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Shokurov, V. V. "3-FOLD LOG FLIPS." Russian Academy of Sciences. Izvestiya Mathematics 40, no. 1 (February 28, 1993): 95–202. http://dx.doi.org/10.1070/im1993v040n01abeh001862.
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Shokurov, V. V. "SEMISTABLE 3-FOLD FLIPS." Russian Academy of Sciences. Izvestiya Mathematics 42, no. 2 (April 30, 1994): 371–425. http://dx.doi.org/10.1070/im1994v042n02abeh001541.
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Seal, Sudeshna, Daniella B. Kerbauy, Vladimir Lesnikov, Nissa Abbasi-Shafer, and H. Joachim Deeg. "FLIPLong(L) and FLIPShort(S) Overexpression in the Human Myeloid Leukemia Cell Line ML-1 and Its Role in TRAIL [Tumor Necrosis Factor(TNF)-Related Apoptosis-Inducing Ligand] and TNFa Induced Apoptosis." Blood 106, no. 11 (November 16, 2005): 4378. http://dx.doi.org/10.1182/blood.v106.11.4378.4378.
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Abstract TRAIL initiates activation of Caspase-8, which is blocked by the FLICE inhibitory protein (FLIP), resulting in resistance to apoptosis. Here we show that overexpression of FLIPL and FLIPS in ML1 cells, with low constitutive levels of FLIP, protects these cells against apoptosis induced by TRAIL, not only via Caspase-8 inhibition, but also via upregulation of anti-apoptotic molecules. Methods: 1) Apoptosis was determined by Annexin V/ 7-AAD following treatment with TRAIL (100–500ng/ml), or TNFa (20–100ng/ml) in ML1 cells transduced with FLIPL.GFP (green fluorescent protein), FLIPS.GFP or Neo.GFP (control). 2) Caspase-8, Caspase-3, Bid, Bcl-xL, XIAP, phosphorylated (P)-IKBa and P-Akt were determined by western blots. 3) Active Caspase-3 was determined using EnzChek Caspase-3 assay kit. Results: Both FLIPL and FLIPS transduction protected ML1 cells against apoptosis induced by TRAIL (300ng/ml), while no protection was observed in Neo.GFP cells. FLIPL had a more profound protective effect than FLIPS (Fig.1A). Both FLIPL and FLIPS, but not Neo.GFP, blocked Caspase-8 and Caspase-3 activation (Fig.1B); FLIPS cells showed two-fold higher levels of active Caspase-3 than FLIPL cells, consistent with higher apoptosis in FLIPS cells. Caspase-3 can be activated through Caspase-8 (extrinsic pathway) or via Caspase-8/Bid (intrinsic pathway). The latter was responsible for high active Caspase-3 levels in FLIPS cells as shown by the presence of cleaved Bid (t-Bid) (Fig.1B); cleavage of Bid was inhibited by combination of TRAIL and Z-IETD-FMK (Caspase-8 inhibitor). Anti-apoptotic molecules, including Bcl-xL, XIAP and FLIP are regulated by NF-kB and FLIP participates in an NF-kB auto-amplification loop. While Neo.GFP cells showed little Bcl-xL after 4h of TRAIL exposure and there was a twofold reduction in FLIPS cells, only a slight reduction of Bcl-xL was noted in FLIPL cells. FLIPL cells showed the lowest rates of apoptosis when exposed to TNFa and BMS543541, a specific inhibitor of IkB kinase (Fig. 1C). In the presence of BMS543541, phosphorylation of IkBa and levels of Bcl-xL and XIAP decreased in Neo.GFP and FLIPS but not in FLIPL cells. Additional data suggest that the PI3-kinase/Akt pathway is involved in constitutive NF-kB activation and differentially affected by FLIPL and FLIPS (Fig. 1D). Preliminary results in immunodeficient mice transplanted with transduced ML1 cells indicated the in vivo relevance of the differences between FLIPL and FLIPS with FLIPL cells engrafting earlier and showing earlier signs of sickness. Conclusions: FLIPL and FLIPS conferred resistance to TRAIL induced apoptosis but showed differential effects: Caspase-8/Bid was involved in the apoptosis pathway in FLIPS, but not in FLIPL cells. FLIPL cells’ resistance was due not only to caspase inhibition but to the recruitment of downstream anti-apoptotic pathways such as NF-kB and PI3K/Akt. In vivo data further substantiated the antiapoptotic/pro-survival behavior of FLIPL cells. Figure Figure
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Shokurov, V. V. "AN ADDENDUM TO THE PAPER “3-FOLD LOG FLIPS”." Russian Academy of Sciences. Izvestiya Mathematics 43, no. 3 (June 30, 1994): 527–58. http://dx.doi.org/10.1070/im1994v043n03abeh001579.
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WALDRON, JOE. "THE LMMP FOR LOG CANONICAL 3-FOLDS IN CHARACTERISTIC." Nagoya Mathematical Journal 230 (February 20, 2017): 48–71. http://dx.doi.org/10.1017/nmj.2017.2.
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We prove that one can run the log minimal model program for log canonical 3-fold pairs in characteristic $p>5$. In particular, we prove the cone theorem, contraction theorem, the existence of flips and the existence of log minimal models for pairs with log divisor numerically equivalent to an effective divisor. These follow from our main results, which are that certain log minimal models are good.
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Troeger, Anja, Ingo Schmitz, Ludmila Glouchkova, Meinolf Siepermann, Gritta Janka-Schaub, Klaus Schulze-Osthoff, and Dagmar Dilloo. "Upregulation of FLIPs upon CD40 Stimulation - A Novel Inhibititory Mechanism of CD95-Induced Apoptosis in Precursor B-ALL Blasts in Children." Blood 106, no. 11 (November 16, 2005): 855. http://dx.doi.org/10.1182/blood.v106.11.855.855.
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Abstract The influence of the microenvironment on the activation status and behaviour of ALL blasts is critical for interactions with the immune system in vivo. The capacity of B cells to respond to CD40-ligand (CD40L) stimulation is critical for their sensitisation to immunological control mechanisms and susceptibility to apoptotic signals. Primary precursor B-ALL blasts (BCP-ALL; n=32) lack CD95-expression (mean±SE; 4.2±0.6% positive cells) and are resistant to apoptosis while significant up-regulation of CD95 is apparent upon CD40-stimulation in BCP-ALL blasts that reaches a plateau after 72 h. Yet, in spite of equivalent CD95-upregulation in ALL blasts (58.3±6.5%; n=17) and normal B cells (59.3±13.1%) specific apoptosis is markedly lower in ALL compared to mature B cells (19.1±3% vs 36.7±5.5%). Resistance to apoptosis in ALL blasts and its reversibility after cycloheximid treatment suggest that anti-apoptotic mechanisms prevent induction of cell death via CD95 ligation in CD40 activated blasts. In accordance, in CD40-activated ALL blasts caspase 8 and 3 activity is not enhanced upon CD95 ligation in contrast to an 1.8±0.3 and 1.7±0.3 fold increase in caspase activity in stimulated normal B cells (n=7), suggesting a block of the apoptotic cascade in BCP-ALLrelatively close to the receptor level. CD40L-activated ALL blasts and normal B cells were submitted to western blot analysis with respect to the molecules associated to the death-inducing signalling complex (DISC). FADD and the zymogen form of caspase-8 are constitutively expressed in both malignant and non malignant B cells with no modulation following CD40 ligation. In contrast, the anti-apoptotic short isoform of the c-FLICE inhibitory protein FLIPS is weakly expressed in naïve blasts and B cells, but strongly up-regulated upon 72h CD40-ligation in ALL with only barely detectable levels in CD40-activated normal B cells. We therefore propose, that prolonged induction of the FLIPS expression inhibits the onset of apoptosis despite high CD95 surface expression levels in BCP-ALL blasts. As an additional anti-apoptotic mechanism inhibiting the downstream effector caspases we demonstrated significant upregulation of the inhibitor of apoptosis protein (IAP) survivin in CD40-activated BCP-ALL (n=6) compared to the unstimulated control (632pg/ml±200pg/ml vs 180pg/ml±52pg/ml). Thus, we identified FLIPS as a CD40-regulated upstream anti-apoptotic element and concomitant downstream upregulation of survivin protein expression as critical mechanisms contributing to blast cell resistance to apoptosis.
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Qin, Haixia, Michael A. Frohman, and Wendy B. Bollag. "Phospholipase D2 Mediates Acute Aldosterone Secretion in Response to Angiotensin II in Adrenal Glomerulosa Cells." Endocrinology 151, no. 5 (March 10, 2010): 2162–70. http://dx.doi.org/10.1210/en.2009-1159.
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In primary bovine adrenal glomerulosa cells, the signaling enzyme phospholipase D (PLD) is suggested to mediate priming, the enhancement of aldosterone secretion after pretreatment with and removal of angiotensin II (AngII), via the formation of persistently elevated diacylglycerol (DAG). To further explore PLD’s role in priming, glomerulosa cells were pretreated with an exogenous bacterial PLD. Using this approach, phosphatidic acid (PA) is generated on the outer, rather than the inner, leaflet of the plasma membrane. Although PA is not readily internalized, the PA is nonetheless rapidly hydrolyzed by cell-surface PA phosphatases to DAG, which efficiently flips to the inner leaflet and accesses the cell interior. Pretreatment with bacterial PLD resulted in priming upon subsequent AngII exposure, supporting a role of DAG in this process, because the increase in DAG persisted after exogenous PLD removal. To determine the PLD isoform mediating aldosterone secretion, and presumably priming, primary glomerulosa cells were infected with adenoviruses expressing GFP, PLD1, PLD2, or lipase-inactive mutants. Overexpressed PLD2 increased aldosterone secretion by approximately 3-fold over the GFP-infected control under basal conditions, with a significant enhancement to about 16-fold over the basal value upon AngII stimulation. PLD activity was also increased basally and upon stimulation with AngII. In contrast, PLD1 overexpression had little effect on aldosterone secretion, despite the fact that PLD activity was enhanced. In both cases, the lipase-inactive PLD mutants showed essentially no effect on PLD activity or aldosterone secretion. Our results suggest that PLD2 is the isoform that mediates aldosterone secretion and likely priming.
