TRP14 is the rate-limiting enzyme for intracellular cystine reduction and regulates proteome cysteinylation.

It has remained unknown how cells reduce cystine taken up from the extracellular space, which is a required step for further utilization of cysteine in key processes such as protein or glutathione synthesis. Here, we show that the thioredoxin-related protein of 14 kDa (TRP14, encoded by TXNDC17) is the rate-limiting enzyme for intracellular cystine reduction. When TRP14 is genetically knocked out, cysteine synthesis through the transsulfuration pathway becomes the major source of cysteine in human cells, and knockout of both pathways becomes lethal in C. elegans subjected to proteotoxic stress. TRP14 can also reduce cysteinyl moieties on proteins, rescuing their activities as here shown with cysteinylated peroxiredoxin 2. Txndc17 knockout mice were, surprisingly, protected in an acute pancreatitis model, concomitant with activation of Nrf2-driven antioxidant pathways and upregulation of transsulfuration. We conclude that TRP14 is the evolutionarily conserved enzyme principally responsible for intracellular cystine reduction in C. elegans, mice, and humans.

A comprehensive approach to identify challenges for clinical reasoning development in undergraduate dental students and their potential solutions.

INTRODUCTION: Clinical reasoning is a core competence in health professions that impacts the ability to solve patients' health problems. Due to its relevance, it is necessary to identify difficulties arising from different sources that affect clinical reasoning development in students. The aim of this study was to explore a comprehensive approach to identify challenges for clinical reasoning development in undergraduate dental students and their potential solutions. METHODS: Mixed methods were used in four stages: (1) students and clinical teachers focus groups to identify challenges to clinical reasoning development; (2) literature review to explore potential solutions for these challenges; (3) Delphi technique for teacher consensus on pertinence and feasibility of solutions (1-5 scale); and (4) teachers' self-perception of their ability to implement the solutions. RESULTS: Three categories and seven subcategories of challenges were identified: (I) educational context factors influencing the clinical reasoning process; (II) teacher's role in clinical reasoning development; and (III) student factors influencing the clinical reasoning process. From 134 publications identified, 53 were selected for review, resulting in 10 potential solutions. Through two Delphi rounds, teachers rated the potential solutions very highly in terms of relevance (4.50-4.85) and feasibility (3.50-4.29). Finally, a prioritisation ranking of these solutions was generated using their scores for relevance, feasibility, and teachers' self-perception of their ability to implement them. CONCLUSIONS: The present comprehensive approach identified challenges for clinical reasoning development in dental students and their potential solutions, perceived as relevant and feasible by teachers, requiring further research and follow-up actions to address them.

Assessment of liver damage in patients with COVID-19 is sub-optimal: results of a survey of medical practitioners.

Liver damage, defined by an increase in liver chemistry parameters, is related to more unfavorable severity and prognosis in patients with COVID-19. These patients are also treated with immunomodulatory drugs capable of reactivating hepatitis B virus (HBV), with an indication for prophylaxis in specific situations. Due to its importance in this pathology, we wondered whether physicians should perform a systematic search for liver damage and HBV.

Large Amplitude Motions in 2,3-Dimethylfluorobenzene: Steric Effects Failing to Interpret Hindered Methyl Torsion.

The microwave spectrum of 2,3-dimethylfluorobezene, one of the six isomers of dimethylfluorobenzene, was recorded using a pulsed molecular jet Fourier transform microwave spectrometer operating in the frequency range from 2 to 26.5 GHz. The internal rotations of two inequivalent methyl groups, causing splittings of up to several hundred MHz of all rotational energy levels into quintets, were analyzed and modeled. The torsional barriers of the methyl groups at the ortho and the meta positions were determined to be 215.5740(56) cm-1 and 488.53(11) cm-1. A comparison with the barrier heights observed for the two isomers 2,6-dimethylfluorobenzene and 3,4-dimethylfluorobenzene has shown that the methyl group at the meta position seems to be invisible to its neighboring ortho-methyl group, while the meta-methyl group clearly senses the ortho one. Steric effects are not able to explain this observation, and electrostatic effects are most probably the reason. Highly accurate molecular parameters determined experimentally were compared with those obtained from quantum chemical calculations at different levels of theory.

