Miracle-dz/UniFAR-FTUs huggingface dataset:
Functional Segregation of the TCR and Antigen-MHC Complexes on the Surface of CTL 1

As CTL adhere to and lyze their targets, they extract cognate Ag-MHC and represent this on their own cell surface. Whether such self-presented cognate Ag stimulate the TCR of a CTL is uncertain. To analyze this, we examined TCR capping in response to self-presented Ag. We found that OVA peptide-specific OT-1 CTL that were pulsed with cognate peptide Ag did not cap their TCR, implying that the autologously presented MHC-Ag complex does not normally stimulate the TCR. However, this functional separation of the TCR and its ligand on the cell surface was not absolute. Treatment of Ag-pulsed OT-1 CTL with agents that alter cell surface charge, including trypsin, papain, tunicamycin, neuraminidase, and polybrene, allowed Ag-specific TCR capping. The TCR capped together with the restricting MHC molecule on the surface of the cell, implying an interaction between the TCR and cell-associated Ag. Further, the treated CTL underwent a time- and dose-dependent suicidal death that was both Fas- and perforin-dependent. Therefore, our results indicate that the association of the TCR with its MHC-peptide ligand on the surface of a CTL is normally proscribed by biophysical properties of the plasma membrane. Overcoming this restriction allows TCR stimulation and induces CTL effector functions and cell suicide.
Fibronectin assembly during early embryo development: A versatile communication system between cells and tissues

Background: Fibronectin extracellular matrix is essential for embryogenesis. Its assembly is a cell‐mediated process where secreted fibronectin dimers bind to integrin receptors on receiving cells, which actively assemble fibronectin into a fibrillar matrix. During development, paracrine communication between tissues is crucial for coordinating morphogenesis, typically being mediated by growth factors and their receptors. Recent reports of situations where fibronectin is produced by one tissue and assembled by another, with implications on tissue morphogenesis, suggest that fibronectin assembly may also be a paracrine communication event in certain contexts. Results: Here we addressed which tissues express fibronectin (Fn1) while also localizing assembled fibronectin matrix and determining the mRNA expression and/or protein distribution pattern of integrins α5 and αV, α chains of the major fibronectin assembly receptors, during early chick and mouse development. We found evidence supporting a paracrine system in fibronectin matrix assembly in several tissues, including immature mesenchymal tissues, components of central and peripheral nervous system and developing muscle. Conclusions: Thus, similarly to growth factor signaling, fibronectin matrix assembly during early development can be both autocrine and paracrine. We therefore propose that it be considered a cell–cell communication event at the same level and significance as growth factor signaling during embryogenesis. Developmental Dynamics 245:520–535, 2016. © 2015 Wiley Periodicals, Inc.
Coexistence of two adamantane binding sites in the influenza A M2 ion channel

The influenza A virus contains a proton-selective ion channel (M2) that is the target of the adamantane family of drug inhibitors. Two recently published studies relating to adamantane binding of the M2 ion channel using X-ray crystallography and solution NMR have reignited interest in the potential use of adamantanes in combating the spread of influenza A. However, these two studies propose different binding sites for the adamantane drugs with the X-ray M2/amantadine structure favoring an ion channel pore-binding model and the solution NMR M2/rimantadine structure suggesting the existence of a lipid-facing binding pocket. We conducted a series of surface plasmon resonance (SPR) experiments designed to accurately measure the affinity of amantadine and rimantadine to M2 ion channels embedded in 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC) liposomes. We find that this class of drug is capable of binding M2 with two different affinities in the order of 10−4 and 10−7 M, suggesting that both proposed binding sites are feasible. Furthermore, by examining drug binding to M2 mutant constructs (V27A, S31N, and D44A), it was possible to probe the location of the two binding sites. We show that a high-affinity binding site corresponds to the M2 ion channel pore whereas the secondary, low-affinity binding site can be attributed to the lipid face of the pore. These SPR results are in excellent agreement with the most recent solid-state NMR study of amantadine-bound M2 in lipid bilayers and provide independent support that the ion channel pore-binding site is responsible for the pharmacological activity elicited by the adamantane drugs.
Sex differences in the risk of rapid cycling and other indicators of adverse illness course in patients with bipolar I and II disorder.