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Miyazono, Kenichi, Yoshikazu Furuta, Miki Watanabe-Matsui, Takuya Miyakawa, Tomoko Ito, Ichizo Kobayashi, and Masaru Tanokura. "Sequence-specific DNA glycosylase found in a restriction-modification system." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C213. http://dx.doi.org/10.1107/s2053273314097861.
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Restriction-modification systems consist of genes that encode a restriction enzyme and a cognate modification methyltransferase. It was believed that restriction enzymes are sequence-specific endonucleases that introduce double-strand breaks at specific sites by catalyzing the cleavages of phosphodiester bonds. R.PabI is a type II restriction enzyme from a hyperthermophilic archaea Pyrococcus abyssi that recognizes 5'-GTAC-3' sequence and cleaves DNA duplexes without the addition of a divalent cation. The structural and mutational analyses of R.PabI in our previous work showed that R.PabI forms a homodimer and has a novel DNA-binding fold called a "half-pipe," which consists of a highly curved anti-parallel β-sheet. Because the structure of R.PabI shares no structural similarity to any other protein, the structural basis of the sequence-recognition and DNA-cleavage mechanisms remained unclear. In this study, we report the crystal structure of R.PabI in complex with a DNA duplex containing the R.PabI recognition sequence. The structure of the R.PabI-DNA complex shows that R.PabI unwinds a DNA duplex at a 5'-GTAC-3' site and flips the guanine and adenine bases out of the DNA helix to recognize the sequence. The electron-density map of the R.PabI-DNA complex shows that R.PabI releases adenine bases from the R.PabI recognition sequence. Biochemical assays using HPLC and MALDI-TOF MS spectrometry also support the observation that R.PabI releases adenine bases by hydrolysis. These results show that R.PabI is not an endonuclease but a sequence-specific adenine DNA glycosylase. R.PabI is the first example of a restriction enzyme that shows DNA glycosylase activity. Mutational analysis reveals the active site of the adenine DNA glycosylase activity of R.PabI. The two opposing apurinic/apyrimidinic (AP) sites generated by R.PabI are cleaved by heat promoted β elimination and/or by endogenous AP endonucleases of host cells to introduce a double-strand break.
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Tan, GMY, SMAR Hosseini, A. Poudel, and AD Mclellan. "O6 Expression of anti-apoptotic gene cFLIP to enhance persistence in CAR T cells." Journal for ImmunoTherapy of Cancer 8, Suppl 2 (October 2020): A6.1—A6. http://dx.doi.org/10.1136/jitc-2020-itoc7.11.
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BackgroundCAR T cell therapy has been successful for targeting blood cancers, but treatment of solid cancers has been limited due to the heterogenous nature of tumour-associated antigen expression on solid cancers, and the suppressive tumour microenvironment.1 Another major obstacle to CAR T cell therapy is activation-induced cell death (AICD) of the CAR T cells.2 In this study, we expressed the anti-apoptotic cellular FLICE-like inhibitory protein (c-FLIP short; c-FLIPs) together with the CAR construct to enhance CAR T cell persistence.3Materials and MethodsThe anti-Her2 FRP5 CAR T construct with P2A-linked cFLIPs or cFLIPp43 was cloned into the Sleeping Beauty (SB) transposon vector (pSBtet-GP) or lentiviral vector, under the control of either a tet-on or a constitutive promoter. Construct expression was validated by qPCR and immunoblot analysis. CAR T cells were generated by SB transposition or lentiviral transduction of CD3/CD28 stimulated primary human T cells that were subsequently maintained with IL-2. Mitochondrial function and apoptosis were determined by resazurin assay and by flow cytometry using tetramethyl rhodamine (TMRE).ResultsOverexpression of cFLIP (cFLIPp43 and cFLIPs) in pSBtet-GP demonstrated protection in both Jurkat T cell line and primary human T cells. pSBtet-GP was modified to overexpress cFLIPs and cFLIPp43 under tet-on promoter, with the anti-her2 CAR, GFP and rtTA under constitutive promoter. Transfer of the inducible cassette from the SB transposon to a lentiviral system resulted in a significant loss of tightness. Doxycycline treated CAR T cells showed only ~13-fold overexpression of cFLIPs or cFLIPp43 compared to untreated cells, and doxycycline significantly inhibited (approximately 30%) primary CAR T cell expansion. In contrast, constitutive expression of CAR-cFLIPs or cFLIPp43 construct gave a >3 × 105-fold cFLIP overexpression, as compared to CAR-only control. While the transduction efficiency of CAR-only was around 70–80% control in primary T cells, this dropped to 20–25% when using the more genetically complex tet-on system.ConclusionscFLIP protects T cells from Fas-induced apoptosis. The tet-on system demonstrates several drawbacks in the lentiviral system, including toxicity of the inducer drug (and/or squelching effects resulting in lowered viability), loss of responsiveness and lowered transduction frequencies. Therefore, a constitutive promoter system is preferred in lentiviral systems for the control of genes of interest within CAR T cells, while the SB transposon system may be preferred for tet-on control within CAR T cells.ReferencesPitt JM, Marabelle A, Eggermont A, Soria JC, Kroemer G, and Zitvogel L. Targeting the tumor microenvironment: removing obstruction to anticancer immune responses and immunotherapy. Ann Oncol 2016;27:1482–1492.Yeku O, Li X, Brentjens RJ. Adoptive T-Cell Therapy for Solid Tumors. Am Soc Clin Oncol Educ Book 2017;37:193–204.Dohrman A, Kataoka T, Cuenin S, Russell JQ, Tschopp J, and Budd RC. Cellular FLIP (long form) regulates CD8+ T cell activation through caspase-8-dependent NF-kappa B activation. J Immunol 2005; 174:5270–5278.Disclosure InformationG.M.Y. Tan: None. S.M.A.R. Hosseini: None. A. Poudel: None. A.D. Mclellan: None.
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Donovan, Will, and Michael Wemyss. "Twists and braids for general 3-fold flops." Journal of the European Mathematical Society 21, no. 6 (February 1, 2019): 1641–701. http://dx.doi.org/10.4171/jems/868.
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KAWAMATA, YUJIRO. "TERMINATION OF LOG FLIPS FOR ALGEBRAIC 3-FOLDS." International Journal of Mathematics 03, no. 05 (October 1992): 653–59. http://dx.doi.org/10.1142/s0129167x92000308.
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BROWN, GAVIN. "Flips arising as quotients of hypersurfaces." Mathematical Proceedings of the Cambridge Philosophical Society 127, no. 1 (July 1999): 13–31. http://dx.doi.org/10.1017/s0305004198003351.
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Flips occur in the theory of minimal models of algebraic varieties. For an introduction and references see [1, lecture no. 5]. For varieties X− and X+, I denote the canonical class by K− and respectively. A flip is a diagram X−→X←X+ of normal complex quasiprojective 3-folds satisfying the conditions:1. both morphisms are birational and projective, contracting only finitely many curves C±⊂X± to an isolated singular point P∈X;2. the divisors −K− and K+ are relatively ample, that is, −K−Γ>0 for any curve Γ contracted by the morphism X−→X and similarly for K+;3. the two varieties X− and X+ have only terminal singularities.A diagram satisfying condition 1 is called a flip diagram. It is said to be directed by the canonical class if it also satisfies condition 2. Notice that condition 3 is overstated since under all the other conditions X+ will automatically have terminal singularities (see [4, 5-1-11(2)]).
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Jiang, Chen. "A gap theorem for minimal log discrepancies of noncanonical singularities in dimension three." Journal of Algebraic Geometry 30, no. 4 (June 9, 2021): 759–800. http://dx.doi.org/10.1090/jag/759.
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We show that there exists a positive real number δ > 0 \delta >0 such that for any normal quasi-projective Q \mathbb {Q} -Gorenstein 3 3 -fold X X , if X X has worse than canonical singularities, that is, the minimal log discrepancy of X X is less than 1 1 , then the minimal log discrepancy of X X is not greater than 1 − δ 1-\delta . As applications, we show that the set of all noncanonical klt Calabi–Yau 3 3 -folds are bounded modulo flops, and the global indices of all klt Calabi–Yau 3 3 -folds are bounded from above.
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Birkar, Caucher. "Existence of flips and minimal models for 3-folds in char $p$." Annales scientifiques de l'École normale supérieure 49, no. 1 (2016): 169–212. http://dx.doi.org/10.24033/asens.2279.
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Mwangala, Felix S., and Terry D. Galloway. "SUSCEPTIBILITY OF HORN FLIES, HAEMATOBIA IRRITANS (L.) (DIPTERA: MUSCIDAE), TO PYRETHROIDS IN MANITOBA." Canadian Entomologist 125, no. 1 (February 1993): 47–53. http://dx.doi.org/10.4039/ent12547-1.
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AbstractResistance of horn fly, Haematobia irritans (L.), to fenvalerate and permethrin was evaluated in Manitoba from 1987 to 1989. The number of resistant populations and the intensity of resistance increased during the period. In 1987, resistant flies were observed on three of 18 herds sampled. Resistance, determined by comparison with a susceptible strain at the LC50, was less than 6-fold for fenvalerate and 3-fold for permethrin except for one population whose resistance was 14-fold for permethrin. In 1988, resistant flies were observed on six of 26 herds sampled. Resistance ranged from 0.03- to 38-fold for fenvalerate and 0.1- to over 100-fold for permethrin. In 1989, resistant flies were found on 10 of 22 herds sampled. Resistance ranged from 1- to 62-fold for fenvalerate and 0.8- to over 100-fold for permethrin. Resistant populations were interspersed among susceptible ones.