Contribution of K2P Potassium Channels to Cardiac Physiology and Pathophysiology.

Years before the first two-pore domain potassium channel (K2P) was cloned, certain ion channels had already been demonstrated to be present in the heart with characteristics and properties usually attributed to the TREK channels (a subfamily of K2P channels). K2P channels were later detected in cardiac tissue by RT-PCR, although the distribution of the different K2P subfamilies in the heart seems to depend on the species analyzed. In order to collect relevant information in this regard, we focus here on the TWIK, TASK and TREK cardiac channels, their putative roles in cardiac physiology and their implication in coronary pathologies. Most of the RNA expression data and electrophysiological recordings available to date support the presence of these different K2P subfamilies in distinct cardiac cells. Likewise, we show how these channels may be involved in certain pathologies, such as atrial fibrillation, long QT syndrome and Brugada syndrome.

Abnormal liver chemistry constitutes an independent prognostic factor of less favorable clinical course in patients with COVID-19.

INTRODUCTION: abnormal liver biochemistry (ALB) is correlated with increased clinical involvement or severity in COVID-19, but its prognostic implications have not been studied extensively. The aim of this study was to determine whether ALB is a risk factor for unfavorable clinical outcome and involvement. MATERIALS AND METHODS: a retrospective, single-center study in confirmed COVID-19 cases. Patients with pharmacological hepatotoxicity or liver diseases were excluded. ALB was defined as any elevation of total bilirubin, AST, ALT, alkaline phosphatase, and/or GGT above the upper limit of normal. First, an assessment was made of the correlation between ALB and need for hospitalization. This was followed by an assessment of the correlation of ALB in hospitalized patients with demographic variables, comorbidities, and treatment for COVID-19, and with clinical involvement and outcome. The statistical analysis was performed using an age-adjusted multiple logistic regression with a p-value < 0.05. RESULTS: of 1,277 confirmed cases, 346 required hospitalization and 302 were included. The prevalence of ALB was higher in hospitalized patients compared to non-hospitalized patients (60.9 % vs. 10.3 %, p ˂ 0.001). Among hospitalized patients, there was no correlation between ALB and demographic variables, comorbidities, or treatment for COVID-19, except for low molecular weight heparin. There was a significant correlation between ALB and moderate/severe COVID-19 involvement and between unfavorable clinical outcomes and elevated total bilirubin. The period of greatest clinical worsening and deterioration of liver biochemistry parameters occurred during the first seven days. There was a significant correlation of ALB with longer hospital stay and admission to the intensive care unit, but this did not imply increased mortality. CONCLUSIONS: ALB correlates with greater clinical involvement and worse clinical outcomes in hospitalized patients with COVID-19.

Obesity causes PGC-1α deficiency in the pancreas leading to marked IL-6 upregulation via NF-κB in acute pancreatitis.

