players governing the interaction between the drug candidate and its target. Here, we propose to calculate electric fields to explicitly link structure to function in molecular dynamics simulations, a method that can easily be integrated within the rational drug discovery workflow. By projecting the electric fields onto specific bonds, we can identify the system components that are at the origin of stabilizing intermolecular interactions (covalent and non-covalent) in the active site. This helps to significantly narrow the exploration space when predicting new inhibitors. To illustrate this method, we characterize the binding of the non-covalent inhibitor X77 to the main protease of SARS-CoV-2, a particularly time-sensitive drug discovery problem. With electric field calculations, we were able to identify three key residues (Asn-142, Met-165 and Glu-166), that have functional consequences on X77. This contrasts with the nearly 20 residues reported in previous studies as being in close contact with inhibitors in the active site of the protease. As a result, the search for new non-covalent inhibitors can now be accelerated by techniques that look to optimize the interaction between candidate molecules and these residues.
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Liao, Clara, e Alex C. Kwan. "Applying Reinforcement Learning to Rodent Stress Research". Chronic Stress 5 (gennaio 2021): 247054702098473. http://dx.doi.org/10.1177/2470547020984732.
Abstract (sommario):
Rodent models are an invaluable tool for studying the pathophysiological mechanisms underlying stress and depressive disorders. However, the widely used behavioral assays to measure depressive-like states in rodents have serious limitations. In this commentary, we suggest that learning tasks, particularly those that can be analyzed with the framework of reinforcement learning, are ideal for assaying reward processing deficits relevant to depression. The key advantages of these tasks are their repeatable, quantifiable nature and the link to clinical studies. By optimizing the behavioral readout of stress-induced phenotypes in rodents, a reinforcement learning-based approach may help bridge the translational gap and advance antidepressant discovery.
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Schrader, Michael, e Hartmut Selle. "The Process Chain for Peptidomic Biomarker Discovery". Disease Markers 22, n. 1-2 (2006): 27–37. http://dx.doi.org/10.1155/2006/174849.
Abstract (sommario):
Over the last few years the interest in diagnostic markers for specific diseases has increased continuously. It is expected that they not only improve a patient's medical treatment but also contribute to accelerating the process of drug development. This demand for new biomarkers is caused by a lack of specific and sensitive diagnosis in many diseases. Moreover, diseases usually occur in different types or stages which may need different diagnostic and therapeutic measures. Their differentiation has to be considered in clinical studies as well. Therefore, it is important to translate a macroscopic pathological or physiological finding into a microscopic view of molecular processes and vice versa, though it is a difficult and tedious task. Peptides play a central role in many physiological processes and are of importance in several areas of drug research. Exploration of endogenous peptides in biologically relevant sources may directly lead to new drug substances, serve as key information on a new target and can as well result in relevant biomarker candidates. A comprehensive analysis of peptides and small proteins of a biological system corresponding to the respective genomic information (peptidomics®methods) was a missing link in proteomics. A new peptidomic technology platform addressing peptides was recently presented, developed by adaptation of the striving proteomic technologies. Here, concepts of using peptidomics technologies for biomarker discovery are presented and illustrated with examples. It is discussed how the biological hypothesis and sample quality determine the result of the study. A detailed study design, appropriate choice and application of technology as well as thorough data interpretation can lead to significant results which have to be interpreted in the context of the underlying disease. The identified biomarker candidates will be characterised in validation studies before use. This approach for discovery of peptide biomarkes has potential for improving clinical studies.
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Konar, Aritra, e Nicholas D. Sidiropoulos. "Optimal Quasi-clique: Hardness, Equivalence with Densest-k-Subgraph, and Quasi-partitioned Community Mining". Proceedings of the AAAI Conference on Artificial Intelligence 38, n. 8 (24 marzo 2024): 8608–16. http://dx.doi.org/10.1609/aaai.v38i8.28705.
Abstract (sommario):
Dense subgraph discovery (DSD) is a key primitive in graph mining that typically deals with extracting cliques and near-cliques. In this paper, we revisit the optimal quasi-clique (OQC) formulation for DSD and establish that it is NP--hard. In addition, we reveal the hitherto unknown property that OQC can be used to explore the entire spectrum of densest subgraphs of all distinct sizes by appropriately varying a single hyperparameter, thereby forging an intimate link with the classic densest-k-subgraph problem (DkS). We corroborate these findings on real-world graphs by applying the simple greedy algorithm for OQC with improved hyperparameter tuning, to quickly generate high-quality approximations of the size-density frontier. Our findings indicate that OQC not only extracts high quality (near)-cliques, but also large and loosely-connected subgraphs that exhibit well defined local community structure. The latter discovery is particularly intriguing, since OQC is not explicitly geared towards community detection.
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Kershner, Aaron M., Heaji Shin, Tyler J. Hansen e Judith Kimble. "Discovery of two GLP-1/Notch target genes that account for the role of GLP-1/Notch signaling in stem cell maintenance". Proceedings of the National Academy of Sciences 111, n. 10 (24 febbraio 2014): 3739–44. http://dx.doi.org/10.1073/pnas.1401861111.
Abstract (sommario):
A stem cell’s immediate microenvironment creates an essential “niche” to maintain stem cell self-renewal. Many niches and their intercellular signaling pathways are known, but for the most part, the key downstream targets of niche signaling remain elusive. Here, we report the discovery of two GLP-1/Notch target genes, lst-1 (lateral signaling target) and sygl-1 (synthetic Glp), that function redundantly to maintain germ-line stem cells (GSCs) in the nematode Caenorhabditis elegans. Whereas lst-1 and sygl-1 single mutants appear normal, lst-1 sygl-1 double mutants are phenotypically indistinguishable from glp-1/Notch mutants. Multiple lines of evidence demonstrate that GLP-1/Notch signaling activates lst-1 and sygl-1 expression in GSCs within the niche. Therefore, these two genes fully account for the role of GLP-1/Notch signaling in GSC maintenance. Importantly, lst-1 and sygl-1 are not required for GLP-1/Notch signaling per se. We conclude that lst-1 and sygl-1 forge a critical link between Notch signaling and GSC maintenance.