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Donovan, Will. "Contractions of 3-folds: Deformations and invariants." International Journal of Mathematics 27, no. 07 (June 2016): 1640004. http://dx.doi.org/10.1142/s0129167x16400048.
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This paper discusses recent new approaches to studying flopping curves on 3-folds. In a joint paper [Noncommutative deformation and flops, Duke Math. J. 165(8) (2016) 1397–1414], the author and Wemyss introduced a 3-fold invariant, the contraction algebra, which may be associated to such curves. It characterizes their geometric and homological properties in a unified manner, using the theory of noncommutative deformations. Toda has now clarified the enumerative significance of the contraction algebra for flopping curves, calculating its dimension in terms of Gopakumar-Vafa invariants [Noncommutative width and Gopakumar–Vafa invariants, Manuscripta Math. 148(3–4) (2015) 521–533]. Before reviewing these results, and others, the author gives a brief introduction to the rich geometry of flopping curves on 3-folds, starting from the resolutions of Kleinian surface singularities. This is based on a talk given at VBAC 2014 in Berlin.
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Karki, Durga, Nikhil Mehta, and Ravi Prakash Narayan. "Post-burn axillary contracture: A therapeutic challenge!" Indian Journal of Plastic Surgery 47, no. 03 (September 2014): 375–80. http://dx.doi.org/10.4103/0970-0358.146594.
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ABSTRACT Background: Axillary post-burn scar contracture is a challenging problem to the reconstructive surgeon owing to the wide range of abduction that should be achieved. The aim of this paper was to highlight the various options used in managing axillary contractures in our hospital. Materials and Methods: This is a retrospective hospital-based study of axillary contractures managed at Safdarjung Hospital (a tertiary care hospital) from 2009 to 2013.The study consisted of 44 patients from all age group and both sex included in it. Patients with a bilateral axillary contracture were excluded. Axillary contracture was released and resurfaced using split skin graft and/or with different types of flaps including the propeller flap, parascapular flap. All the reconstructed cases were followed-up for a period of 12 months. Assessment was done on the basis of functional and aesthetic outcome. Results: Forty-four patients consisting of 25 males and 19 females presented with axillary contractures that involved 44 axillae. The mean age of the study group was 17.1 years. Injuries involved the anterior axillary fold in 8 (18.18%), posterior fold in ten (22.72%), both folds and axillary fossa in 14 (31.81%) and both folds plus part of the chest wall and arm (sparing the axillary fossa) in 12 (27.27%) axillae. Surgical treatment included split-thickness skin graft in 15 (34.1%), local skin flaps in 4 (9.1%), Z-plasties in 4 (9.1%), parascapular flaps in 3 (6.82%), while propeller flaps in 12 (27.27%) and square flap were used in 6 (13.64%) patients. The percentage of improvement in abduction had a mean of 156°. The functional and aesthetic results were satisfactory. Conclusion: The choice of surgical procedure for reconstruction of post-burn axillary contractures can be made according to the pattern of scar contracture and the state of the surrounding skin. The choice of a flap should have priority over the skin graft because of the superior functional and aesthetic results of flaps.
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Mori, Shigefumi. "Flip Theorem and the Existence of Minimal Models for 3-Folds." Journal of the American Mathematical Society 1, no. 1 (January 1988): 117. http://dx.doi.org/10.2307/1990969.
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Mori, Shigefumi. "Flip theorem and the existence of minimal models for $3$-folds." Journal of the American Mathematical Society 1, no. 1 (January 1, 1988): 117. http://dx.doi.org/10.1090/s0894-0347-1988-0924704-x.
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Kachi, Yasuyuki. "Flips of semi-stable 4-folds whose degenerate fibers are unions of Cartier divisors which are terminal factorial 3-folds." Mathematische Annalen 307, no. 4 (April 2, 1997): 647–62. http://dx.doi.org/10.1007/s002080050054.
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Alzahrani, Saad M. "Evaluation of triflumuron and pyriproxyfen as alternative candidates to control house fly, Musca domestica L. (Diptera: Muscidae), in Riyadh city, Saudi Arabia." PLOS ONE 16, no. 4 (April 8, 2021): e0249496. http://dx.doi.org/10.1371/journal.pone.0249496.
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This study was conducted to determine the susceptibility and resistance of some house fly strains of Musca domestica L. to the insect growth regulator insecticides triflumuron and pyriproxyfen in some locations in Riyadh city. Field-collected strains of M. domestica L. from five sites in Riyadh city that represented five slaughterhouse sites where flies spread significantly were tested against triflumuron and pyriproxyfen. Triflumuron LC50 values for the five collected strains ranged from 2.6 to 5.5 ppm, and the resistance factors (RFs) ranged from 13-fold to 27-fold that of the susceptible laboratory strain. Pyriproxyfen LC50 values for the field strains ranged from 0.9 to 1.8 ppm with RFs of 3-fold to 5-fold. These results indicate that pyriproxyfen is an effective insecticide to control house flies and should be used in rotation with other insecticides in the control programs applied by Riyadh municipality.
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Asfaw, Netsanet, Berhanu Hiruy, Netsanet Worku, and Fekadu Massebo. "Evaluating the efficacy of various traps in catching tsetse flies at Nech Sar and Maze National Parks, Southwestern Ethiopia: An Implication for Trypanosoma Vector Control." PLOS Neglected Tropical Diseases 16, no. 12 (December 22, 2022): e0010999. http://dx.doi.org/10.1371/journal.pntd.0010999.
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Tsetse flies are the vector of protozoan parasite of the genus Trypanosoma, the causative agent of human African sleeping sickness and animal trypanosomiasis. Traps such as Nguruman (NGU), biconical and sticky traps are in use for tsetse flies sampling and monitoring. However, there is no evidence regarding their comparative efficiency in catching flies using olfactory cues. Therefore, the present study aimed to evaluate the efficiency of different types of traps in catching tsetse flies at Nech Sar and Maze National Parks, Southwestern Ethiopia. The study was done for six consecutive months from February to July 2019. Briefly, a 3×4 Latin square design was performed, and tsetse flies were collected for three days each month in four different vegetation types, including wood grassland, bush land, forest, and riverine forest. To avoid trapping position bias, rotation of traps has been done every day. Almost all (99.5%) of the flies were Glossina pallidipes and the remaining were G. fuscipes. The latter were present only at Maze national park. NGU traps were the most efficient type with 12.1 flies/trap/day at Nech Sar National Park and it was 2.2 flies/trap/day at Maze National Park followed by biconical and sticky traps. The number of tsetse flies collected by biconical trap was three-fold lower than NGU trap, and it was four-fold lower in sticky trap than NGU trap in both Nech Sar and Maze National Parks. A substantial number (41%) of G. pallidipes were collected from woody grassland (WGL). In conclusion, G. pallidipes monitoring and evaluation activities could consider NGU trap model as it performed better in most vegetation types in the region.
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Ma, Yue, Matthew R. Naunheim, Jill Gregory, and Peak Woo. "Transoral Tubed Supraglottoplasty: A New Minimally Invasive Procedure for Aspiration." Annals of Otology, Rhinology & Laryngology 128, no. 12 (July 17, 2019): 1122–28. http://dx.doi.org/10.1177/0003489419862581.
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Objectives: We describe a new procedure for aspiration called tubed supraglottoplasty (TS). TS is a transoral procedure that approximates the aryepiglottic (AE) folds and arytenoids. This narrows the laryngeal inlet. This procedure has been used to improve swallowing and reduce aspiration in patients with vocal fold paralysis. We describe the technical aspects of TS and report on 11 patients. Methods: TS is done by oral intubation followed by suspension laryngoscopy. An incision is made along the AE fold into the posterior commissure and then continued to the opposite AE fold. Dissection within this incision creates two mucosal flaps, one based on the laryngeal surface and the other on the pharyngeal surface. Two 1-cm releasing incisions are made at each end of the AE fold. The laryngeal mucosal flap is approximated using a 3-0 self-locking running suture. The pharyngeal mucosal flap is approximated as a second layer. This double-layered mucosal V-Y advancement flap builds up the posterior laryngeal height. It narrows and “tubes” the supraglottis. Results: All patients tolerated TS without airway complications. Ten of the 11 patients reported improved swallowing function with less aspiration. Six of the 8 patients with prior G-tubes had their gastrostomy tube removed. Postoperative laryngoscopy showed a narrowed “tubed” supraglottis with a higher posterior wall preventing spillover and aspiration. An improved Functional Oral Intake Scale was recorded in ten of eleven patients. Conclusion: TS is a minimally invasive procedure that can improve swallowing and reduce aspiration.
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Thomas, Jimiece, Haddon Smith, C. Aaron Smith, Lori Coward, Gregory Gorman, Maria De Luca, and Patricia Jumbo-Lucioni. "The Angiotensin-Converting Enzyme Inhibitor Lisinopril Mitigates Memory and Motor Deficits in a Drosophila Model of Alzheimer’s Disease." Pathophysiology 28, no. 2 (June 18, 2021): 307–19. http://dx.doi.org/10.3390/pathophysiology28020020.