Obesity is associated with local and systemic complications in acute pancreatitis. PPARγ coactivator 1α (PGC-1α) is a transcriptional coactivator and master regulator of mitochondrial biogenesis that exhibits dysregulation in obese subjects. Our aims were: (1) to study PGC-1α levels in pancreas from lean or obese rats and mice with acute pancreatitis; and (2) to determine the role of PGC-1α in the inflammatory response during acute pancreatitis elucidating the signaling pathways regulated by PGC-1α. Lean and obese Zucker rats and lean and obese C57BL6 mice were used first; subsequently, wild-type and PGC-1α knockout (KO) mice with cerulein-induced pancreatitis were used to assess the inflammatory response and expression of target genes. Ppargc1a mRNA and protein levels were markedly downregulated in pancreas of obese rats and mice versus lean animals. PGC-1α protein levels increased in pancreas of lean mice with acute pancreatitis, but not in obese mice with pancreatitis. Interleukin-6 (Il6) mRNA levels were dramatically upregulated in pancreas of PGC-1α KO mice after cerulein-induced pancreatitis in comparison with wild-type mice with pancreatitis. Edema and the inflammatory infiltrate were more intense in pancreas from PGC-1α KO mice than in wild-type mice. The lack of PGC-1α markedly enhanced nuclear translocation of phospho-p65 and recruitment of p65 to Il6 promoter. PGC-1α bound phospho-p65 in pancreas during pancreatitis in wild-type mice. Glutathione depletion in cerulein-induced pancreatitis was more severe in KO mice than in wild-type mice. PGC-1α KO mice with pancreatitis, but not wild-type mice, exhibited increased myeloperoxidase activity in the lungs, together with alveolar wall thickening and collapse, which were abrogated by blockade of the IL-6 receptor glycoprotein 130 with LMT-28. In conclusion, obese rodents exhibit PGC-1α deficiency in the pancreas. PGC-1α acts as selective repressor of nuclear factor-κB (NF-κB) towards IL-6 in pancreas. PGC-1α deficiency markedly enhanced NF-κB-mediated upregulation of Il6 in pancreas in pancreatitis, leading to a severe inflammatory response. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

PIP2 Mediated Inhibition of TREK Potassium Currents by Bradykinin in Mouse Sympathetic Neurons.

Bradykinin (BK), a hormone inducing pain and inflammation, is known to inhibit potassium M-currents (IM) and to increase the excitability of the superior cervical ganglion (SCG) neurons by activating the Ca2+-calmodulin pathway. M-current is also reduced by muscarinic agonists through the depletion of membrane phosphatidylinositol 4,5-biphosphate (PIP2). Similarly, the activation of muscarinic receptors inhibits the current through two-pore domain potassium channels (K2P) of the "Tandem of pore-domains in a Weakly Inward rectifying K+ channel (TWIK)-related channels" (TREK) subfamily by reducing PIP2 in mouse SCG neurons (mSCG). The aim of this work was to test and characterize the modulation of TREK channels by bradykinin. We used the perforated-patch technique to investigate riluzole (RIL) activated currents in voltage- and current-clamp experiments. RIL is a drug used in the palliative treatment of amyotrophic lateral sclerosis and, in addition to blocking voltage-dependent sodium channels, it also selectively activates the K2P channels of the TREK subfamily. A cell-attached patch-clamp was also used to investigate TREK-2 single channel currents. We report here that BK reduces spike frequency adaptation (SFA), inhibits the riluzole-activated current (IRIL), which flows mainly through TREK-2 channels, by about 45%, and reduces the open probability of identified single TREK-2 channels in cultured mSCG cells. The effect of BK on IRIL was precluded by the bradykinin receptor (B2R) antagonist HOE-140 (d-Arg-[Hyp3, Thi5, d-Tic7, Oic8]BK) but also by diC8PIP2 which prevents PIP2 depletion when phospholipase C (PLC) is activated. On the contrary, antagonizing inositol triphosphate receptors (IP3R) using 2-aminoethoxydiphenylborane (2-APB) or inhibiting protein kinase C (PKC) with bisindolylmaleimide did not affect the inhibition of IRIL by BK. In conclusion, bradykinin inhibits TREK-2 channels through the activation of B2Rs resulting in PIP2 depletion, much like we have demonstrated for muscarinic agonists. This mechanism implies that TREK channels must be relevant for the capture of information about pain and visceral inflammation.

Contribution of KCNQ and TREK Channels to the Resting Membrane Potential in Sympathetic Neurons at Physiological Temperature.