OBJECTIVES To examine the independent effects of sex on the risk of rapid cycling and other indicators of adverse illness course in patients with bipolar I disorder (BP-I) or bipolar II disorder (BP-II). METHODS We analyzed data from the first 1,225 patients enrolled in the Mayo Clinic Individualized Medicine Biobank for Bipolar Disorder. Demographic and clinical variables were ascertained using standardized questionnaires; height and weight were assessed to determine body mass index (BMI). Rates of rapid cycling, cycle acceleration, and increased severity of mood episodes over time were compared between women and men overall and within subgroups defined by bipolar disorder subtype (BP-I or BP-II). Multiple logistic regression analysis was used to assess the independent effect of sex on the risk of these indicators of adverse illness course. RESULTS Women had significantly higher rates of rapid cycling than men. Overall rates of rapid cycling were higher in patients with BP-II than BP-I; and sex differences in the rate of rapid cycling were more pronounced in patients with BP-II than BP-I, although the power to detect statistically significant differences was reduced due to the lower sample size of subjects with BP-II. Female sex was a significant predictor of rapid cycling, cycle acceleration, and increased severity of mood episodes over time after adjusting for age, bipolar disorder subtype, BMI, having any comorbid psychiatric disorder, and current antidepressant use. CONCLUSIONS Female sex was associated with significantly higher risk of rapid cycling, cycle acceleration, and increased severity of mood episodes over time in a sample of 1,225 patients with bipolar disorders.
Hypophosphatemia and hypomagnesemia induced by cooling in patients with severe head injury.

OBJECT Induced hypothermia in patients with severe head injury may prevent additional brain injury and improve outcome. However, this treatment is associated with severe side effects, including life-threatening cardiac tachyarrhythmias. The authors hypothesized that these arrhythmias might be caused by electrolyte disorders and therefore studied the effects of induced hypothermia on urine production and electrolyte levels in patients with severe head injury. METHODS Urine production, urine electrolyte excretion, and plasma levels of Mg, phosphate, K, Ca, and Na were measured in 41 patients with severe head injury. Twenty-one patients (Group I, study group) were treated using induced hypothermia and pentobarbital administration, and 20 patients (Group 2, controls) were treated with pentobarbital administration alone. In Group 1, Mg levels decreased from 0.98+/-0.15 to 0.58+/-0.13 mmol/L (mean +/- standard deviation; p < 0.01), phosphate levels from 1.09+/-0.19 to 0.51+/-0.18 mmol/L (p < 0.01), Ca levels from 2.13+/-0.25 to 1.94+/-0.14 mmol/L (p < 0.01), and K levels from 4.2+/-0.59 to 3.6+/-0.7 mmol/L (p < 0.01) during the first 6 hours of cooling. Electrolyte levels in the control Group 2 remained unchanged. Electrolyte depletion in Group I occurred despite the fact that moderate and, in some cases, substantial doses of electrolyte supplementation were given to many patients, and supplementation doses were often increased during the cooling period. Average urine production increased during the cooling period, from 219+/-70 to 485+/-209 ml/hour. When the targeted core temperature of 32 micro C was reached, urine production returned to levels that approximated precooling levels (241+/-102 ml/hour). Electrolyte levels rose in response to high-dose supplementation. In the control group, urine production and electrolyte excretion remained unchanged throughout the study period. CONCLUSIONS Induced hypothermia is associated with severe electrolyte depletion, which is at least partly due to increased urinary excretion through hypothermia-induced polyuria. This may be the mechanism through which induced hypothermia can lead to arrhythmias. When using this promising new treatment in patients with severe head injury, stroke, or postanoxic coma following cardiopulmonary resuscitation, prophylactic electrolyte supplementation should be considered and electrolyte levels should be monitored frequently.
Blood pressure and vasoactive hormones in mild preeclampsia and normal pregnancy.