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The use of angiotensin-converting enzyme inhibitors (ACEis) has been reported to reduce symptoms of cognitive decline in patients with Alzheimer’s disease (AD). Yet, the protective role of ACEis against AD symptoms is still controversial. Here, we aimed at determining whether oral treatment with the ACEi lisinopril has beneficial effects on cognitive and physical functions in a Drosophila melanogaster model of AD that overexpresses the human amyloid precursor protein and the human β-site APP-cleaving enzyme in neurons. We found a significant impairment in learning and memory as well as in climbing ability in young AD flies compared to control flies. After evaluation of the kynurenine pathway of tryptophan metabolism, we also found that AD flies displayed a >30-fold increase in the levels of the neurotoxic 3-hydroxykynurenine (3-HK) in their heads. Furthermore, compared to control flies, AD flies had significantly higher levels of the reactive oxygen species (ROS) hydrogen peroxide in their muscle-enriched thoraces. Lisinopril significantly improved deficits in learning and memory and climbing ability in AD flies. The positive impact of lisinopril on physical function might be, in part, explained by a significant reduction in ROS levels in the thoraces of the lisinopril-fed AD flies. However, lisinopril did not affect the levels of 3-HK. In conclusion, our findings provide novel and relevant insights into the therapeutic potential of ACEis in a preclinical AD model.
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Roth, Bruce. "Reviews - Flips for 3-folds and 4-folds, Alessio Corti (ed.). Pp. 200. £41.00. 2007. ISBN 978 0 19 857061 5 (Oxford University Press)." Mathematical Gazette 94, no. 529 (March 2010): 188–89. http://dx.doi.org/10.1017/s0025557200007518.
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Hafez, Abdulwahab M. "First Evaluation of Field Evolved Resistance to Commonly Used Insecticides in House Fly Populations from Saudi Arabian Dairy Farms." Insects 12, no. 12 (December 14, 2021): 1120. http://dx.doi.org/10.3390/insects12121120.
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The house fly, Musca domestica L. (Diptera: Muscidae), is one of the major vectors of several pathogens that affect humans and animals. We evaluated the toxicity of eight insecticides commonly used for house fly control using five field populations collected from dairies in Riyadh, Saudi Arabia. Among the five tested pyrethroids, non to moderate resistance was found in adults of both sexes compared to a susceptible strain. Resistance ratios ranged from 0.5- to 7-fold for alpha-cypermethrin, 2- to 21-fold for deltamethrin, 4- to 19-fold for bifenthrin, 1- to 9-fold for cyfluthrin, and 1- to 8-fold for cypermethrin. Among the three tested organophosphates, low to moderate resistance was found among adult flies compared to the susceptible strain, and the resistance ratios ranged from 4- to 27-fold for fenitrothion, 2- to 14-fold for chlorpyrifos, and 3- to 12-fold for malathion. The median lethal times for the tested insecticides were 3–33 h for alpha-cypermethrin, 3–24 h for deltamethrin, 5–59 h for bifenthrin, 1–7 h for cypermethrin, 0.3–7 h for cyfluthrin, 6–36 h for fenitrothion, 2–21 h for chlorpyrifos, and 3–34 h for malathion. This study presents baseline data pertaining to registered public health insecticides, and the results will assist future studies monitoring insecticide resistance, and the planning of effective integrated vector management programs.
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Eskandari, Zohreh, Javad Alidousti, and Reza Khoshsiar Ghaziani. "Codimension-One and -Two Bifurcations of a Three-Dimensional Discrete Game Model." International Journal of Bifurcation and Chaos 31, no. 02 (February 2021): 2150023. http://dx.doi.org/10.1142/s0218127421500231.
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In this paper, bifurcation analysis of a three-dimensional discrete game model is provided. Possible codimension-one (codim-1) and codimension-two (codim-2) bifurcations of this model and its iterations are investigated under variation of one and two parameters, respectively. For each bifurcation, normal form coefficients are calculated through reduction of the system to the associated center manifold. The bifurcations detected in this paper include transcritical, fold, flip (period-doubling), Neimark–Sacker, period-doubling Neimark–Sacker, resonance 1:2, resonance 1:3, resonance 1:4 and fold-flip bifurcations. Moreover, we depict bifurcation diagrams corresponding to each bifurcation with the aid of numerical continuation method. These bifurcation curves not only confirm our analytical results, but also reveal a richer dynamics of the model especially in the higher iterations.
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Baxter, Deborah F., Martin Kirk, Amy F. Garcia, Alejandra Raimondi, Mats H. Holmqvist, Kimberly K. Flint, Dejan Bojanic, Peter S. Distefano, Rory Curtis, and Yu Xie. "A Novel Membrane Potential-Sensitive Fluorescent Dye Improves Cell-Based Assays for Ion Channels." Journal of Biomolecular Screening 7, no. 1 (February 2002): 79–85. http://dx.doi.org/10.1177/108705710200700110.
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The study of ion channel-mediated changes in membrane potential using the conventional bisoxonol fluorescent dye DiBAC4(3) has several limitations, including a slow onset of response and multistep preparation, that limit both the fidelity of the results and the throughput of membrane potential assays. Here, we report the characterization of the FLIPR Membrane Potential Assay Kit (FMP) in cells expressing voltage- and ligand-gated ion channels. The steady-state and kinetics fluorescence properties of FMP were compared with those of DiBAC4(3), using both FLIPR and whole-cell patch-clamp recording. Our experiments with the voltage-gated K+ channel, hElk-1, revealed that FMP was 14-fold faster than DiBAC4(3) in response to depolarization. On addition of 60 mM KCl, the kinetics of fluorescence changes of FMP using FLIPR were identical to those observed in the electrophysiological studies using whole-cell current clamp. In addition, KCl concentration-dependent increases in FMP fluorescence correlated with the changes of membrane potential recorded in whole-cell patch clamp. In studies examining vanilloid receptor-1, a ligand-gated nonselective cation channel, FMP was superior to DiBAC4(3) with respect to both kinetics and amplitude of capsaicin-induced fluorescence changes. FMP has also been used to measure the activation of KATP1 and hERG.2 Thus this novel membrane potential dye represents a powerful tool for developing high-throughput screening assays for ion channels.
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Webb, J. D., and F. W. Knapp. "Use of Self-Activating Automatic Spray System in Controlling Face Flies and Horn Flies, 1990." Insecticide and Acaricide Tests 16, no. 1 (January 1, 1991): 285. http://dx.doi.org/10.1093/iat/16.1.285.
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Abstract The spray apparatus consisted of a self-contained automatic system with a 30-gal reservoir powered by a 12-volt, battery operated, spray pump. The sprayer was housed in a walkin mineral station mounted on skids to facilitate transport. The mineral box, located at one end of the station, required cattle to walk inside and lift a wooden lid to access the mineral. When a cow lifted the lid over the mineral box and held it open for 10 s or more, 2 spray nozzles above the animal's back were activated for 3 s. As the animal backed out of the sprayer, it was treated with the insecticide mixture contained in the reservoir. For this experiment, a 0.5% water mixture of Vapona feedlot spray was used in the automatic spray system. Before evaluating the automated spray system for horn fly control, horn flies from the experimental herds were tested for resistance against both permethrin and diazinon. The horn fly populations were susceptible to diazinon, but exhibited a 48-fold resistance to permethrin. Prior to treatment and at 2-wk intervals thereafter, horn fly densities were estimated on one side of ten mature animals while face flies were counted on the head and face of these same animals. Untreated cattle within a 1-km radius were used as a control. The test was repeated in two similar herds.
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Rozen, Warren M., Ken G. W. Teo, Gausihi Sivarajah, and Rafael Acosta. "Limited Bilateral Advancement of the Sternocostal Head of Pectoralis Major for Sternal Reconstruction: Preserving the Axillary Fold." International Surgery 102, no. 3-4 (March 1, 2017): 189–95. http://dx.doi.org/10.9738/intsurg-d-15-00029.1.
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The introduction of well-vascularized flaps for infected sternotomy wound reconstruction has improved mortality rates dramatically. Multiple variations of the pectoralis major flap have been described in this context. However, unresolved limitations of this flap include poor cosmesis and problematic coverage of the inferior third of the sternotomy wound. We describe an approach to address these issues. The humeral attachments are preserved and bilateral muscles are advanced in a limited fashion. The left sternocostal head is advanced medially and rotated anticlockwise, using this portion to fill the upper half of the sternum while the caudal portion of the right pectoralis muscle is used as a turnover flap at the lower half of the wound. In all 25 patients, the anterior axillary fold was preserved bilaterally and the infection completely resolved. Complications included 3 cases of hematoma, 2 cases of coagulopathy, and 1 late bone sequestrum (aseptic). Although the study had a limited sample size, we had a high rate of success and few complications. With the preservation of bilateral axillary folds, good cosmesis, and adequate wound coverage, we recommend this modification of the pectoralis major flap in even complicated cases of mediastinitis.
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Perez, Lia E., Nancy Parquet, Marina Molisano, Ken Shain, Melisa Alsina, Claudio Anasetti, and William Dalton. "Environmental Mediated-Immune Resistance (EM-IR) to APO2L/TRAIL Mediated Apoptosis." Blood 110, no. 11 (November 16, 2007): 3521. http://dx.doi.org/10.1182/blood.v110.11.3521.3521.