The ionic mechanisms controlling the resting membrane potential (RMP) in superior cervical ganglion (SCG) neurons have been widely studied and the M-current (IM, KCNQ) is one of the key players. Recently, with the discovery of the presence of functional TREK-2 (TWIK-related K+ channel 2) channels in SCG neurons, another potential main contributor for setting the value of the resting membrane potential has appeared. In the present work, we quantified the contribution of TREK-2 channels to the resting membrane potential at physiological temperature and studied its role in excitability using patch-clamp techniques. In the process we have discovered that TREK-2 channels are sensitive to the classic M-current blockers linopirdine and XE991 (IC50 = 0.310 ± 0.06 µM and 0.044 ± 0.013 µM, respectively). An increase from room temperature (23 °C) to physiological temperature (37 °C) enhanced both IM and TREK-2 currents. Likewise, inhibition of IM by tetraethylammonium (TEA) and TREK-2 current by XE991 depolarized the RMP at room and physiological temperatures. Temperature rise also enhanced adaptation in SCG neurons which was reduced due to TREK-2 and IM inhibition by XE991 application. In summary, TREK-2 and M currents contribute to the resting membrane potential and excitability at room and physiological temperature in the primary culture of mouse SCG neurons.

Chemometric comparison of almond oxidation rates using kinetic parameters obtained by infrared spectroscopy.

BACKGROUND: The study of almond fat stability is essential from a quality control perspective meanly because, in most of the cases, almonds are sold skinned and thermally treated. In this work an alternative method to Rancimat test based on attenuated total reflectance-Fourier-transform infrared (ATR-FTIR) spectrometry was adapted for checking the induced degradation at 75 °C of seven almond oil cultivars, three of the top Californian producing varieties, and, four traditional cultivars harvested in Spain. RESULTS: The thermal oil degradation evolution was followed by measuring the changes in the absorbance of the selected FTIR spectra bands (3470, 3006, 1730, 1630, 988 and 970 cm-1 ). A first-order kinetic behaviour was observed, after an induction time in all bands. CONCLUSIONS: Kinetic coefficients and induction times were easily obtained as the absorbance values (from difference spectra) fitted to pseudo-first-order kinetics after the induction time. Principal component analysis was applied to the kinetic parameters to visualize which variables could be useful to classify the almond cultivars based on their resistance to thermal oxidation processes. It was found that selecting only the induction times corresponding to the bands 3470, 3006, 1630 and 970 cm-1 a separate classification of the Californian cultivars from the Spanish ones was possible. Finally, a linear discriminant analysis was assayed using only the four induction times previously selected. Validated classification and correct in 100% of the cases was obtained for all the samples based on their Spanish or Californian origin. © 2020 Society of Chemical Industry.

Role of obesity in the release of extracellular nucleosomes in acute pancreatitis: a clinical and experimental study.

BACKGROUND/OBJECTIVES: A high body mass index increases the risk of severe pancreatitis and associated mortality. Our aims were: (1) To determine whether obesity affects the release of extracellular nucleosomes in patients with pancreatitis; (2) To determine whether pancreatic ascites confers lipotoxicity and triggers the release of extracellular nucleosomes in lean and obese rats. METHODS: DNA and nucleosomes were determined in plasma from patients with mild or moderately severe acute pancreatitis either with normal or high body mass index (BMI). Lipids from pancreatic ascites from lean and obese rats were analyzed and the associated toxicity measured in vitro in RAW 264.7 macrophages. The inflammatory response, extracellular DNA and nucleosomes were determined in lean or obese rats with pancreatitis after peritoneal lavage. RESULTS: Nucleosome levels in plasma from obese patients with mild pancreatitis were higher than in normal BMI patients; these levels markedly increased in obese patients with moderately severe pancreatitis vs. those with normal BMI. Ascites from obese rats exhibited high levels of palmitic, oleic, stearic, and arachidonic acids. Necrosis and histone 4 citrullination-marker of extracellular traps-increased in macrophages incubated with ascites from obese rats but not with ascites from lean rats. Peritoneal lavage abrogated the increase in DNA and nucleosomes in plasma from lean or obese rats with pancreatitis. It prevented fat necrosis and induction of HIF-related genes in lung. CONCLUSIONS: Extracellular nucleosomes are intensely released in obese patients with acute pancreatitis. Pancreatitis-associated ascitic fluid triggers the release of extracellular nucleosomes in rats with severe pancreatitis.

Intraspecific variation in lizard heat tolerance alters estimates of climate impact.