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Venkatesan, Aravind, Jee-Hyub Kim, Francesco Talo, Michele Ide-Smith, Julien Gobeill, Jacob Carter, Riza Batista-Navarro, Sophia Ananiadou, Patrick Ruch e Johanna McEntyre. "SciLite: a platform for displaying text-mined annotations as a means to link research articles with biological data". Wellcome Open Research 1 (12 dicembre 2016): 25. http://dx.doi.org/10.12688/wellcomeopenres.10210.1.
Abstract (sommario):
Biological databases are fundamental to biological research and discovery. Database curation adds highly precise and useful information, usually extracted from the literature through experts reading research articles. The significant amount of time and effort put in by curators, against the backdrop of tremendous data growth, makes manual curation a high value task. Therefore, there is an urgent need to find ways to scale curation efforts by improving data integration, linking literature to the underlying data. As part of the development of Europe PMC, we have developed a new platform, SciLite, that overlays text-mined annotations on research articles. The aim is to aid Europe PMC users in finding key concepts more easily and provide links to related resources or tools, bridging the gap between literature and biological data.
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Zee, Barry M., Artyom A. Alekseyenko, Kyle A. McElroy e Mitzi I. Kuroda. "Streamlined discovery of cross-linked chromatin complexes and associated histone modifications by mass spectrometry". Proceedings of the National Academy of Sciences 113, n. 7 (1 febbraio 2016): 1784–89. http://dx.doi.org/10.1073/pnas.1522750113.
Abstract (sommario):
Posttranslational modifications (PTMs) are key contributors to chromatin function. The ability to comprehensively link specific histone PTMs with specific chromatin factors would be an important advance in understanding the functions and genomic targeting mechanisms of those factors. We recently introduced a cross-linked affinity technique, BioTAP-XL, to identify chromatin-bound protein interactions that can be difficult to capture with native affinity techniques. However, BioTAP-XL was not strictly compatible with similarly comprehensive analyses of associated histone PTMs. Here we advance BioTAP-XL by demonstrating the ability to quantify histone PTMs linked to specific chromatin factors in parallel with the ability to identify nonhistone binding partners. Furthermore we demonstrate that the initially published quantity of starting material can be scaled down orders of magnitude without loss in proteomic sensitivity. We also integrate hydrophilic interaction chromatography to mitigate detergent carryover and improve liquid chromatography-mass spectrometric performance. In summary, we greatly extend the practicality of BioTAP-XL to enable comprehensive identification of protein complexes and their local chromatin environment.
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Martinez, Ana, Carmen Gil e Daniel I. Perez. "Glycogen Synthase Kinase 3 Inhibitors in the Next Horizon for Alzheimer's Disease Treatment". International Journal of Alzheimer's Disease 2011 (2011): 1–7. http://dx.doi.org/10.4061/2011/280502.
Abstract (sommario):
Glycogen synthase kinase 3 (GSK-3), a proline/serine protein kinase ubiquitously expressed and involved in many cellular signaling pathways, plays a key role in the pathogenesis of Alzheimer's disease (AD) being probably the link betweenβ-amyloid and tau pathology. A great effort has recently been done in the discovery and development of different new molecules, of synthetic and natural origin, able to inhibit this enzyme, and several kinetics mechanisms of binding have been described. The small molecule called tideglusib belonging to the thiadiazolidindione family is currently on phase IIb clinical trials for AD. The potential risks and benefits of this new kind of disease modifying drugs for the future therapy of AD are discussed in this paper.
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Lin, Chun-Hung Richard, Chun-Hao Wen, Ying-Chih Lin, Kuang-Yuan Tung, Rung-Wei Lin e Chun-Yuan Lin. "A P2P Framework for Developing Bioinformatics Applications in Dynamic Cloud Environments". International Journal of Genomics 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/361327.
Abstract (sommario):
Bioinformatics is advanced from in-house computing infrastructure to cloud computing for tackling the vast quantity of biological data. This advance enables large number of collaborative researches to share their works around the world. In view of that, retrieving biological data over the internet becomes more and more difficult because of the explosive growth and frequent changes. Various efforts have been made to address the problems of data discovery and delivery in the cloud framework, but most of them suffer the hindrance by a MapReduce master server to track all available data. In this paper, we propose an alternative approach, called PRKad, which exploits aPeer-to-Peer(P2P) model to achieve efficient data discovery and delivery. PRKad is a Kademlia-based implementation withRound-Trip-Time(RTT) as the associated key, and it locates data according toDistributed Hash Table(DHT) and XOR metric. The simulation results exhibit that our PRKad has the low link latency to retrieve data. As an interdisciplinary application of P2P computing for bioinformatics, PRKad also provides good scalability for servicing a greater number of users in dynamic cloud environments.
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Rajapaksha, Harindu, Dinesh R. Pandithavidana e Jayangika N. Dahanayake. "Demystifying Chronic Kidney Disease of Unknown Etiology (CKDu): Computational Interaction Analysis of Pesticides and Metabolites with Vital Renal Enzymes". Biomolecules 11, n. 2 (10 febbraio 2021): 261. http://dx.doi.org/10.3390/biom11020261.
