Miracle-dz/UniFAR-FTUs huggingface dataset:
The Transient Receptor Potential Melastatin 2 (TRPM2) Channel Contributes to β-Amyloid Oligomer-Related Neurotoxicity and Memory Impairment

In Alzheimer's disease, accumulation of soluble oligomers of β-amyloid peptide is known to be highly toxic, causing disturbances in synaptic activity and neuronal death. Multiple studies relate these effects to increased oxidative stress and aberrant activity of calcium-permeable cation channels leading to calcium imbalance. The transient receptor potential melastatin 2 (TRPM2) channel, a Ca2+-permeable nonselective cation channel activated by oxidative stress, has been implicated in neurodegenerative diseases, and more recently in amyloid-induced toxicity. Here we show that the function of TRPM2 is augmented by treatment of cultured neurons with β-amyloid oligomers. Aged APP/PS1 Alzheimer's mouse model showed increased levels of endoplasmic reticulum stress markers, protein disulfide isomerase and phosphorylated eukaryotic initiation factor 2α, as well as decreased levels of the presynaptic marker synaptophysin. Elimination of TRPM2 in APP/PS1 mice corrected these abnormal responses without affecting plaque burden. These effects of TRPM2 seem to be selective for β-amyloid toxicity, as ER stress responses to thapsigargin or tunicamycin in TRPM2−/− neurons was identical to that of wild-type neurons. Moreover, reduced microglial activation was observed in TRPM2−/−/APP/PS1 hippocampus compared with APP/PS1 mice. In addition, age-dependent spatial memory deficits in APP/PS1 mice were reversed in TRPM2−/−/APP/PS1 mice. These results reveal the importance of TRPM2 for β-amyloid neuronal toxicity, suggesting that TRPM2 activity could be potentially targeted to improve outcomes in Alzheimer's disease. SIGNIFICANCE STATEMENT Transient receptor potential melastatin 2 (TRPM2) is an oxidative stress sensing calcium-permeable channel that is thought to contribute to calcium dysregulation associated with neurodegenerative diseases, including Alzheimer's disease. Here we show that oligomeric β-amyloid, the toxic peptide in Alzheimer's disease, facilitates TRPM2 channel activation. In mice designed to model Alzheimer's disease, genetic elimination of TRPM2 normalized deficits in synaptic markers in aged mice. Moreover, the absence of TRPM2 improved age-dependent spatial memory deficits observed in Alzheimer's mice. Our results reveal the importance of TRPM2 for neuronal toxicity and memory impairments in an Alzheimer's mouse model and suggest that TRPM2 could be targeted for the development of therapeutic agents effective in the treatment of dementia.
Activated intrinsic apoptosis pathway is a key related prognostic parameter in acute myeloid leukemia.

PURPOSE By parallel assessment of multiple apoptosis-related transcripts, we aimed to refine the current concept of apoptosis resistance in acute myeloid leukemia (AML) and identify the combination of genes best predicting overall survival (OS). PATIENTS AND METHODS The reverse transcriptase multiplex ligation-dependent probe amplification technique was used for simultaneous quantification of 31 apoptosis-related transcripts in viable (7AAD-/AnnexinV-) blasts (CD45dim) from bone marrow aspirates of 120 newly diagnosed AML patients. By forward selection, a prognosis-predicting gene expression profile was constructed. The predictive validity of this profile was assessed by cross validation. RESULTS High transcript levels were associated with poor OS for seven of 31 genes, three of which were proapoptotic. The average expression of all 12 antiapoptotic genes was associated with poor OS (P = .029). A similar association with poor OS was found for the average expression of all 19 proapoptotic genes (P = .009). Forward selection and cross validation revealed the antiapoptotic gene BIRC3 and the proapoptotic genes BAX-(l) and BMF to optimally predict OS. Three equally sized patient groups, constructed by ranking the cross-validated prognoses of the patients, were clearly distinct (median OS times were 8.2, 16.7, and 85.6 months). CONCLUSION High expression of both pro- and antiapoptotic genes predicted poor OS, which postulates a mechanism of activation of the apoptosis pathway as a whole. This mechanism, which culminates in a three-gene expression signature, allows accurate clinical outcome prediction in AML and puts efforts to target single antiapoptosis genes in a new perspective.
A Cohort Mortality Study of Employees in the U.S. Carbon Black Industry