OBJECTIVE Changes in vasoactive hormones are reported to play an important role in the pathogenesis of preeclampsia linking placental hypoperfusion with hypertension, systemic disease, and proteinuria. We, therefore, studied diurnal patterns of vasoactive hormones in mild preeclampsia. METHODS Venous blood samples were drawn every 2 h over 25 h for measurements of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), norepinephrine, renin activity, and aldosterone and two urine collections (12 h each) for stable prostaglandin metabolite measurements. The patients were nine women with mild preeclampsia and, for comparison, nine control women matched for gestation and parity. RESULTS Women with mild preeclampsia had higher norepinephrine levels throughout 25 h, and lower systemic prostacyclin production as measured by the urinary 2,3-dinor-6-keto PGF1 alpha excretion during the daytime. Plasma endothelin and ANP and BNP concentrations tended to be higher throughout 25 h in preeclampsia, but differences between the two groups did not reach levels of statistical significance. Plasma renin activity and aldosterone did not differ between the groups. Whereas control women exhibited a diurnal variation in plasma norepinephrine, ANP, BNP, and aldosterone, and in both urinary prostacyclin and thromboxane A2 metabolites, this was less distinct or absent in patients with mild preeclampsia. CONCLUSIONS We conclude that mild preeclampsia is associated with elevated plasma norepinephrine levels, lower systemic daytime production of prostacyclin, and blunting of the normal diurnal variation for a number of indices including plasma levels of BNP, ANP, norepinephrine, and aldosterone, and urinary prostacyclin metabolites.
Impact of paraquat regulation on suicide in South Korea.

BACKGROUND Ingestion of pesticides (mainly paraquat) accounted for one-fifth of suicides in South Korea in 2006-10. We investigated the effect on suicide mortality of regulatory action, culminating in a ban on paraquat in South Korea in 2011-12. METHODS We calculated age-standardized method-specific suicide mortality rates among people aged ≥15 in South Korea (1983-2013) using registered death data. Negative binomial regression was used to estimate changes in the rate and number of pesticide suicides in 2013, compared with those expected based on previous trends (2003-11). RESULTS Pesticide suicide mortality halved from 5.26 to 2.67 per 100 000 population between 2011 and 2013. Compared with the number expected based on previous trends, the regulations were followed by an estimated 847 [95% confidence interval (CI) -1180 to -533] fewer pesticide suicides, a 37% reduction in rates (rate ratio = 0.63, 95% CI 0.55 to 0.73) in 2013. The decline in pesticide suicides after the regulations was seen in all age/sex/geographical groups. The absolute reduction in the number of suicides was greatest among men, the elderly and in rural areas. The reduction in pesticide suicides contributed to 56% of the decline in overall suicides that occurred between 2011 and 2013. There was no impact of the regulations on crop yield. CONCLUSIONS The regulation of paraquat in South Korea in 2011-12 was associated with a reduction in pesticide suicide. Further legislative interventions to prevent the easy availability of highly lethal suicide methods are recommended for reducing the number of suicides worldwide.
Hematoma growth and outcomes in intracerebral hemorrhage

Objective: Uncertainty exists over the size of potential beneficial effects of medical treatments targeting hematoma growth in intracerebral hemorrhage (ICH). We report associations of hematoma growth parameters on clinical outcomes in the pilot phase, Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT1) (ClinicalTrials.gov NCT00226096). Methods: In randomized patients with both baseline and 24-hour brain CT (n = 335), associations between measures of absolute and relative hematoma growth and 90-day poor outcomes of death and dependency (modified Rankin Scale score 3–5) were assessed in logistic regression models, with data reported as odds ratios (OR) and 95% confidence intervals (CI). Results: A total of 10.7 mL (1 SD) increase in hematoma volume over 24 hours was strongly associated with poor outcome (adjusted OR 1.72, 95% CI 1.19–2.49; p = 0.004). An association was also evident for relative growth (adjusted OR 1.67, 95% 1.22–2.27; p = 0.001 for 1 SD increase). The analyses were adjusted for age, sex, achieved systolic blood pressure, elevated NIH Stroke Scale score (≥14), hematoma location, baseline hematoma volume, intraventricular extension, antithrombotic therapy, baseline glucose, time from ICH to baseline CT scan, and time from baseline to repeat CT scan. A 1 mL increase in hematoma growth was associated with a 5% (95% CI 2%–9%) higher risk of death or dependency. Conclusion: Medical treatments, such as rapid intensive blood pressure lowering, could achieve ∼2–4 mL absolute attenuation of hematoma growth. There is hope that this could translate into modest but still clinically worthwhile (∼10%–20% better chance) outcome from ICH.
A 12-Month Survey of Gastrointestinal Helminth Infections of Lemurs Kept in Two Zoos in Madagascar