Abstract (sommario):
Chronic kidney disease of unknown etiology (CKDu) has been recognized as a global non-communicable health issue. There are many proposed risk factors for CKDu and the exact reason is yet to be discovered. Understanding the inhibition or manipulation of vital renal enzymes by pesticides can play a key role in understanding the link between CKDu and pesticides. Even though it is very important to take metabolites into account when investigating the relationship between CKDu and pesticides, there is a lack of insight regarding the effects of pesticide metabolites towards CKDu. In this study, a computational approach was used to study the effects of pesticide metabolites on CKDu. Further, interactions of selected pesticides and their metabolites with renal enzymes were studied using molecular docking and molecular dynamics simulation studies. It was evident that some pesticides and metabolites have affinity to bind at the active site or at regulatory sites of considered renal enzymes. Another important discovery was the potential of some metabolites to have higher binding interactions with considered renal enzymes compared to the parent pesticides. These findings raise the question of whether pesticide metabolites may be a main risk factor towards CKDu.
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Clement, Bernd, e Michel A. Struwe. "The History of mARC". Molecules 28, n. 12 (12 giugno 2023): 4713. http://dx.doi.org/10.3390/molecules28124713.
Abstract (sommario):
The mitochondrial amidoxime-reducing component (mARC) is the most recently discovered molybdoenzyme in humans after sulfite oxidase, xanthine oxidase and aldehyde oxidase. Here, the timeline of mARC’s discovery is briefly described. The story begins with investigations into N-oxidation of pharmaceutical drugs and model compounds. Many compounds are N-oxidized extensively in vitro, but it turned out that a previously unknown enzyme catalyzes the retroreduction of the N-oxygenated products in vivo. After many years, the molybdoenzyme mARC could finally be isolated and identified in 2006. mARC is an important drug-metabolizing enzyme and N-reduction by mARC has been exploited very successfully for prodrug strategies, that allow oral administration of otherwise poorly bioavailable therapeutic drugs. Recently, it was demonstrated that mARC is a key factor in lipid metabolism and likely involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). The exact link between mARC and lipid metabolism is not yet fully understood. Regardless, many now consider mARC a potential drug target for the prevention or treatment of liver diseases. This article focusses on discoveries related to mammalian mARC enzymes. mARC homologues have been studied in algae, plants and bacteria. These will not be discussed extensively here.
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Liu, Wei, Beverley Sparks e Alexandra Coghlan. "Fun, inspiration and discovery: from momentary experiences to overall evaluations". International Journal of Contemporary Hospitality Management 29, n. 7 (10 luglio 2017): 1937–55. http://dx.doi.org/10.1108/ijchm-12-2015-0735.
Abstract (sommario):
Purpose This paper aims to use a concurrent mixed method approach to explore the key variables that can influence customer experience at a food and wine event. Design/methodology/approach A concurrent mixed methods approach, using a participant-generated image (PGI) method, together with a recall survey, provided images with associated narratives, descriptive statistics, correlations and hierarchical multiple regression analysis to explore how attendees appraise their experiences based on their goals and the link between experience appraisals and overall evaluations. Findings Through the PGI method (N = 25), the authors determined that customer experience at the event could be viewed as a hierarchical model, comprising a fundamental sensory experience together with three higher-order customer experience components (fun, discovery and inspiration). A separate concurrent recall study (N = 598) demonstrated the relationship between the same four customer experience components and overall satisfaction as well as recommendation and repeat visitation. Practical implications The results suggest that to promote positive customer experiences, along with the product of the event itself, event managers should focus on activity programs that are fun, inspirational and novel, as well as sensory. Originality/value This study focuses on a single case study of an event to examine and extend our understanding of customer experience. The use of a concurrent mixed methods approach provides us with different types of data from two separate samples of participants. By integrating data from each study the authors are able to build a conceptual model of the salient dimensions of customer experience and then quantitatively analyze how these salient dimensions are related to outcome variables.
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Vuckovic, Biljana, e Mirjana Djeric. "Lipoprotein (a): A link between thrombogenesis and atherogenesis". Medical review 60, n. 1-2 (2007): 37–41. http://dx.doi.org/10.2298/mpns0702037v.
Abstract (sommario):
Introduction It is well known that numerous mechanisms of thrombogenesis can participate in every stage of atherosclerotic disease. The discovery of Lp(a) lipoprotein and its structural similarity with plasminogen suggests another pathogenic link between atherogenesis and thrombogenesis. Some characteristics of Lp(a) lipoprotein This lipoprotein is present in the whole human population in a wide range of plasma concentrations. It has numerous different isoforms. Its synthesis occurs in the liver, but it is practically metabolically independent from other lipoproteins. Today, Lp(a) lipoprotein is considered to be an independent risk factor for heart and brain ischemic disease. Fibrinolytic mechanisms The primary role of the fibrinolytic mechanism is to prevent thrombus formation during circulation and to remove already formed ones. Plasmin has a central role in this process, due to the inactive proenzyme plasminogen. Its basic activators are tissue-type plasminogen activator (t-PA) and urokinase plasminogen activator (u-PA). The most important inhibitors of plasminogen are alpha2-antiplasmin and plasminogen activator inhibitors 1 and 2 (PAI-1 and PAI-2). Structural similarity of Lp(a) and plasminogen The apo(a) and plasminogen genes are very closely linked on the long arm of chromosome 6. Because of that they are structuraly very similar and they have a cross immunological reactivity. Their common elements are so-called "kringle" structures. The key difference in structure of Lp(a) and plasminogen is replacement of Arg with Ser at position 560. This prevents splitting of apo(a) by plasminogen activators. Lp(a) and fibrinolysis Lp(a) lipoprotein inhibits activation of plasminogen by streptokinase. It is also a competitive inhibitor of plasminogen for its binding to plasminogen receptors. Furthermore, it successfully achieves competitive inhibition of plasminogen for binding to tetranectin and thrombospondin. Also, Lp(a) inhibits activation of transforming growth factor alpha (TGF-alpha). It positively correlates with PAI-1 and it is assumed that it promotes release of tissue factor pathway inhibitor (TFPI) from endothelial cell surfaces. Conclusion In regulation of the hemostatic system via apolipoprotein(a) antifibrinolytic effects, Lp(a) lipoprotein offers a molecular solution to the link between thrombogenesis and atherogenesis.