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Abstract Resistance to chemotherapy arises in a complex microenvironment and it is essential to study how it influences apoptosis in order to identify novel therapeutic targets. APO2L/TRAIL anti-tumor activity is attractive since it spares normal tissue. Previous studies in our laboratory have shown that cancer:stroma microenvironment interactions confer resistance to immune control via APO2L/TRAIL, a process referred to as environmental mediated-immune resistance (EM-IR). We studied EM-IR in multiple myeloma because it is a disease subject to bone marrow environmental influences and expresses the specific APO2L/TRAIL receptor(s). We have shown in a transwell assay, with myeloma (RPMI-8226, U266 and MM1s) in the upper well and HS5 stromal cells in the lower well, that APO2L/TRAIL (5 to 50ng/mL for 5 hours) apoptosis is reduced when compared to cells exposed to medium in the lower well. Additional studies using conditioned medium from HS5 and myeloma patient’s stroma (n=3) grown for 14 days, confirmed that soluble factor(s) produced by tumor bone marrow microenvironment protected cells from APO2/TRAIL apoptosis. APO2/TRAIL resistance was reversible as sensitivity was restored after HS5 stroma cells were removed (20 min). APO2/TRAIL signaling pathway studies showed that baseline levels of c-FLIP, an anti-apoptotic factor, increased in RPMI-8226 (2.86 fold), in U266 (9.5 fold increase) and in MM1s (1.34 fold increase) myeloma cell lines. Inhibition of c-FLIP by means of RNA interference using siRNA duplex that targeted both c-FLIP isoforms, c-FLIP long and short, increased APO2/TRAIL sensitivity of RPMI-8226 treated in the presence of HS5 stroma. Sub-cellular fractionation showed that c-FLIP is maintained in the membrane fraction and is not significantly increased in the cytosol when exposed to soluble factor(s). Pre-treatment (19 hours) with cyclohexamide, a protein synthesis inhibitor, restored APO2L/TRAIL sensitivity in association with down regulation of c-FLIP while maintained anti-apoptotic c-IAP, Bcl2 and Mcl-1 levels suggesting that c-FLIP synthesis, not intracellular traffic, is essential for soluble factors to regulate c-FLIP. To dissect which soluble factor(s) are involved in apoptosis resistance we have tested the effects of HS27a stroma cells. HS27a lack IL-6 and/or IL-1 production compared to HS5 stroma and do not confer APO2/TRAIL resistance suggesting that these cytokines may be involved in apoptosis resistance. Treatment with neutralizing IL-6 specific antibody of HS5 transwell decreased IL-6 levels and partially restored sensitivity to APO2L/TRAIL in myeloma. Treatment with rh-IL-6 (0.001ng/mL to 10ng/mL) with APO2L/TRAIL conferred a dose-dependent resistance to APO2L/TRAIL in myeloma cells associated with increased c-FLIP levels. IL-1 receptor antagonist (IL-1ra) either by pre-treatment (1hour–18 hours) or co-administration with APO2L/TRAIL did not reverse APO2L/TRAIL resistance. These findings suggest that IL-6 in part mediates APO2L/TRAIL EM-IR by increasing c-FLIP levels among other unknown mechanisms. We conclude that c-FLIP up-regulation inhibitors and/or targeting hematopoietic soluble factor(s) may contribute to enhanced APO2/TRAIL function.
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Minkoff, C., and T. G. Wilson. "The competitive ability and fitness components of the Methoprene-tolerant (Met) Drosophila mutant resistant to juvenile hormone analog insecticides." Genetics 131, no. 1 (May 1, 1992): 91–97. http://dx.doi.org/10.1093/genetics/131.1.91.
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Abstract The Methoprene-tolerant (Met) mutation of Drosophila melanogaster results in a high (100-fold) level of resistance to the insecticide methoprene, a chemical analog of juvenile hormone. Pest species that are under control with methoprene may therefore have the potential to evolve resistance via a mutation homologous to Met. To evaluate the potential of such mutants to persist in wild populations, we must understand the fitness of flies carrying Met. In the absence of methoprene, Met flies were outcompeted by a wild-type strain both in a multigeneration population cage and in single-generation competition experiments. To determine which fitness component(s) is responsible for the competitive disadvantage, the survival, time of development, and fecundity of flies homozygous for each of five Met alleles were compared with wild type. Small but significant differences were found between the pooled Met alleles and wild type for pupal development time, pupal mortality, and early adult fecundity. These differences result in a large competitive disadvantage. Although Met flies were found to have reduced fitness by these measures, the phenotype is not as severe as might be expected from a knowledge of the disruption of juvenile hormone regulation seen in Met flies. It is concluded that (1) although Met flies have a large advantage under methoprene selection, they will quickly become outcompeted upon relaxation of methoprene usage, (2) even a seemingly severe disruption of juvenile hormone regulation has no drastic effect on the vital functions of the insect and (3) small differences in fitness components can translate into a large competitive disadvantage.
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Mehta, Milind A., Vikrant Ranjan, Prayas Kumar, and Pradnya Sarwade. "Coverage in head and neck malignancies; our institutional experience." International Surgery Journal 5, no. 12 (November 28, 2018): 3799. http://dx.doi.org/10.18203/2349-2902.isj20185006.
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Background: Cancer of the head and neck can have a major impact on patients. It is vitally important that the surgeon appreciate the anatomy of the head and neck, the varieties of tumours and their metastatic patterns of spread, the ablative techniques, the adjunctive treatments, and the potential need for reconstruction. The obvious advantages to immediate reconstruction of a defect after ablation of a tumor have been recognized for more than 3 decades and are still valid today.Methods: Those patients who required reconstructive management were included in the study. The patients with head and neck malignancy were operated in association with ENT surgeon’s team or Onco-surgery team. Reconstruction of the defect was done by Plastic Surgeons.Results: In this series various types of reconstructive methods ranging from Split thickness skin graft, full thickness skin graft, fasciocutaneous flaps, fascial flaps, muscle flaps and musculo-cutaneous flaps were used. The defects were primarily sutured in 11% patients. The defects were covered with split thickness skin graft in 6.6% patients. Full thickness skin graft was used in 8.8% patients. Local flaps were used in 6.6% and loco regional flaps were used in 60% for coverage of head and neck defects. Free flaps were used in 6.6% of patients.Conclusions: The study concluded that for management of such defects local flaps were reliable, quick to execute, and capable of covering large defects. It provides skin of excellent colour and texture, and most of the scars are hidden in natural skin folds.
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Stefanescu, Radu, Dustin Bassett, Rozbeh Modarresi, Francisco Santiago, Mohamad Fakruddin, and Jeffrey Laurence. "Synergistic interactions between interferon-γ and TRAIL modulate c-FLIP in endothelial cells, mediating their lineage-specific sensitivity to thrombotic thrombocytopenic purpura plasma–associated apoptosis." Blood 112, no. 2 (July 15, 2008): 340–49. http://dx.doi.org/10.1182/blood-2007-10-119552.
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Abstract Microvascular endothelial cell (MVEC) injury coupled to progression of platelet microthrombi facilitated by ADAMTS13 deficiency is characteristic of idiopathic and HIV-linked thrombotic thrombocytopenic purpura (TTP). Cytokines capable of inducing MVEC apoptosis in vitro are up-regulated in both TTP and HIV infection. However, the concentrations of these cytokines required to elicit EC apoptosis in vitro are 2- to 3-log–fold greater than present in patient plasmas. We report that clinically relevant levels of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and interferon (IFN)–γ act in synergy to induce apoptosis in dermal MVECs, but have no effect on large-vessel ECs or pulmonary MVECs. This reflects the tissue distribution of TTP lesions in vivo. Sensitivity to TTP plasma or TRAIL plus IFN-γ is paralleled by enhanced ubiquitination of the caspase-8 regulator cellular FLICE-like inhibitory protein (c-FLIP), targeting it for proteasome degradation. c-FLIP silencing with anti-FLIP short interfering RNA (siRNA) in pulmonary MVECs rendered them susceptible to TTP plasma– and cytokine-mediated apoptosis, while up-regulation of c-FLIP by gene transfer partially protected dermal MVECs from such injury. TTP plasma–mediated apoptosis appears to involve cytokine-induced acceleration of c-FLIP degradation, sensitizing cells to TRAIL-mediated caspase-8 activation and cell death. Suppression of TRAIL or modulation of immunoproteasome activity may have therapeutic relevance in TTP.
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Torr, S. J., D. R. Hall, R. J. Phelps, and G. A. Vale. "Methods for dispensing odour attractants for tsetse flies (Diptera: Glossinidae)." Bulletin of Entomological Research 87, no. 3 (June 1997): 299–311. http://dx.doi.org/10.1017/s0007485300037251.
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AbstractMethods for dispensing tsetse attractants using sealed polyethylene sachets and bottles were studied in the laboratory and field. 1-Octen-3-ol (octenol), 4-methylphenol and 3-n-propylphenol were dispensed singly or as blends from sachets 25–200 cm2 in surface area and with a wall thickness of 0.06–0.32 mm; butanone was dispensed from polyethylene bottles. The release rates of attractants, assessed gravimetrically or by GC analysis of volatiles released, were independent of the amount present. The rates were related directly to surface area, inversely related to wall thickness and increased exponentially with temperature. With blends of the attractants, the release rates of the two phenols were directly proportional to the concentration present, but that of octenol showed an exponential dependence. A similar exponential effect was seen with blends of the attractants and an involatile diluent. For mixtures of chemicals, the ratio of the released components was not affected significantly by temperature, sachet size or wall thickness. Release rates from polyethylene sachets and bottles in the field varied 100-fold according to temperature differences related to the time of day, season, and degree of insolation. Day-degree models to predict the losses of attractants from a polyethylene sachet in shade or in full sunlight were highly correlated (r2 = 0.84 and 0.81 respectively) with observed losses. The practical implications of these findings are discussed.
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Mariño Pérez, Laura, Francesco S. Ielasi, Luiza M. Bessa, Damien Maurin, Jaka Kragelj, Martin Blackledge, Nicola Salvi, Guillaume Bouvignies, Andrés Palencia, and Malene Ringkjøbing Jensen. "Visualizing protein breathing motions associated with aromatic ring flipping." Nature 602, no. 7898 (February 16, 2022): 695–700. http://dx.doi.org/10.1038/s41586-022-04417-6.