Research addressing the effects of global warming on the distribution and persistence of species generally assumes that population variation in thermal tolerance is spatially constant or overridden by interspecific variation. Typically, this rationale is implicit in sourcing one critical thermal maximum (CTmax ) population estimate per species to model spatiotemporal cross-taxa variation in heat tolerance. Theory suggests that such an approach could result in biased or imprecise estimates and forecasts of impact from climate warming, but limited empirical evidence in support of those expectations exists. We experimentally quantify the magnitude of intraspecific variation in CTmax among lizard populations, and the extent to which incorporating such variability can alter estimates of climate impact through a biophysical model. To do so, we measured CTmax from 59 populations of 15 Iberian lizard species (304 individuals). The overall median CTmax across all individuals from all species was 42.8°C and ranged from 40.5 to 48.3°C, with species medians decreasing through xeric, climate-generalist and mesic taxa. We found strong statistical support for intraspecific differentiation in CTmax by up to a median of 3°C among populations. We show that annual restricted activity (operative temperature > CTmax ) over the Iberian distribution of our study species differs by a median of >80 hr per 25-km2 grid cell based on different population-level CTmax estimates. This discrepancy leads to predictions of spatial variation in annual restricted activity to change by more than 20 days for six of the study species. Considering that during restriction periods, reptiles should be unable to feed and reproduce, current projections of climate-change impacts on the fitness of ectotherm fauna could be under- or over-estimated depending on which population is chosen to represent the physiological spectra of the species in question. Mapping heat tolerance over the full geographical ranges of single species is thus critical to address cross-taxa patterns and drivers of heat tolerance in a biologically comprehensive way.

Ion Channels and Thermosensitivity: TRP, TREK, or Both?

Controlling body temperature is a matter of life or death for most animals, and in mammals the complex thermoregulatory system is comprised of thermoreceptors, thermosensors, and effectors. The activity of thermoreceptors and thermoeffectors has been studied for many years, yet only recently have we begun to obtain a clear picture of the thermosensors and the molecular mechanisms involved in thermosensory reception. An important step in this direction was the discovery of the thermosensitive transient receptor potential (TRP) cationic channels, some of which are activated by increases in temperature and others by a drop in temperature, potentially converting the cells in which they are expressed into heat and cold receptors. More recently, the TWIK-related potassium (TREK) channels were seen to be strongly activated by increases in temperature. Hence, in this review we want to assess the hypothesis that both these groups of channels can collaborate, possibly along with other channels, to generate the wide range of thermal sensations that the nervous system is capable of handling.

Epigenetic Regulation of Early- and Late-Response Genes in Acute Pancreatitis.

Chromatin remodeling seems to regulate the patterns of proinflammatory genes. Our aim was to provide new insights into the epigenetic mechanisms that control transcriptional activation of early- and late-response genes in initiation and development of severe acute pancreatitis as a model of acute inflammation. Chromatin changes were studied by chromatin immunoprecipitation analysis, nucleosome positioning, and determination of histone modifications in promoters of proinflammatory genes in vivo in the course of taurocholate-induced necrotizing pancreatitis in rats and in vitro in rat pancreatic AR42J acinar cells stimulated with taurocholate or TNF-α. Here we show that the upregulation of early and late inflammatory genes rely on histone acetylation associated with recruitment of histone acetyltransferase CBP. Chromatin remodeling of early genes during the inflammatory response in vivo is characterized by a rapid and transient increase in H3K14ac, H3K27ac, and H4K5ac as well as by recruitment of chromatin-remodeling complex containing BRG-1. Chromatin remodeling in late genes is characterized by a late and marked increase in histone methylation, particularly in H3K4. JNK and p38 MAPK drive the recruitment of transcription factors and the subsequent upregulation of early and late inflammatory genes, which is associated with nuclear translocation of the early gene Egr-1 In conclusion, specific and strictly ordered epigenetic markers such as histone acetylation and methylation, as well as recruitment of BRG-1-containing remodeling complex are associated with the upregulation of both early and late proinflammatory genes in acute pancreatitis. Our findings highlight the importance of epigenetic regulatory mechanisms in the control of the inflammatory cascade.