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Bayfield, Michael, Lauren Kark e Tracie J. Barber. "Development of a Kinematic Model of a Proto-Wing". Applied Mechanics and Materials 553 (maggio 2014): 261–66. http://dx.doi.org/10.4028/www.scientific.net/amm.553.261.
Abstract (sommario):
Since the discovery of Archaeopteryx, various theories have been suggested to explain the evolutionary link between reptilian dinosaurs and avian species and therefore the evolution of flight. Often these theories focus on the potential use for early wings, which are not yet developed enough for flight. Understanding the purpose of these ‘proto-wings’ is considered key to revealing the driving force behind avian evolution. A computerised, musculoskeletal model of a proto-wing was developed and used to analyse a simplified motion that is theoretically typical of proto-wings. Through biomechanical analysis we can infer if this could be feasibly made, what forces are significant in making such a motion and how kinematically and kinetically sound the simulation is. As such, the proto-wing model is a significant analytical tool for understanding pre-flight kinematics.
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Zayed, Ahmed A., James M. Wainaina, Guillermo Dominguez-Huerta, Eric Pelletier, Jiarong Guo, Mohamed Mohssen, Funing Tian et al. "Cryptic and abundant marine viruses at the evolutionary origins of Earth’s RNA virome". Science 376, n. 6589 (8 aprile 2022): 156–62. http://dx.doi.org/10.1126/science.abm5847.
Abstract (sommario):
Whereas DNA viruses are known to be abundant, diverse, and commonly key ecosystem players, RNA viruses are insufficiently studied outside disease settings. In this study, we analyzed ≈28 terabases of Global Ocean RNA sequences to expand Earth’s RNA virus catalogs and their taxonomy, investigate their evolutionary origins, and assess their marine biogeography from pole to pole. Using new approaches to optimize discovery and classification, we identified RNA viruses that necessitate substantive revisions of taxonomy (doubling phyla and adding >50% new classes) and evolutionary understanding. “Species”-rank abundance determination revealed that viruses of the new phyla “ Taraviricota ,” a missing link in early RNA virus evolution, and “ Arctiviricota ” are widespread and dominant in the oceans. These efforts provide foundational knowledge critical to integrating RNA viruses into ecological and epidemiological models.
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SEEMAN, OWEN D., MARIA MINOR, MICHELLE R. BAKER e DAVID EVANS WALTER. "A revision of the Heatherellidae (Parasitiformes: Mesostigmata) with a new genus and two new species from Australasia". Zootaxa 4434, n. 3 (18 giugno 2018): 441. http://dx.doi.org/10.11646/zootaxa.4434.3.3.
Abstract (sommario):
The discovery of a new genus of Heatherellidae in New Zealand has led us to revise this enigmatic family and its constituent genera. Aheatherella n. gen., based on A. mira n. sp. from the North Island of New Zealand, lacks some of the derived character states that link the Australian Heatherella, most notably the lack of sexual dimorphism in the dorsal shields and in the presence of peritremes in adult Aheatherella. Heatherella osleri n. sp. is described from New South Wales, extending the distribution of this genus beyond Queensland. New collection records of H. callimaulos and a key to the genera and species of the family are provided. We propose that the Heatherellidae—previously placed in its own cohort outside the Gamasina—are best considered a superfamily of gamasine mites within the subcohort Epicriiae.
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Martellucci, Stefano, Costantino Santacroce, Francesca Santilli, Valeria Manganelli, Maurizio Sorice e Vincenzo Mattei. "Prion Protein in Stem Cells: A Lipid Raft Component Involved in the Cellular Differentiation Process". International Journal of Molecular Sciences 21, n. 11 (11 giugno 2020): 4168. http://dx.doi.org/10.3390/ijms21114168.
Abstract (sommario):
The prion protein (PrP) is an enigmatic molecule with a pleiotropic effect on different cell types; it is localized stably in lipid raft microdomains and it is able to recruit downstream signal transduction pathways by its interaction with various biochemical partners. Since its discovery, this lipid raft component has been involved in several functions, although most of the publications focused on the pathological role of the protein. Recent studies report a key role of cellular prion protein (PrPC) in physiological processes, including cellular differentiation. Indeed, the PrPC, whose expression is modulated according to the cell differentiation degree, appears to be part of the multimolecular signaling pathways of the neuronal differentiation process. In this review, we aim to summarize the main findings that report the link between PrPC and stem cells.
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Sisto, Margherita, Domenico Ribatti e Sabrina Lisi. "ADAM 17 and Epithelial-to-Mesenchymal Transition: The Evolving Story and Its Link to Fibrosis and Cancer". Journal of Clinical Medicine 10, n. 15 (29 luglio 2021): 3373. http://dx.doi.org/10.3390/jcm10153373.
Abstract (sommario):
For decades, metalloproteinase 17 (ADAM17) has been the goal of wide investigation. Since its discovery as the tumour necrosis factor-α convertase, it has been studied as the main drug target, especially in the context of inflammatory conditions and tumour. In fact, evidence is mounting to support a key role of ADAM17 in the induction of the proliferation, migration and progression of tumour cells and the trigger of the pro-fibrotic process during chronic inflammatory conditions; this occurs, probably, through the activation of epithelial-to-mesenchymal transition (EMT). EMT is a central morphologic conversion that occurs in adults during wound healing, tumour progression and organ fibrosis. EMT is characterised by the disassembly of cell–cell contacts, remodelling of the actin cytoskeleton and separation of cells, and generates fibroblast-like cells that express mesenchymal markers and have migratory properties. This transition is characterised by loss of epithelial proteins such as E-cadherin and the acquisition of new mesenchymal markers, including vimentin and a-smooth muscle actin. The present review discusses the current understanding of molecular mechanisms involved in ADAM17-dependent EMT in order to individuate innovative therapeutic strategies using ADAM17-related pathways.