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AbstractAromatic residues cluster in the core of folded proteins, where they stabilize the structure through multiple interactions. Nuclear magnetic resonance (NMR) studies in the 1970s showed that aromatic side chains can undergo ring flips—that is, 180° rotations—despite their role in maintaining the protein fold1–3. It was suggested that large-scale ‘breathing’ motions of the surrounding protein environment would be necessary to accommodate these ring flipping events1. However, the structural details of these motions have remained unclear. Here we uncover the structural rearrangements that accompany ring flipping of a buried tyrosine residue in an SH3 domain. Using NMR, we show that the tyrosine side chain flips to a low-populated, minor state and, through a proteome-wide sequence analysis, we design mutants that stabilize this state, which allows us to capture its high-resolution structure by X-ray crystallography. A void volume is generated around the tyrosine ring during the structural transition between the major and minor state, and this allows fast flipping to take place. Our results provide structural insights into the protein breathing motions that are associated with ring flipping. More generally, our study has implications for protein design and structure prediction by showing how the local protein environment influences amino acid side chain conformations and vice versa.
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PACZKOWSKA, Marta, and Jarosław SELECH. "AN INVESTIGATION OF THE INFLUENCE OF LASER ALLOYING OF THE SURFACE LAYER ON ABRASIVE WEAR RESISTANCE OF CAST IRON ELEMENTS." Tribologia 282, no. 6 (December 31, 2018): 107–17. http://dx.doi.org/10.5604/01.3001.0012.8428.
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The purpose of the study was to evaluate the influence of the laser alloying of the coulter flaps working in a sand medium on the intensity of their abrasive wear. The treatment was performed with a dual diode TRUDISK 1000 laser device. Two types of alloying were performed (with boron and the mixture of boron and chromium). The wear experiment was carried out with a “rotating bowl” device to testing wear in a sandy medium. In comparison to the surface layer of the base coulter flaps (only chilled – with white cast iron microstructure) after laser alloying finer, more homogenous and additionally hardened microstructure of the surface layer was achieved. Such microstructure improved the hardness by approx. 2 times for laser alloying with boron and 3 times for the alloying with boron and chromium. Wear tests proved that this translated into over 2-fold improvement in durability of treated coulter flaps. Mass loss was similar in the case of both types of alloying despite of achieving the higher value of hardness by laser alloying with boron and chromium than by alloying only with boron. It may result from some discontinuities observed in the microstructure of the layer containing chromium that was created due to the technology. It was also observed that alloying with boron improved the surface roughness parameters.
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Marciscano, Ariel E., Neel Gupta, Zhigang Zhang, Julie Teruya-Feldstein, and Ariela Noy. "Rituximab Fails to Reduce Histologic Transformation (HT) Rate of Follicular Lymphoma (FL) to Diffuse Large B-Cell Lymphoma (DLBCL)." Blood 112, no. 11 (November 16, 2008): 837. http://dx.doi.org/10.1182/blood.v112.11.837.837.
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Abstract Background: Histologic Transformation (HT) of indolent follicular lymphoma to aggressive lymphoma is a critical and sometimes fatal event in a patient’s disease course. It is unclear if rituximab influences HT. We have previously shown that single agent rituximab is used earlier in the disease course than traditional chemotherapy likely due to rituximab’s high therapeutic index (Cohler et al., ASH 2007). Others have shown rituximab also improves the complete response rate, disease free and overall survival of follicular lymphoma when used as a single agent and in combination with chemotherapy. Theoretically, this could reduce the disease burden over a patient’s lifetime and consequently the transformation rate. Methods: We retrospectively screened 3500 patients and identified 584 eligible patients at Memorial Sloan Kettering Cancer Center (MSKCC) with newly diagnosed, treatment naïve, indolent follicular lymphoma. We compared two cohorts of rituximab usage: 1998– 2000 and 2001–2006. In the former, patients received rituximab predominantly in the relapsed setting. In the latter, patients liberally received rituximab even as single agent first line therapy. Histologic transformation to diffuse large B cell lymphoma (DLBCL) was the primary study endpoint. All therapy was recorded. Results: Median follow-up time was 92 months for the 1998–2000 cohort and 41 months for the 2001–2006 cohort. Patients in the latter cohort received rituximab both earlier in the course of follow up and more often as a first line therapy. The median time from diagnosis to first rituximab was 21 months vs. 2 months, respectively. Rituximab was given alone or in combination as first line systemic therapy to 36% of the 1998–2000 cohort, but to 93% of the 2001–2006 cohort. The comparative risks of transformation between the two cohorts were not statistically significant (P-value = 0.41 by log rank comparison). The cumulative incidence of transformation 36 months after diagnosis was 8.1% for the 1998– 2000 cohort and 4.4% for the 2001–2006 cohort. Furthermore, patients receiving rituximab first line, either single agent or in combination, compared to patients receiving rituximab as salvage therapy, showed essentially no difference in risk of histologic transformation. (P-value = 0.68) Surprisingly, patients never receiving rituximab had a significantly lower risk of transformation than those who received rituximab at any point (p-value = 0.0095), however, these rituximab naïve patients had lower risk FLIPI scores accounting for the difference (p-value = 0.15). Notably, 173/584 patients never received systemic therapy, and 102 of these were expectantly monitored without any local therapy, such as radiotherapy or therapeutic surgery). None of these 102 patients had transformation within the first 36-months of follow up. Finally, we confirm Ginè et al.’s earlier finding that a higher risk FLIPI score confers a higher risk of transformation. (Annals of Oncology, 2006) For each unit increase of FLIPI risk score (e.g., 3 à 4), the probability of histologic transformation at any time point increases 1.72 fold. Moreover, high-risk FLIPI patients (3–5 risk factors) have a 3.3-fold increase in risk of HT (p-value <0.0001). Conclusions: Patients diagnosed with FL in 2001–2006 received rituximab earlier in their disease and more frequently than those diagnosed in 1998–2000. However, in contrast to our hypothesis, this did not translate to a lower risk of transformation for the 2001– 2006 cohort. The 36-month risk of transformation was lower in patients with lower FLIPI scores. This data supports the clinical decision to expectantly monitor low-risk FLIPI patients.
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Floate, K. D. "Field trials of Trichomalopsis sarcophagae (Hymenoptera: Pteromalidae) in cattle feedlots: a potential biocontrol agent of filth flies (Diptera: Muscidae)." Canadian Entomologist 135, no. 4 (August 2003): 599–608. http://dx.doi.org/10.4039/n02-093.
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AbstractA field study was performed in southern Alberta, Canada, to assess the native wasp, Trichomalopsis sarcophagae (Gahan), as a potential biocontrol agent for house fly, Musca domestica L., and stable fly, Stomoxys calcitrans (L.). The wasp was readily reared in large numbers, which allowed for the cumulative release of an estimated 4.63 million wasps into three commercial feedlots during the 2-year study. Each of several releases predictably and repeatedly enhanced parasitism of sentinel house fly pupae, whereas parasitism remained low in three paired control feedlots where wasps were not released. Releases every 2nd week had a disproportionately greater effect than releases every 2nd month. In 1998, 1.2 million wasps were released into treatment feedlots resulting in the recovery of 3 952 T. sarcophagae from 31 500 sentinel pupae (0.13 wasps/pupa). In 1999, 3.43 million wasps were released into treatment feedlots, with the recovery of 37 763 wasps from 47 720 sentinel pupae (0.79 wasps/pupa). Hence, a 2.8-fold increase in the number of wasps released in 1999 resulted in a 6.1-fold increase in the recovery of wasps. This result supports industry recommendations of regular, repeated releases of wasps every 2nd or 4th week versus one or infrequent releases throughout the summer. There was no evidence that releases augmented overwintering populations of the wasp in subsequent years. These results provide proof-of-concept for the mass-rearing and release of T. sarcophagae as an inundative biocontrol agent for the control of pest flies in cattle confinements. Further studies will be required to assess the effect of T. sarcophagae releases on natural populations of pest flies.
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Vale, G. A. "Visual responses of tsetse flies (Diptera: Glossinidae) to odour-baited targets." Bulletin of Entomological Research 83, no. 2 (June 1993): 277–89. http://dx.doi.org/10.1017/s0007485300034775.
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AbstractField studies in Zimbabwe showed how targets 1 m tall and 25–400 cm wide, composed of vertical panels of visual material and net and baited with odours of acetone, 1-octen-3-ol, and phenols, could be refined for controlling Glossina morsitans morsitans Westwood and G. pallidipes Austen. Attraction from a distance was not affected by swivelling movement but improved several-fold as the width of visual panels increased from 25 to 200 cm. Blue or blue/black targets were about as effective as black for G. m. morsitans but slightly more effective for G. pallidipes. Fine and coarse net was unattractive at long range but the flies avoided coarse net when close. The percentage of tsetse alighting on visual panels before flying round increased up to several times when the panels were widened, and when non-shiny black replaced blue or shiny black, but the percentage of flies alighting before departure was not much affected expect by panel width, being near 0% at 25 cm and 85% at 2 m. Most tsetse alighted first near the centre of targets, especially where black contrasted with nearby blue. Studies of various fabrics and paints and of restricted deposition of insecticide suggested several disposable targets that could have the costs of materials and insecticide, with efficacy preserved for G. m. morsitans and increased by up to 50% for G. pallidipes.
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Jose, R. M., N. Timoney, R. Vidyadharan, and R. Lester. "Syndactyly correction: an aesthetic reconstruction." Journal of Hand Surgery (European Volume) 35, no. 6 (March 17, 2010): 446–50. http://dx.doi.org/10.1177/1753193410362638.