Objectives: The objectives of this study are to evaluate historical mortality patterns, especially due to cancers, among employees of the U.S. carbon black industry and to address the methodological shortcomings of previous U.S. mortality studies. Methods: We followed mortality of 5011 workers employed 1 year or more since the 1930s at 18 carbon black facilities through December 31, 2003. Age-, race-, sex-, and calendar year-adjusted standardized mortality ratios (SMRs) were calculated using state-specific mortality rates. Results: Follow up was 96% complete. All-cause (SMR = 0.74, 95% confidence interval [CI] = 0.70–0.78) and all-cancer mortality (SMR = 0.83, 95% CI = 0.74–0.92) showed significant deficits. No excess was observed from lung (SMR = 0.97, 95% CI = 0.82–1.15) or bladder (SMR = 0.93, 95% CI = 0.47–1.87) cancers or from nonmalignant respiratory diseases (SMR = 0.99, 95% CI = 0.83–1.18). No trends were seen with duration of employment or time since hire for any cause of death. Conclusion: Employment in carbon black production in the United States seems not to be associated with increased mortality overall, cancer overall and, in particular, lung cancer. Further research, however, incorporating a detailed exposure assessment is needed to determine whether exposure to carbon black at high levels may be associated with an increased risk of cancer.
Analysis of cytokine production by Mycobacterium-reactive T cells. Failure to explain Mycobacterium leprae-specific nonresponsiveness of peripheral blood T cells from lepromatous leprosy patients.

Recent analyses of antimycobacterial T cells clones from a small number of individuals indicate that mycobacteria preferentially induce Th cells that produce high levels of IFN-gamma and no or little IL-4 in Mycobacterium leprae-resistant tuberculoid leprosy (TT) patients and healthy subjects, whereas in one study M. leprae-induced Ts clones from polar lepromatous leprosy (LL) patients showed a reciprocal cytokine secretion profile and mediated their suppressive activity via the release of high levels of IL-4. We have evaluated these findings in peripheral blood T cells from a larger panel of TT and LL patients as well as healthy individuals. Mycobacterium-reactive T cell lines generated from the PBMC of these individuals were tested for cytokine secretion and proliferative capacity in response to M. leprae, Mycobacterium tuberculosis, and various individual mycobacterial Ag. The lepromatous pole of the leprosy spectrum was additionally investigated by analyzing the cytokine-secretion profile of M. leprae-induced (suppressor) T cell clones as well as primary ex vivo PBMC. All T cell lines from healthy individuals and TT patients responding to M. leprae, M. tuberculosis, or individual Ag, produced high levels of IFN-gamma and TNF-alpha but little or no IL-4 and IL-6. At the lepromatous pole, T cell lines failed to proliferate upon stimulation with M. leprae but in some cases produced significant levels of IFN-gamma. No IL-4 or IL-6 secretion was observed in response to M. leprae. These lines displayed strong proliferation and Th1-like cytokine production upon stimulation with M. tuberculosis. Similarly, stimulation of primary PBMC from LL patients with M. leprae or M. tuberculosis resulted in the release of IFN-gamma but no detectable IL-4 production. Control tetanus toxoid-reactive T cell lines from the same individuals instead produced large amounts of IL-4 and low levels of IFN-gamma. The analysis of M. leprae-induced T cell clones, including those with known suppressive activity, revealed that all lepromatous T cell clones produced large amounts of IFN-gamma. Most of these clones released no or little IL-4, but some clones produced higher levels of IL-4 in addition to IFN-gamma. Most clones tested produced IL-10 as well. The suppressor activity of suppressor T cell clones could not be inhibited by a neutralizing anti-IL-4 antibody and only in one case by neutralizing anti-IL-10 antibody. Anti-IL-4 and anti-IL-10 could not overcome the M. leprae-specific unresponsiveness observed in primary PBMC from LL patients. (ABSTRACT TRUNCATED AT 400 WORDS)
Expansion of endothelial surface by an increase of vessel diameter during tumor angiogenesis in experimental and hepatocellular and pancreatic cancer.