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Efeyan, Alejo, e David M. Sabatini. "Nutrients and growth factors in mTORC1 activation". Biochemical Society Transactions 41, n. 4 (18 luglio 2013): 902–5. http://dx.doi.org/10.1042/bst20130063.
Abstract (sommario):
Growth factors and nutrients regulate the mTORC1 [mammalian (or mechanistic) target of rapamycin complex 1] by different mechanisms. The players that link growth factors and mTORC1 activation have been known for several years and mouse models have validated its relevance for human physiology and disease. In contrast with the picture for growth factor signalling, the means by which nutrient availability leads to mTORC1 activation have remained elusive until recently, with the discovery of the Rag GTPases upstream of mTORC1. The Rag GTPases recruit mTORC1 to the outer lysosomal surface, where growth factor signalling and nutrient signalling converge on mTORC1 activation. A mouse model of constitutive RagA activity has revealed qualitative differences between growth-factor- and nutrient-dependent regulation of mTORC1. Regulation of mTORC1 activity by the Rag GTPases in vivo is key for enduring early neonatal starvation, showing its importance for mammalian physiology.
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Triggle, Chris R., Andrew Howarth, Zhong Jian Cheng e Hong Ding. "Twenty-five years since the discovery of endothelium-derived relaxing factor (EDRF): does a dysfunctional endothelium contribute to the development of type 2 diabetes?" Canadian Journal of Physiology and Pharmacology 83, n. 8-9 (1 agosto 2005): 681–700. http://dx.doi.org/10.1139/y05-069.
Abstract (sommario):
Twenty-five years ago, the discovery of endothelium-derived relaxing factor opened a door that revealed a new and exciting role for the endothelium in the regulation of blood flow and led to the discovery that nitric oxide (NO) multi-tasked as a novel cell-signalling molecule. During the next 25 years, our understanding of both the importance of the endothelium as well as NO has greatly expanded. No longer simply a barrier between the blood and vascular smooth muscle, the endothelium is now recognized as a complex tissue with heterogeneous properties. The endothelium is the source of not only NO but also numerous vasoactive molecules and signalling pathways, some of which are still not fully characterized such as the putative endothelium-derived relaxing factor. Dysfunction of the endothelium is a key risk factor for the development of macro- and microvascular disease and, by coincidence, the discovery that NO was generated in the endothelium corresponds approximately in time with the increased incidence of type 2 diabetes. Primarily linked to dietary and lifestyle changes, we are now facing a global pandemic of type 2 diabetes. Characterized by insulin resistance and hyperglycaemia, type 2 diabetes is increasingly being diagnosed in adolescents as well as children. Is there a link between dietary-related hyperglycaemic insults to the endothelium, blood flow changes, and the development of insulin resistance? This review explores the evidence for and against this hypothesis.Key words: diabetes, endothelium, hyperglycaemia, insulin, nitric oxide, oxidative stress.
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Lu, WeiPing, DeCai Huo e Sibo Jia. "Analysis of Key Factors of College Students’ Ideological and Political Education Based on Complex Network". Journal of Sensors 2022 (28 luglio 2022): 1–10. http://dx.doi.org/10.1155/2022/6577878.
Abstract (sommario):
Rapid updating and complex network means bringing more development opportunities for the education industry. As for ideological classes and political science at colleges and universities, how to use sophisticated online technology to educate and educate ideological and political classes and improve the formation of ideological and political classes has been a complex theory in the education industry in recent years. Complex network is an abstract representation of complex systems in the real world, with broad research value and application prospects, and has many advantages in complex network research, with interpretability, expression ability, generalization ability, flexibility, etc., and has been used in various network analysis tasks, such as community discovery, link prediction, network representation, and political learning. The second part of this article focuses on (1) the concept of ideological education, (2) the advantages of ideological education, (3) the contradiction of the mode of ideological education, and (4) how to innovate ideological education. The third part proposes the basic characteristics and models of complex networks and proposes the emergence of fractal structures. The fourth part analyzes complex network models in detail and compares the number of points and sides of the real network with the respective irregular networks, indicating that the real world is not fully defined or completely irregular, and that the real network has the nature of a small world and a high-quality cluster. The key factors of complex networks applied propose theoretical and political education and ultimately influence theoretical and political teachers and students in the complex networks examined through empirical questionnaires. He proposes that large universities should be able to use a network environment to promote ideological and political education.
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Lek, Angela, Yuanfan Zhang, Keryn G. Woodman, Shushu Huang, Alec M. DeSimone, Justin Cohen, Vincent Ho et al. "Applying genome-wide CRISPR-Cas9 screens for therapeutic discovery in facioscapulohumeral muscular dystrophy". Science Translational Medicine 12, n. 536 (25 marzo 2020): eaay0271. http://dx.doi.org/10.1126/scitranslmed.aay0271.