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Various flaps have been used with and without skin grafts to separate digits with syndactyly. Dorsal flap techniques with and without grafts result in dorsal and thus more visible scars. Some of the recent techniques which use no grafts are only applicable for some simple syndactylies. The technique described in this paper uses a combination of techniques which have been described previously. A shaped palmar flap is used to create the web space; narrow V-flaps and full-thickness skin grafts are used to resurface the lateral defects on the fingers and reciprocal pulp flaps are used to create aesthetically pleasing nail folds. This technique allows the full thickness grafts to be hidden on the radial and ulnar sides of the fingers and palm. It increases the span of the hand in conditions where there is shortage of palmar skin. A retrospective review has been undertaken of 102 patients in whom 221 webs were reconstructed through 176 surgical procedures. There were 54 cases of simple syndactylies (53%) and the rest were complex. Complications were encountered in 11 operations (6%) and web creep was noted in 12 web spaces (5%). Re-operation for web creep has been carried out in seven web spaces (3%).
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Zeitels, Steven M., and Robert E. Hillman. "A Method for Reconstruction of Anterior Commissure Glottal Webs With Endoscopic Fibro-Mucosal Flaps." Annals of Otology, Rhinology & Laryngology 128, no. 3_suppl (January 27, 2019): 82S—93S. http://dx.doi.org/10.1177/0003489418820031.
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Background: Anterior-commissure (AC) cicatrization and web formation is a difficult problem that can result from a variety of clinical scenarios. An advancement-rotation flap utilizing papillomatous epithelium and subepithelial fibrous tissue has been previously described. For patients in whom there was not excessive redundant papillomatosis covering the AC web, including other clinical scenarios, a microlaryngoscopic procedure was designed to lengthen the glottal/subglottal aperture using substantial local fibro-mucosal tissue. Although it has been done for over a decade, this approach is not widely known and to our knowledge not photo-documented. Study Design: Retrospective. Material and Methods: An analysis was done with Institutional Review Board approval that identified 42 patients who underwent 53 procedures to treat AC webs, which were reconstructed with local soft-tissue flaps and without any device/stent to maintain the glottal aperture. The microlaryngoscopic method and technical nuances for this approach with and without diseased epithelium are described and photo-documented. Tactical mucosal incisions were made to facilitate advancement and/or rotation of fibro-mucosal flaps with enough length to resurface the medial aspect of 1 vocal fold. The scarred submucosal soft tissue in the AC region was separated with cold instruments, and the flaps were sutured in position. Variations of this method are demonstrated mobilizing fibro-mucosal soft tissue from different locations, including the web itself, contralateral vocal fold, infrapetiole region, and/or the inner aspect of the thyroid lamina below the anterior-commissure tendon. Results: Of the 53 cases in which anterior commissure glottal webs were reconstructed with endoscopic fibro-mucosal flaps, 31 of 53 had recurrent respiratory papillomatosis (RRP). Redundant RRP comprised the majority of the flap in 14 of 31 RRP cases. Fibro-mucosal tissue without a substantial amount of disease occurred in 17 of 31 RRP cases. Of the remaining 22 AC web cases, the primary diagnoses observed were: glottic cancer = 7 of 22, intraepithelial dysplasia = 10 of 22, glottic trauma = 3 of 22, congenital = 1 of 22, and radiotherapy = 1 of 22. Conclusion: Endolaryngeal utilization of local fibro-mucosal tissue to lengthen the glottal/subglottal aperture for AC webs is an effective strategy. It can be done without using devices or keels for webs that are congenital or from nonsurgical trauma, idiopathic disease, or postsurgical traumatic cicatrization of the anterior commissure subsequent to treatment of epithelial disease (eg, cancer, dysplasia, and RRP). Normalizing the architecture of the anterior commissure was a valuable asset in patients who require future treatment of epithelial diseases, especially in an office-based setting.
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Zhou, Wei, Peter Madrid, Amy Fluitt, Andreas Stahl, and Xinmin (Simon) Xie. "Development and Validation of a High-Throughput Screening Assay for Human Long-Chain Fatty Acid Transport Proteins 4 and 5." Journal of Biomolecular Screening 15, no. 5 (May 6, 2010): 488–97. http://dx.doi.org/10.1177/1087057110369700.
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Dietary long-chain fatty acid (LCFA) uptake across cell membranes is mediated principally by fatty acid transport proteins (FATPs). Six subtypes of this transporter are differentially expressed throughout the human and rodent body. To facilitate drugs discovery against FATP subtypes, the authors used mammalian cell lines stably expressing the recombinant human FATP4 and 5 and developed a high-throughput screening (HTS) assay using a 96-well fluorometric imaging plate reader (FLIPR). LCFA uptake signal-to-background ratios were between 3- and 5-fold. Two 4-aryl-dihydropyrimidinones, j3 and j5, produced inhibition of FATP4 with a half-maximal inhibitory concentration (IC50) of 0.21 and 0.63 µM, respectively, and displayed approximately 100-fold selectivity over FATP5. The US Drug Collection library was screened against the FATP5. A hit rate of around 0.4% was observed with a Z′ factor of 0.6 ± 0.2. Two confirmed hits are bile acids, chenodiol and ursodiol with an IC50 of 2.4 and 0.22 µM, respectively. To increase throughput, a single time point measurement in a 384-well format was developed using the Analyst HT, and the results are comparable with the 96-well format. In conclusion, the FATP4 and 5 cell-based fluorescence assays are suitable for a primary drug screen, whereas differentiated cell lines are useful for a secondary drug screen.
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August, Jenny. "On the finiteness of the derived equivalence classes of some stable endomorphism rings." Mathematische Zeitschrift 296, no. 3-4 (February 6, 2020): 1157–83. http://dx.doi.org/10.1007/s00209-020-02475-y.
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Abstract We prove that the stable endomorphism rings of rigid objects in a suitable Frobenius category have only finitely many basic algebras in their derived equivalence class and that these are precisely the stable endomorphism rings of objects obtained by iterated mutation. The main application is to the Homological Minimal Model Programme. For a 3-fold flopping contraction $$f :X \rightarrow {\mathrm{Spec}\;}\,R$$ f : X → Spec R , where X has only Gorenstein terminal singularities, there is an associated finite dimensional algebra $$A_{{\text {con}}}$$ A con known as the contraction algebra. As a corollary of our main result, there are only finitely many basic algebras in the derived equivalence class of $$A_{\text {con}}$$ A con and these are precisely the contraction algebras of maps obtained by a sequence of iterated flops from f. This provides evidence towards a key conjecture in the area.
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Allmann, Stefan, Marion Wargnies, Nicolas Plazolles, Edern Cahoreau, Marc Biran, Pauline Morand, Erika Pineda, et al. "Glycerol suppresses glucose consumption in trypanosomes through metabolic contest." PLOS Biology 19, no. 8 (August 13, 2021): e3001359. http://dx.doi.org/10.1371/journal.pbio.3001359.
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Microorganisms must make the right choice for nutrient consumption to adapt to their changing environment. As a consequence, bacteria and yeasts have developed regulatory mechanisms involving nutrient sensing and signaling, known as “catabolite repression,” allowing redirection of cell metabolism to maximize the consumption of an energy-efficient carbon source. Here, we report a new mechanism named “metabolic contest” for regulating the use of carbon sources without nutrient sensing and signaling. Trypanosoma brucei is a unicellular eukaryote transmitted by tsetse flies and causing human African trypanosomiasis, or sleeping sickness. We showed that, in contrast to most microorganisms, the insect stages of this parasite developed a preference for glycerol over glucose, with glucose consumption beginning after the depletion of glycerol present in the medium. This “metabolic contest” depends on the combination of 3 conditions: (i) the sequestration of both metabolic pathways in the same subcellular compartment, here in the peroxisomal-related organelles named glycosomes; (ii) the competition for the same substrate, here ATP, with the first enzymatic step of the glycerol and glucose metabolic pathways both being ATP-dependent (glycerol kinase and hexokinase, respectively); and (iii) an unbalanced activity between the competing enzymes, here the glycerol kinase activity being approximately 80-fold higher than the hexokinase activity. As predicted by our model, an approximately 50-fold down-regulation of the GK expression abolished the preference for glycerol over glucose, with glucose and glycerol being metabolized concomitantly. In theory, a metabolic contest could be found in any organism provided that the 3 conditions listed above are met.
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Robinow, S., W. S. Talbot, D. S. Hogness, and J. W. Truman. "Programmed cell death in the Drosophila CNS is ecdysone-regulated and coupled with a specific ecdysone receptor isoform." Development 119, no. 4 (December 1, 1993): 1251–59. http://dx.doi.org/10.1242/dev.119.4.1251.
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At adult emergence, the ventral CNS of Drosophila shows a group of approximately 300 neurons, which are unique in that they express 10-fold higher levels of the A isoform of the ecdysone receptor (EcR-A) than do other central neurons. This expression pattern is established early in metamorphosis and persists throughout the remainder of the pupal stage. Although these cells represent a heterogeneous group of neurons, they all share the same fate of undergoing rapid degeneration after the adult emerges from the pupal case. One prerequisite for this death is the decline of ecdysteroids at the end of metamorphosis. Treatment of flies with 20-hydroxyecdysone blocks the death of the cells, but only if given at least 3 hours before the normal time of degeneration. The correlation of a unique pattern of receptor isoform expression with a particular steroid-regulated fate suggests that variations in the pattern of receptor isoform expression may serve as important switches during development.
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Witte, David G., Steven C. Cassar, Jeffrey N. Masters, Timothy Esbenshade, and Arthur A. Hancock. "Use of a Fluorescent Imaging Plate Reader-Based Calcium Assay to Assess Pharmacological Differences between the Human and Rat Vanilloid Receptor." Journal of Biomolecular Screening 7, no. 5 (October 2002): 466–75. http://dx.doi.org/10.1177/108705702237679.