AIM A low vessel density is a common feature of malignant tumors. We suggested that the expansion of vessel diameter might reconstitute the oxygen and nutritient's supply in this situation. The aim of the present study was to compare the number and diameter of blood vessels in pancreatic and liver carcinoma with normal tissue. METHODS Tumor induction of pancreatic (DSL6A) or hepatocellular (Morris-hepatoma) carcinoma was performed in male Lewis (pancreatic cancer) and ACI (hepatoma) rats by an orthotopic inoculation of solid tumor fragments (pancreatic cancer) or tumor cells (hepatoma). Six weeks (pancreatic cancer) or 12 d (hepatoma) after tumor implantation, the tumor microvasculature as well as normal pancreatic or liver blood vessels were investigated by intravital microscopy. The number of perfused blood vessels in tumor and healthy tissue was assessed by computer-assisted image analysis. RESULTS The vessel density in healthy pancreas (565+/-89 n/mm(2)) was significantly higher compared to pancreatic cancer (116+/-36 n/mm(2)) (P<0.001). Healthy liver showed also a significantly higher vessel density (689+/-36 n/mm(2)) compared to liver carcinoma (286+/-32 n/mm(2)) (P<0.01). The comparison of diameter frequency showed a significant increase of vessel diameter in both malignant tumors compared to normal tissue (P<0.05). CONCLUSION The expansion of endothelial cells during tumor angiogenesis is accompanied to a large extent by an increase of vessel diameter rather than by formation of new blood vessels. This may be a possible adaptive mechanism by which experimental pancreatic and hepatocellular cancers expand their endothelial diffusion surface of endothelium to compensate for inadequate neoangiogenesis.
Skin rash and good performance status predict improved survival with gefitinib in patients with advanced non-small cell lung cancer.

BACKGROUND Gefitinib (Iressa) is active as a single agent in the treatment of select patients with recurrent non-small cell lung cancer (NSCLC). The clinical characteristics of patients treated with gefitinib on an Expanded Access Program (EAP) at our institution identified predictive variables associated with better outcome. PATIENTS AND METHODS Patients (n=199) with advanced NSCLC were treated with gefitinib (250 mg) upon progression with chemotherapy. Baseline patient characteristics were: median age, 69 years; males, 57%; adenocarcinoma, 56%. RESULTS Partial responses were noted in two patients (1%) and disease stabilization in 66 (35%) patients. The median survival (MS) was 5.9 months [95% confidence interval (CI) 4.1-7.1] and median time to progression was 3 months (95% CI 2.0-3.0). The predictive factors analyzed were gender, skin rash, diarrhea, tumor histology and performance status (PS). Patients who developed skin rash (any grade) had MS of 10.8 months versus 4.0 months for those without rash (P <0.0001, log rank test). Patients with PS 0, 1 and 2 had MS of 8.4, 6.2 and 2.8 months, respectively (P <0.0002). The other factors did not impact survival. CONCLUSIONS Occurrence of skin rash and baseline PS of 0/1 were associated with improved survival with gefitinib for recurrent NSCLC patients at our institution.
Inheritance of six anthropometric traits in Vaidyas of West Bengal, India

Background: Anthropometric traits are important quantitative traits used by biological anthropologists. Surprisingly little is known about their pattern of inter-generational transmission, probably due to lack of use of developed statistical analysis in previous studies. Aim: The present study is an attempt to approach the problem of the inheritance of anthropometric traits through advanced statistical applications. Subjects and methods: Measurements of 824 individuals from 200 families including two generations were collected from Barasat, West Bengal. The study includes age correction by regression, familial correlation, heritability estimation and segregation analyses. Results: Results showed that there is strong involvement of the familial component in variation of anthropometric traits. The magnitude of heritability (h2 = 57–83%) also supports their strong genetic basis. The results indicated that additive genes are not the only contributing factor; the effect of environment is considerable and that of dominant genes not negligible. Due to genetic interaction with the local environment (specific for each trait), heritabilities vary from one trait to another. Length measurements have higher heritability than breadth measurements. Segregation analysis revealed that either the additive or dominant major gene (MG) is responsible for this effect, which follows simple Mendelian transmission. Beside this, the possibility of the existence of an additional minor gene cannot be discarded. Conclusion: Anthropometric traits have a genetic basis but their mode of inheritance is quite complex in nature. There is evidence of major gene effect (along with polygenes) with Mendelian transmission.
METHODS USED DURING GROSS NECROPSY TO DETERMINE WATERCRAFT-RELATED MORTALITY IN THE FLORIDA MANATEE (TRICHECHUS MANATUS LATIROSTRIS)