Abstract (sommario):
The emergence of CRISPR-Cas9 gene-editing technologies and genome-wide CRISPR-Cas9 libraries enables efficient unbiased genetic screening that can accelerate the process of therapeutic discovery for genetic disorders. Here, we demonstrate the utility of a genome-wide CRISPR-Cas9 loss-of-function library to identify therapeutic targets for facioscapulohumeral muscular dystrophy (FSHD), a genetically complex type of muscular dystrophy for which there is currently no treatment. In FSHD, both genetic and epigenetic changes lead to misexpression of DUX4, the FSHD causal gene that encodes the highly cytotoxic DUX4 protein. We performed a genome-wide CRISPR-Cas9 screen to identify genes whose loss-of-function conferred survival when DUX4 was expressed in muscle cells. Genes emerging from our screen illuminated a pathogenic link to the cellular hypoxia response, which was revealed to be the main driver of DUX4-induced cell death. Application of hypoxia signaling inhibitors resulted in increased DUX4 protein turnover and subsequent reduction of the cellular hypoxia response and cell death. In addition, these compounds proved successful in reducing FSHD disease biomarkers in patient myogenic lines, as well as improving structural and functional properties in two zebrafish models of FSHD. Our genome-wide perturbation of pathways affecting DUX4 expression has provided insight into key drivers of DUX4-induced pathogenesis and has identified existing compounds with potential therapeutic benefit for FSHD. Our experimental approach presents an accelerated paradigm toward mechanistic understanding and therapeutic discovery of a complex genetic disease, which may be translatable to other diseases with well-established phenotypic selection assays.
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Quatto, Piero, Nicolò Margaritella, Isa Costantini, Francesca Baglio, Massimo Garegnani, Raffaello Nemni e Luigi Pugnetti. "Brain networks construction using Bayes FDR and average power function". Statistical Methods in Medical Research 29, n. 3 (14 maggio 2019): 866–78. http://dx.doi.org/10.1177/0962280219844288.
Abstract (sommario):
Brain functional connectivity is a widely investigated topic in neuroscience. In recent years, the study of brain connectivity has been largely aided by graph theory. The link between time series recorded at multiple locations in the brain and the construction of a graph is usually an adjacency matrix. The latter converts a measure of the connectivity between two time series, typically a correlation coefficient, into a binary choice on whether the two brain locations are functionally connected or not. As a result, the choice of a threshold τ over the correlation coefficient is key. In the present work, we propose a multiple testing approach to the choice of τ that uses the Bayes false discovery rate and a new estimator of the statistical power called average power function to balance the two types of statistical error. We show that the proposed average power function estimator behaves well both in case of independence and weak dependence of the tests and it is reliable under several simulated dependence conditions. Moreover, we propose a robust method for the choice of τ using the 5% and 95% percentiles of the average power function and False Discovery Rate bootstrap distributions, respectively, to improve stability. We applied our approach to functional magnetic resonance imaging and high density electroencephalogram data.
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Thornicroft, G., H. Lempp e M. Tansella. "The place of implementation science in the translational medicine continuum". Psychological Medicine 41, n. 10 (15 febbraio 2011): 2015–21. http://dx.doi.org/10.1017/s0033291711000109.
Abstract (sommario):
There is a growing consensus that the transfer of knowledge from biomedical discoveries into patient and public benefit should be accelerated. At the same time there is a persistent lack of conceptual clarity about the precise nature of the phases of the translational continuum necessary to implement this. In this paper, we: (i) propose an integrated schema to understand the five sequential phases that link basic biomedical research with clinical science and implementation; (ii) discuss the nature of three blocks along this translational pathway; (iii) outline key issues that need to be addressed in removing such barriers. The five research phases described are: (0) basic science discovery; (1) early human studies; (2) early clinical trials; (3) late clinical trials; (4) implementation (which includes adoption in principle, early implementation and persistence of implementation). This schema also sets out three points at which communication blocks can occur. The application of ‘implementation science’ is in its early stages within mental health and psychiatric research. This paper therefore aims to develop a consistent terminology to understand the discovery, development, dissemination and implementation of new interventions. By better understanding the factors that promote or delay knowledge to flow across these blocks, we can accelerate progression along translational medicine pathways and so realize earlier patient benefit.
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Haid, Robin Thomas Ulrich, e Andreas Reichel. "A Mechanistic Pharmacodynamic Modeling Framework for the Assessment and Optimization of Proteolysis Targeting Chimeras (PROTACs)". Pharmaceutics 15, n. 1 (5 gennaio 2023): 195. http://dx.doi.org/10.3390/pharmaceutics15010195.
Abstract (sommario):
The field of targeted protein degradation is growing exponentially. Yet, there is an unmet need for pharmacokinetic/pharmacodynamic models that provide mechanistic insights, while also being practically useful in a drug discovery setting. Therefore, we have developed a comprehensive modeling framework which can be applied to experimental data from routine projects to: (1) assess PROTACs based on accurate degradation metrics, (2) guide compound optimization of the most critical parameters, and (3) link degradation to downstream pharmacodynamic effects. The presented framework contains a number of first-time features: (1) a mechanistic model to fit the hook effect in the PROTAC concentration-degradation profile, (2) quantification of the role of target occupancy in the PROTAC mechanism of action and (3) deconvolution of the effects of target degradation and target inhibition by PROTACs on the overall pharmacodynamic response. To illustrate applicability and to build confidence, we have employed these three models to analyze exemplary data on various compounds from different projects and targets. The presented framework allows researchers to tailor their experimental work and to arrive at a better understanding of their results, ultimately leading to more successful PROTAC discovery. While the focus here lies on in vitro pharmacology experiments, key implications for in vivo studies are also discussed.
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Veres, Patrick R., J. Andrew Neuman, Timothy H. Bertram, Emmanuel Assaf, Glenn M. Wolfe, Christina J. Williamson, Bernadett Weinzierl et al. "Global airborne sampling reveals a previously unobserved dimethyl sulfide oxidation mechanism in the marine atmosphere". Proceedings of the National Academy of Sciences 117, n. 9 (18 febbraio 2020): 4505–10. http://dx.doi.org/10.1073/pnas.1919344117.