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The cloned vanilloid receptor 1 (VR1) is a ligand-gated calcium channel that is believed to be the capsaicin-activated vanilloid receptor found in native tissues, based on similarities regarding molecular mass, tissue distribution, and electrophysiological properties. Using a Fluorescent Imaging Plate Reader (FLIPR), along with Fluo-3 to signal intracellular calcium levels ([Ca++]i), rat VR1 (rVR1) and a human orthologue (hVR1) were pharmacologically characterized with various VR1 ligands. HEK-293 cells, stably expressing rVR1 or hVR1, exhibited dose-dependent increases in [Ca++]i when challenged with capsaicin (EC50s ≅ 10 nM). Responses to capsaicin were blocked by the VR1 antagonist capsazepine and were dependent on VR1 expression. Potencies for 10 structurally diverse VR1 agonists revealed rVR1 potencies highly correlated to that of hVR1 ( R2 = 0.973). However, a subset of agonists (tinyatoxin, gingerol, and zingerone) was approximately 10-fold more potent for rVR1 compared to hVR1. Schild analysis for blockade of capsaicin-induced responses by capsazepine was consistent with competitive antagonism, whereas ruthenium red displayed noncompetitive antagonism. Compared to rVR1, hVR1 was more sensitive to blockade by both antagonists. For both rVR1 and hVR1, time-response waveforms elicited by resiniferatoxin increased more gradually compared to other agonists. Tinyatoxin also displayed slow responses with hVR1 but showed rapid responses with rVR1. Thus, FLIPR technology can be used to readily reveal differences between rVR1 and hVR1 pharmacology with respect to potencies, efficacies, and kinetics for several VR1 ligands.
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WAHL, G., P. ENYONG, A. NGOSSO, J. M. SCHIBEL, R. MOYOU, H. TUBBESING, D. EKALE, and A. RENZ. "Onchocerca ochengi: epidemiological evidence of cross-protection against Onchocerca volvulus in man." Parasitology 116, no. 4 (April 1998): 349–62. http://dx.doi.org/10.1017/s003118209700228x.
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In North Cameroon, the vector of Onchocerca volvulus (causative agent of human onchocerciasis) also transmits 2 filariae of animals: O. ochengi from cattle and O. ramachandrini from wart hogs. In order to assess the qualitative and quantitative roles of these ‘animal filariae’ in the epidemiology of O. volvulus, the transmission of the 3 parasites was measured in 2 villages and related to the endemicity of human onchocerciasis. In Galim, a cattle-farming Guinea savanna village where wild animals are rare, the overwhelming majority of all filarial infections found in the Simulium damnosum s.l. vectors throughout the year were O. ochengi (89%). The remaining infections were mainly O. volvulus (10·5%), and a few O. ramachandrini (0·5%). In Karna, a crop-farming Sudan savanna village where cattle are rare, but wild animals common, flies were also more frequently infected with animal filariae than with the human parasite. In the dry season, when nomadic cattle are present, 54% of all infections were O. ochengi, 36% O. volvulus and 10% O. ramachindrini. In the rainy season, when the cattle move away, flies were mainly infected with O. ramachandrini (52% of all infections) and secondly with O. volvulus (48%). In Karna, the relationship between the Annual Transmission Potential (ATP) of O. volvulus and its prevalence in the human population conformed to other onchocerciasis foci, in that a moderate ATP led to hyperendemic onchocerciasis. In Galim, however, a 7-fold higher O. volvulus-ATP (caused by a very high biting rate of the flies) contrasted with a strikingly low endemicity of onchocerciasis. Since, at the same time, in Galim the transmission of O. ochengi (measured on man) was very high (15000 L3/fly collector/year), we hypothesize that the reduced endemicity of onchocerciasis in Galim is due to ‘natural heterologous vaccination’ by the large annual number of O. ochengi-L3, inoculated into man by anthropo-boophilic S. damnosum s.l. The importance of micro-epidemiology for the understanding of the interlinkage of human and animal onchocerciasis is discussed.
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WANG, YUEFANG, LEFENG LÜ, and LIHUA HUANG. "NONLINEAR VIBRATION ANALYSIS FOR AN AIRFLOW-EXCITED TRANSLATING STRING." International Journal of Computational Methods 09, no. 04 (December 2012): 1250051. http://dx.doi.org/10.1142/s021987621250051x.
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The nonlinear vibration of transverse motion of a translating string excited by steady wind force is investigated in this paper. The stability of the equilibrium configuration is analyzed and the generation of limit cycles via multiple Hopf bifurcations is presented. Single-, double-, and quadruple-Hopf bifurcations are determined in the parametric space. The limit-cycle response is solved through the method of Incremental Harmonic Balance, with its stability determined by Floquet multipliers. For the forced vibration, the coexistence of periodic and quasiperiodic motions is found with varying excitation frequency and amplitude. The Neimark–Sacker (NS) bifurcation and the flip bifurcation are demonstrated in an example. The continuation software MATCONT is adopted to identify the fold and NS bifurcations of periodic motions, as well as other codim-2 bifurcations of NS–NS, the Chenciner and the 1:1, 1:3, and 1:4 resonances. These bifurcations present the complexity of the string dynamics induced by steady wind excitations.
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Esmailzadeh, Sharmin, Youwen Zhou, and Xiaoyan Jiang. "The Role Of BIN1 Tumor Suppressor Isoforms In Regulation Of Proliferation, Apoptosis and Tumor Formation Of Human Cutanous T-Cell Lymphoma Cells In Vitro and In Vivo." Blood 122, no. 21 (November 15, 2013): 2517. http://dx.doi.org/10.1182/blood.v122.21.2517.2517.
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Abstract Cutaneous T-cell lymphomas (CTCLs) represent a group of lymphoproliferative disorders that are characterized by homing of malignant T-cells to the surface of skin. There are two main types of CTCL: Mycosis Fungoides (MF) and its leukemic variant Sezary Syndrome (SS), which together represent about 65-70% of all CTCL cases. The precise genetic pathogenesis of these diseases remains largely undetermined. Recently, our research group has demonstrated that AHI-1 (Abelson Helper Integration site-1) oncogene is involved in CTCL. Expression of AHI-1 is increased in human leukemia cell lines, with marked upregulation (up to 40 fold) in CTCL lines (Hut78 and Hut102). Moreover, in FACS-purified CD4+CD7- Sezary cells from patients with Sezary Syndrome, AHI-1 expression is higher at both the RNA and protein levels compared to normal CD4+ cells. Furthermore, stable suppression of endogenous AHI-1 in Hut78 cells using small interfering RNA, normalizes their transforming activity both in vitro and in vivo. Thus, lymphomagenic activity of Hut78 cells is partially dependent on the expression of AHI-1. Interestingly, BIN1 (Bridging integrator 1) was identified through microarray analysis as one of the genes that may be involved in AHI-1-mediated leukemic transformation in CTCL cells. BIN1 is a nucleocytosolic adaptor protein with more than ten isoforms; some isoforms, including the BIN1 isoform (+10, +13), act as tumor suppressors, whereas the BIN1 (+12A) behaves as a cancer-related isoform in solid tumor models. However, the role of BIN1 in regulation of normal hematopoiesis and lymphomagenesis remains unknown. We have recently demonstrated that transcript levels of BIN1 isoforms are significantly lower in patients with MF or SS compared to controls. Four isoforms of BIN1 have been identified in Hut78 and primary CD4+CD7- Sezary cells. To investigate the role of BIN1 in CTCL, the BIN1 isoforms (+10, +13) and BIN1 (+12A) lentiviral constructs were transduced into two CTCL cell lines, Hut78 and HH cells. Overexpression of BIN1 isoforms led to a significant reduction in cell proliferation, as assessed by colony forming cell assays and 3H-Thymidine uptake assays (2-3 fold, p<0.05). Furthermore, a significant increase in spontaneous and specific apoptosis was observed in BIN1-transduced cells, with and without exogenous FAS-ligand (2-3 fold, p<0.05). Interestingly, a significant reduction in protein expression of c-FLIP (inhibitor of the FAS-mediated apoptosis pathway) and upregulation of downstream cleaved caspase-8 and caspase-3 was demonstrated in BIN1-transduced cells, suggesting that BIN1 isoforms induce apoptosis by downregulating the expression of c-FLIP, which leads to activation of the FAS-mediated apoptosis pathway. These findings show anti-proliferative and pro-apoptotic roles for BIN1 isoforms in human CTCL cells. In addition, subcellular fractionation and confocal microscopy further indicated that both the BIN1 (+10, +13) and BIN1 (+12A) isoforms are mainly located in the nucleus in Hut78 and HH cells. Furthermore, to investigate the effects of overexpression of BIN1 isoforms on the ability to induce tumors in vivo, we tested their leukemogenic potential by injecting transduced HH cells into non-obese diabetic/severe-combined immunodeficiency (NOD/SCID) mice. Mice injected subcutaneously with either parental HH or control empty vector cells (2 x 107/per mouse), showed local tumor formation in 6 of 6 mice within 4 days post-injection. The local tumors enlarged progressively and were often 1.5–2 cm in diameter by 3 weeks after injection. In contrast, no local tumors formed in mice given injections of equal numbers of BIN1-transduced HH cells after 14 days, in 12 out of 12 mice. Tumor formation was only observed in BIN1-transduced HH cells after 3 weeks post-injection. However, the local tumors were significantly smaller in BIN1-transduced HH cells compared to controls (∼4-fold). These findings further indicate that the two BIN1 isoforms have tumor suppressor activities in NOD/SCID mice and can significantly delay tumor formation and reduce tumor size in vivo. Disclosures: No relevant conflicts of interest to declare.