Abstract Between 1993 and 2003, 713 (24%) of 2,940 dead Florida manatees (Trichechus manatus latirostris) recovered from Florida waters and examined were killed by watercraft-induced trauma. It was determined that this mortality was the result of watercraft trauma because the external wound patterns and the internal lesions seen during gross necropsy are recognizable and diagnostic. This study documents the methods used in determining watercraft-related mortality during gross necropsy and explains why these findings are diagnostic. Watercraft can inflict sharp- and blunt-force trauma to manatees, and both types of trauma can lead to mortality. This mortality may be a direct result of the sharp and blunt forces or from the chronic effects resulting from either force. In cases in which death is caused by a chronic wound-related complication, the original incident is usually considered to be the cause of death. Once a cause of death is determined, it is recorded in an extensive database and is used by Federal and state managers in developing strategies for the conservation of the manatee. Common sequelae to watercraft-induced trauma include skin lesions, torn muscles, fractured and luxated bones, lacerated internal organs, hemothorax, pneumothorax, pyothorax, hydrothorax, abdominal hemorrhage and ascites, and pyoperitoneum.
Biliary cholesterol crystallization characterized by single-crystal cryogenic electron diffraction Published, JLR Papers in Press, March 1, 2005. DOI 10.1194/jlr.M400458-JLR200

Cholesterol crystals are the building blocks of cholesterol gallstones. The exact structure of early-forming crystals is still controversial. We combined cryogenic-temperature transmission electron microscopy with cryogenic-temperature electron diffraction to sequentially study crystal development and structure in nucleating model and native gallbladder biles. The growth and long-term stability of classic cholesterol monohydrate (ChM) crystals in native and model biles was determined. In solutions of model bile with low phospholipid-to-cholesterol ratio, electron diffraction provided direct proof of a novel transient polymorph that had an elongated habit and unit cell parameters differing from those of classic triclinic ChM. This crystal is exactly the monoclinic ChM phase described by Solomonov and coworkers (Biophysical J., In press) in cholesterol monolayers compressed on the air–water interface. We observed no evidence of anhydrous cholesterol crystallization in any of the biles studied. In conclusion, classic ChM is the predominant and stable form in native and model biles. However, under certain (low phospholipid) conditions, transient intermediate polymorphs may form. These findings, documenting single-crystal analysis in bulk solution, provide an experimental approach to investigating factors influencing biliary cholesterol crystal nucleation and growth as well as other processes of nucleation and crystallization in liquid systems.
Myocardial and peripheral vascular functional adaptation to exercise training

Exercise training seems to restore impaired vascular function in both peripheral and myocardial vessels in patients with coronary artery and peripheral vascular disease or in patients with risk factors for these diseases. However, the results on the effects of exercise training on vascular function in apparently healthy subjects are controversial. We studied the effects of long‐term volitionally increased physical activity on peripheral and myocardial vascular function in nine young healthy male monozygotic twin pairs discordant for physical activity and fitness. The brothers were divided into more (MAG) and less active groups according to physical activity and fitness. The difference between groups in VO2max was 18±10% (P<0.001). Myocardial perfusion at rest, during adenosine‐induced vasodilatation and during cold‐pressor test and myocardial oxygen consumption were measured with positron emission tomography. In addition, endothelial function was measured using ultrasound in brachial and left anterior descending coronary arteries, and standard echocardiographic measures were taken. No differences were observed in myocardial perfusion measurements between groups. MAG tended to have a lower oxygen extraction fraction (P=0.06), but oxygen consumption was similar between the groups. No differences were found in coronary artery, myocardial resistance vessel or peripheral endothelial function between groups. These results suggest that when the effects of heredity are controlled, myocardial perfusion reserve and endothelial function, both in peripheral arteries and myocardial vessels, are not enhanced by increased physical activity and fitness in young healthy adult men.
Syndapin I and endophilin I bind overlapping proline‐rich regions of dynamin I: role in synaptic vesicle endocytosis