Abstract Infections with gastrointestinal parasites may be a major threat to lemurs kept in captivity, as they are a common cause of diarrhea. In this study, fecal egg count patterns and clinical signs associated with gastrointestinal nematodes were assessed for 12 mo in 40 lemurs kept under different husbandry and climatic conditions at two sites in Madagascar. Involved species were black-and-white ruffed lemurs (Varecia variegata), eastern grey bamboo lemurs (Hapalemur griseus), greater bamboo lemurs (Prolemur simus), red-bellied lemurs (Eulemur rubriventer), common brown lemurs (Eulemur fulvus), crowned lemurs (Eulemur coronatus), and Sclater's black lemurs (Eulemur macaco flavifrons). At site 1 (Tsimbazaza Zoological Park), lemurs were kept in small enclosures with daily cleaning of the cement soiling and without routine anthelmintic program, whereas at site 2 (Ivoloina Zoological Park), lemurs received routine anthelmintic prophylaxis and were housed in small enclosure with daily cleaning of sandy soil enclosures. A total of five genera of nematode eggs from the orders Strongylida, Oxyurida, and Enoplida were recovered and identified from 198 out of 240 samples (83%) at site 1 and 79% (189 out of 240) at site 2 with the use of a modified McMaster technique. Significant differences were found for parasites from the order Strongylida between the two sites. The differences may be due to climate conditions and the presumed life cycle of these parasites. No significant differences were found for parasites from the other orders. No significant differences were noted between sexes or between seasons. No clinical signs of parasitic gastroenteritis were seen in either lemur collection.
Using testing to improve learning after severe traumatic brain injury.

OBJECTIVE Recent work in cognitive psychology suggests that testing can increase memory for both previously and subsequently studied information. Here we examined whether these beneficial (backward and forward) effects of testing generalize to individuals with severe traumatic brain injury (TBI). METHOD Twenty-four persons with severe TBI, 12.7 years postinjury, and 12 healthy controls participated in the study. Participants studied three lists of items in anticipation of a final cumulative recall test. They were tested immediately between the study of lists or not. RESULTS Immediate testing of Lists 1 and 2 enhanced recall of both the previously studied information (Lists 1 and 2) and the subsequently studied information (List 3). The enhancement for the three lists arose for individuals with severe TBI and healthy controls, and did not differ in size between subject groups. CONCLUSION The findings indicate that TBI persons show a very general benefit from testing, including both backward and forward effects of retrieval practice. Testing thus might be a powerful technique to improve learning and memory in persons with severe TBI.
Significance of genetic polymorphisms in glutathione S-transferase multigene family and lung cancer risk.

A vast number of studies are focused on investigating genetic polymorphism in order to estimate genetic contribution to the development of cancer. Possible cancer susceptibility genes have been sought among oncogenes, tumor suppressor genes, DNA repair genes and genes encoding phase I and phase II enzymes. Large individual differences in the biotransformation of xenobiotics have been explained on the basis of genetic polymorphisms in some detoxifying enzymes, regardless of environmental and occupational exposure. Among these enzymes, glutathione S-transferases (GST) constitute a large multigene family of phase II enzymes involved in detoxification of potentially genotoxic chemicals. Five genetic polymorphisms of GST have been well documented. Total or partial deletions and (or) single nucleotide polymorphisms in alleles encoding GSTM1, GSTM3, GSTPI, GSTT1, GSTZ1 are associated with reduction of enzymatic activity toward several substrates of different GST isoenzymes. In addition, molecular epidemiology studies indicate that a single genetic polymorphism of glutathione S-transferase appears to be a moderate lung cancer risk factor. However, the risk is higher when interactions with more GST polymorphisms and other risk factors (e.g. cigarette smoking) occur. Individuals with decreased rate of detoxification, with "high risk" glutathione S-transferase genotypes have a slightly higher level of carcinogen-DNA adducts and more cytogenetic damages.
The evaporative requirement for heat balance determines whole‐body sweat rate during exercise under conditions permitting full evaporation