Abstract (sommario):
Dimethyl sulfide (DMS), emitted from the oceans, is the most abundant biological source of sulfur to the marine atmosphere. Atmospheric DMS is oxidized to condensable products that form secondary aerosols that affect Earth’s radiative balance by scattering solar radiation and serving as cloud condensation nuclei. We report the atmospheric discovery of a previously unquantified DMS oxidation product, hydroperoxymethyl thioformate (HPMTF, HOOCH2SCHO), identified through global-scale airborne observations that demonstrate it to be a major reservoir of marine sulfur. Observationally constrained model results show that more than 30% of oceanic DMS emitted to the atmosphere forms HPMTF. Coincident particle measurements suggest a strong link between HPMTF concentration and new particle formation and growth. Analyses of these observations show that HPMTF chemistry must be included in atmospheric models to improve representation of key linkages between the biogeochemistry of the ocean, marine aerosol formation and growth, and their combined effects on climate.
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da Cruz Lopes da Rosa, Judson, Cristina de Oliveira Dias, Eduardo Suárez-Morales, Laura Isabel Weber e Luciano Gomes Fischer. "Record of Caromiobenella (Copepoda, Monstrilloida) in Brazil and Discovery of the Male of C. brasiliensis: Morphological and Molecular Evidence". Diversity 13, n. 6 (31 maggio 2021): 241. http://dx.doi.org/10.3390/d13060241.
Abstract (sommario):
Monstrilloid copepods are protelean parasites with a complex life cycle that includes an endoparasitic juvenile phase and free-living early naupliar and adult phases. The monstrilloid copepod genus Caromiobenella Jeon, Lee and Soh, 2018 is known to contain nine species, each one with a limited distribution; except for two species, members of this widespread genus are known exclusively from males. Hitherto, members of Caromiobenella have not been recorded from tropical waters of the South Western Atlantic (SWA). The nominal species Monstrilla brasiliensis Dias and Suárez-Morales, 2000 was originally described from female specimens collected in coastal waters of Espírito Santo and Rio de Janeiro (Brazil), but the male remained unknown. The failure to reliably link both sexes of monstrilloid species is one of the main problems in the current taxonomy of the group, thus leading to a separate treatment for each sex. New zooplankton collections in coastal waters and intertidal rocky pools of the SWA yielded several male and female monstrilloid copepods tentatively identified as Monstrilla brasiliensis. Our results of both morphologic and molecular (mtCOI) analyses allowed us to confirm that these males and females were conspecific. We also found evidence suggesting that Caromiobenella is not a monophyletic taxon. Our male specimens are morphologically assignable to Caromiobenella, therefore, females of the nominal species Monstrilla brasiliensis, are matched here with the aforementioned males and, thus, the species should be known as C. brasiliensis comb. nov. (Dias and Suárez-Morales, 2000). This finding represents the third documented discovery of a female of Caromiobenella, the first record of the genus in the Southwestern Atlantic, and the first documented record of monstrilloids from coastal tidepools. With the addition of C. brasiliensis, Caromiobenella now includes 10 valid species worldwide. This work represents the second successful use of molecular methods to link both sexes of a monstrilloid copepod. The male of C. brasiliensis is herein described, and a key to the known species of Caromiobenella and data on the habitat and local abundance of C. brasiliensis are also provided.
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Chen, Xi, Yue Chen, Arun Sangaiah, Shouxi Luo e Hongfang Yu. "MonLink: Piggyback Status Monitoring over LLDP in Software-Defined Energy Internet". Energies 12, n. 6 (25 marzo 2019): 1147. http://dx.doi.org/10.3390/en12061147.
Abstract (sommario):
While software-defined networking (SDN) has been widely applied in various networking domains including datacenters, WANs (Wide Area Networks), QoS (Quality of Service) provisioning, service function chaining, etc., it also has foreseeable applications in energy internet (EI), which envisions an intelligent energy industry on the basis of (information) internet. Global awareness provided by SDN is especially useful in system monitoring in EI to achieve optimal energy transportation, sharing, etc. Link layer discovery protocol (LLDP) plays a key role in global topology discovery in software-defined energy internet when SDN is applied. Nevertheless, EI-related status information (power loads, etc.) is not collected during the LLDP-based topology discovery process initiated by the SDN controller, which makes the optimal decision making (e.g., efficient energy transportation and sharing) difficult. This paper proposes MonLink, a piggyback status-monitoring scheme over LLDP in software-defined energy internet with SDN-equipped control plane and data plane. MonLink extends the original LLDP by introducing metric type/length/value (TLV) fields so as to collect status information and conduct status monitoring in a piggyback fashion over LLDP during topology discovery simultaneously without the introduction of any newly designed dedicated status monitoring protocol. Several operation modes are derived for MonLink, namely, periodic MonLink, which operates based on periodic timeouts, proactive MonLink, which operates based on explicit API invocations, and adaptive MonLink, which operates sensitively and self-adaptively to status changes. Various northbound APIs are also designed so that upper layer network applications can make full use of the status monitoring facility provided by MonLink. Experiment results indicate that MonLink is a lightweight protocol capable of efficient monitoring of topological and status information with very low traffic overhead, compared with other network monitoring schemes such as sFlow.
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Babic, Ivan, e Elmar Nurmemmedov. "Abstract 3545: Atlas of therapeutic targets: Evolution of druggable proteome". Cancer Research 84, n. 6_Supplement (22 marzo 2024): 3545. http://dx.doi.org/10.1158/1538-7445.am2024-3545.