Dynamin I mediates vesicle fission during synaptic vesicle endocytosis (SVE). Its proline‐rich domain (PRD) binds the Src‐homology 3 (SH3) domain of a subset of proteins that can deform membranes. Syndapin I, amphiphysin I, and endophilin I are its major partners implicated in SVE. Syndapin binding is controlled by phosphorylation at Ser‐774 and Ser‐778 in the dynamin phospho‐box. We now define syndapin and endophilin‐binding sites by peptide competition and site‐directed mutagenesis. Both bound the same region of the dynamin PRD and both exhibited unusual bidirectional binding modes around core PxxP motifs, unlike amphiphysin which employed a class II binding mode. Endophilin binds to tandem PxxP motifs in the sequence 778SPTPQRRAPAVPPARPGSR796 in dynamin, with SPTPQ being an overhang sequence. In contrast, syndapin binding involves two components in the region 772RRSPTSSPTPQRRAPAVPPARPGSR796. It required a single PxxP core and a non‐PxxP N‐terminally anchored extension which bridges the phospho‐box and may contribute to binding specificity and affinity. Syndapin binding is exquisitely sensitive to the introduction of negative charges almost anywhere along this region, explaining why it is a highly tuned phospho‐sensor. Over‐expression of dynamin point mutants that fail to bind syndapin or endophilin inhibit SVE in cultured neurons. Due to overlapping binding sites the interactions between dynamin and syndapin or endophilin were mutually exclusive. Because syndapin acts as a phospho‐sensor, this supports its role in depolarization‐induced SVE at the synapse, which involves dynamin dephosphorylation. We propose syndapin and endophilin function either at different stages during SVE or in mechanistically distinct types of SVE.
Insulin Regulates the Membrane Arrival, Fusion, and C-terminal Unmasking of Glucose Transporter-4 via Distinct Phosphoinositides*

Insulin increases glucose uptake into muscle via glucose transporter-4 (GLUT4) translocation to the cell membrane, but the regulated events in GLUT4 traffic are unknown. Here we focus on the role of class IA phosphatidylinositol (PI) 3-kinase and specific phosphoinositides in the steps of GLUT4 arrival and fusion with the membrane, using L6 muscle cells expressing GLUT4myc. To this end, we detected the availability of the myc epitope at the cell surface or intravesicular spaces and of the cytosol-facing C-terminal epitope, in cells and membrane lawns derived from them. We observed the following: (a) Wortmannin and LY294002 at concentrations that inhibit class IA PI 3-kinase reduced but did not abate the C terminus gain, yet the myc epitope was unavailable for detection unless lawns or cells were permeabilized, suggesting the presence of GLUT4myc in docked, unfused vesicles. Accordingly, GLUT4myc-containing vesicles were detected by immunoelectron microscopy of membranes from cells pretreated with wortmannin and insulin, but not insulin or wortmannin alone. (b) Insulin caused greater immunological availability of the C terminus than myc epitopes, suggesting that C terminus unmasking had occurred. Delivering phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) to intact cells significantly increased lawn-associated myc signal without C terminus gain. Conversely, phosphatidylinositol 3-phosphate (PI3P) increased the detection of C terminus epitope without any myc gain. We propose that insulin regulates GLUT4 membrane arrival, fusion, and C terminus unmasking, through distinct phosphoinositides. PI(3,4,5)P3 causes arrival and fusion without unmasking, whereas PI3P causes arrival and unmasking without fusion.
Paired and Altruistic Kidney Donation in the UK

We study the computational problem of identifying optimal sets of kidney exchanges in the UK. We show how to expand an integer programming-based formulation due to Roth et al. [2007] in order to model the criteria that constitute the UK definition of optimality. The software arising from this work has been used by the National Health Service Blood and Transplant to find optimal sets of kidney exchanges for their National Living Donor Kidney Sharing Schemes since July 2008. We report on the characteristics of the solutions that have been obtained in matching runs of the scheme since this time. We then present empirical results arising from experiments on the real datasets that stem from these matching runs, with the aim of establishing the extent to which the particular optimality criteria that are present in the UK influence the structure of the solutions that are ultimately computed. A key observation is that allowing four-way exchanges would be likely to lead to a moderate number of additional transplants.