• A relative exercise intensity (%) protocol is often used to compare absolute whole‐body sweat rates (WBSRs) during exercise between participants of different aerobic capacity. • Under conditions permitting full evaporation, heat balance theory suggests that exercise intensity should be fixed to elicit the same rate of evaporation required for heat balance (Ereq). • Whole‐body direct calorimetry was employed to measure WBSRs throughout 90 min of exercise across a range of air temperatures and rates of metabolic heat production. • Irrespective of ambient temperature and metabolic heat production, Ereq alone described ∼90% of all variability in WBSR during steady‐state and non‐steady‐state exercise, whereas <2% of variation was independently described by %. • To perform an unbiased comparison of WBSRs (but not necessarily core temperature) between different individuals/groups under conditions allowing full evaporation, future studies should consider using a fixed Ereq irrespective of the % incurred.
Electrical characterization of nanostructured 3D microelectrodes for retinal neuron stimulation

To provide visual information to people blinded by retinal degenerative diseases, retinal prosthetic devices based on multi-channel microelectrodes have been widely researched. A critical requirement of microelectrode is that the electro-electrolyte interface impedance should be small to generated sufficiently large current at a given voltage, to effectively stimulate retinal neurons. To improve the tradeoff, our research group developed an arrowhead-shaped 3D microelectrode, but the 3D microelectrode requires multi-step fabrication process. This paper presents a nanostructured 3D microelectrode with platinum-black which is simple to fabricate. Nanostructured 3D microelectrodes with the diameter of 25 um are fabricated and experimentally parameterized using a three-element circuit model. Maximum allowable current injection experiments are performed and compared to a theoretically estimated injection limit. All the electrical characteristics of the nanostructured 3D microelectrodes are compared with those of the arrowhead-shaped 3D microelectrodes. The electrode-electrolyte interface impedance of the nanostructured 3D microelectrode is 43.2 kH at 1 kHz, which is 79.7% lower than that of the arrowhead-shaped 3D microelectrode with the same diameter of 25 um. The maximum allowable current injection limit of the nanostructured 3D microelectrode is 392 μA, which is 429.7% higher than that of the arrowhead-shaped 3D microelectrode. These results show that the nanostructured 3D microelectrodes are more advantageous than the arrowhead-shaped 3D microelectrodes for high resolution retinal neuron stimulation.
Wickedness, Moral Responsibility, and Access to Transplantable Livers

Abstract: Under the current conditions of scarcity of transplantable livers, difficult decisions need to be made about access. There is a growing consensus that it is morally justified to give people with ARESLD lower priority than those whose need is not self-caused. The purpose of this article is to critically examine the conditions under which such prioritization is morally justified, by challenging arguments put forth by Walter Glannon and Daniel Brudney. There are serious theoretical and practical problems with these views, which have to do with the nature and scope of the (putative) moral duty not to contribute to the competition for scarce transplantable livers, and the difficulty in determining whether people are responsible for their weakness or even wickedness of character. These problems need to be resolved if we are to be morally justified in determining access based on causal and moral responsibility for being in need.
Culture: In the beak of the beholder?

We disagree with two of Rendell and Whitehead's assertions. Culture may be an ancestral characteristic of terrestrial cetacean ancestors; not derived via marine variability, modern cetacean mobility, or any living cetacean social structure. Furthermore, evidence for vocal behavior as culture, social stability, and cognitive ability, is richer in birds than Rendell and Whitehead portray and comparable to that of cetaceans and primates.