Abstract (sommario):
Abstract Selection of therapeutic targets and modalities is of fundamental importance in drug discovery, as it can have a direct impact on the economics of drug discovery as well as its success rate. With the advancement of chem-bio and proteomics methods together with advent of artificial intelligence, the scope of the druggable proteome is expanding. The choice of drug targets gains further importance as we link it to potential clinical efficacy and safety, genetic variation and patient populations. Drug targets are often selected based on inadequate understanding of target biology, tractability by existing toolbox of therapeutic modalities and insufficient insight into possible clinical outcome. We have developed an “Atlas of Therapeutic Targets”, an interactive resource that provides classification of drug target families with linked information on clinical and investigational drugs. The atlas also provides key insights and score for tractability of targets with various therapeutic modalities. Particularly, our scoring system grades the targets on dimensions such as ligandability, involvement in protein-protein complexes, structural disorder, hotspot analysis and cross-referencing with known targets, thus yielding a total tractability score of 1-10. Dissection of targets based on such dimensions, enables critical evaluation therapeutic modalities as well tools and methodologies needed for their conversion into successful drug discovery programs. We curate 900+ human drug targets, analysis of which indicates the continued dominance of privileged target families across disease areas, but also the growth of novel first-in-class mechanisms. This atlas will be available as a resource for the wide drug discovery community. Citation Format: Ivan Babic, Elmar Nurmemmedov. Atlas of therapeutic targets: Evolution of druggable proteome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3545.
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Jaakkola, Elina, e Harri Terho. "Service journey quality: conceptualization, measurement and customer outcomes". Journal of Service Management 32, n. 6 (4 maggio 2021): 1–27. http://dx.doi.org/10.1108/josm-06-2020-0233.
Abstract (sommario):
PurposeThe quality of the customer journey has become a critical determinant of successful service delivery in contemporary business. Extant journey research focuses on the customer path to purchase, but pays less attention to the touchpoints related to service delivery and consumption that are key for understanding customer experiences in service-intensive contexts. The purpose of this study is to conceptualize service journey quality (SJQ), develop measures for the construct and study its key outcomes.Design/methodology/approachThe study uses a discovery-oriented research approach to conceptualize SJQ by synthesizing theory and field-based insights from customer focus group discussions. Next, using consumer survey data (N = 278) from the financial services context, the authors develop measures for the SJQ. Finally, based on an additional survey dataset (N = 239), the authors test the nomological validity and predictive relevance of the SJQ.FindingsSJQ comprises of three dimensions: (1) journey seamlessness, (2) journey personalization and (3) journey coherence. This study demonstrates that SJQ is a critical driver of service quality and customer loyalty in contemporary business. This study finds that the loyalty link is partially mediated through service quality, indicating that SJQ explains loyalty above and beyond service quality.Research limitations/implicationsSince service quality only partially mediates the link between service journey quality and customer loyalty, future studies should examine alternative mediators, such as customer experience, for a more comprehensive understanding of the performance effects.Practical implicationsThe study offers concrete tools for service managers who wish to understand and develop the quality of service journeys.Originality/valueThis study advances the service journey concept, demonstrates that the quality of the service journey is a critical driver of customer performance and provides rigorous journey constructs for future service research.
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Hobbs, Joanne K., Seunghyae M. Lee, Melissa Robb, Fraser Hof, Christopher Barr, Kento T. Abe, Jan-Hendrik Hehemann, Richard McLean, D. Wade Abbott e Alisdair B. Boraston. "KdgF, the missing link in the microbial metabolism of uronate sugars from pectin and alginate". Proceedings of the National Academy of Sciences 113, n. 22 (16 maggio 2016): 6188–93. http://dx.doi.org/10.1073/pnas.1524214113.
Abstract (sommario):
Uronates are charged sugars that form the basis of two abundant sources of biomass—pectin and alginate—found in the cell walls of terrestrial plants and marine algae, respectively. These polysaccharides represent an important source of carbon to those organisms with the machinery to degrade them. The microbial pathways of pectin and alginate metabolism are well studied and essentially parallel; in both cases, unsaturated monouronates are produced and processed into the key metabolite 2-keto-3-deoxygluconate (KDG). The enzymes required to catalyze each step have been identified within pectinolytic and alginolytic microbes; yet the function of a small ORF,kdgF, which cooccurs with the genes for these enzymes, is unknown. Here we show that KdgF catalyzes the conversion of pectin- and alginate-derived 4,5-unsaturated monouronates to linear ketonized forms, a step in uronate metabolism that was previously thought to occur spontaneously. Using enzyme assays, NMR, mutagenesis, and deletion ofkdgF,we show that KdgF proteins from both pectinolytic and alginolytic bacteria catalyze the ketonization of unsaturated monouronates and contribute to efficient production of KDG. We also report the X-ray crystal structures of two KdgF proteins and propose a mechanism for catalysis. The discovery of the function of KdgF fills a 50-y-old gap in the knowledge of uronate metabolism. Our findings have implications not only for the understanding of an important metabolic pathway, but also the role of pectinolysis in plant-pathogen virulence and the growing interest in the use of pectin and alginate as feedstocks for biofuel production.
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Wong, Lok-Sze, e Chun-Ming Wong. "Decoding the Roles of Long Noncoding RNAs in Hepatocellular Carcinoma". International Journal of Molecular Sciences 22, n. 6 (19 marzo 2021): 3137. http://dx.doi.org/10.3390/ijms22063137.
Abstract (sommario):
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide. HCC is associated with several etiological factors, including HBV/HCV infections, cirrhosis, and fatty liver diseases. However, the molecular mechanism underlying HCC development remains largely elusive. The advent of high-throughput sequencing has unveiled an unprecedented discovery of a plethora of long noncoding RNAs (lncRNAs). Despite the lack of coding capacity, lncRNAs have key roles in gene regulation through interacting with various biomolecules. It is increasingly evident that the dysregulation of lncRNAs is inextricably linked to HCC cancer phenotypes, suggesting that lncRNAs are potential prognostic markers and therapeutic targets. In light of the emerging research in the study of the regulatory roles of lncRNAs in HCC, we discuss the association of lncRNAs with HCC. We link the biological processes influenced by lncRNAs to cancer hallmarks in HCC and describe the associated functional mechanisms. This review sheds light on future research directions, including the potential therapeutic applications of lncRNAs.