Autologous platelet-rich plasma in the treatment of venous leg ulcers in primary care: a randomised controlled, pilot study.

OBJECTIVE: To examine the potential efficacy and safety of autologous platelet-rich plasma (PRP) in comparison with the conventional treatment (standard care, SoC) for the treatment of leg ulcers in patients with chronic venous insufficiency, in a primary health-care setting. METHOD: A Phase I-II, open-label, parallel-group, multicentre, randomised pilot study was conducted. The outcome variables at baseline and at weeks five and nine included reduction in the ulcer area, Chronic Venous Insufficiency Quality of Life Questionnaire score, cost of the treatment for up to nine weeks and average weekly cure rate. RESULTS: A total of eight patients, each with at least a six-month history of venous leg ulcer (VLUs), were included in the study. A total of 12 ulcers were treated with either autologous PRP or standard SoC. Patients treated with PRP required wound care only once per week. In the SoC group, patients required intervention 2-3 times per week. A reduction in the mean ulcer size in the PRP group was 3.9cm2 compared with the SoC group at 3.2cm 2 , although the sample size was insufficient to reach statistical significance. Improvement in quality of life (QoL) score was observed in the patients in the PRP group. CONCLUSION: This study offers proof-of-concept of the feasibility and safety of PRP treatment to inform larger clinical trials in patients with VLUs. Our preliminary results suggest that PRP delivers a safe and effective treatment for VLU care that can be implemented in primary health-care settings.

Enhancing LoRaWAN Security through a Lightweight and Authenticated Key Management Approach.

Luckily, new communication technologies and protocols are nowadays designed considering security issues. A clear example of this can be found in the Internet of Things (IoT) field, a quite recent area where communication technologies such as ZigBee or IPv6 over Low power Wireless Personal Area Networks (6LoWPAN) already include security features to guarantee authentication, confidentiality and integrity. More recent technologies are Low-Power Wide-Area Networks (LP-WAN), which also consider security, but present initial approaches that can be further improved. An example of this can be found in Long Range (LoRa) and its layer-two supporter LoRa Wide Area Network (LoRaWAN), which include a security scheme based on pre-shared cryptographic material lacking flexibility when a key update is necessary. Because of this, in this work, we evaluate the security vulnerabilities of LoRaWAN in the area of key management and propose different alternative schemes. Concretely, the application of an approach based on the recently specified Ephemeral Diffie⁻Hellman Over COSE (EDHOC) is found as a convenient solution, given its flexibility in the update of session keys, its low computational cost and the limited message exchanges needed. A comparative conceptual analysis considering the overhead of different security schemes for LoRaWAN is carried out in order to evaluate their benefits in the challenging area of LP-WAN.

Total Knee Arthroplasty After Failed Unicompartmental Knee Arthroplasty. Clinical Results, Radiologic Findings, and Technical Tips.

BACKGROUND: The loss of anatomic references and bone stock turns unicompartmental knee arthroplasty (UKA) revision surgery difficult, and according to some authors, it is technically as challenging as a total knee arthroplasty (TKA) revision surgery. METHODS: A retrospective review of 559 Oxford medial UKA was performed between 2007 and 2013. Nineteen knees were revised to TKA for reasons other than infection, most commonly for osteoarthritis progression. RESULTS: The most frequent cause of failure in our series was osteoarthritis progression (10 cases, 52.63%). In 15 patients (78.95%), tibial stems were needed, and in 10 (55.5%), metallic blocks for augmentation of tibial plateau were used. Postoperative radiographic studies showed a correct implant alignment, preserving adequate joint line (24.8 mm), and patellar (1.1 mm) height (according to Insall-Salvati). After a mean follow-up of 21 months (range 6-51) mean values of 78.8 (standard deviation [SD] = 16.8) and 62.3 (SD = 19.6) were obtained for the physical and mental scores of the Knee Society Score test. In the SF-36 tests mean values of 45.2 (SD = 7.6) and 53 (SD = 5.2) were obtained for the physical and mental scores respectively. In one case, a varus/valgus instability occurred intraoperatively and it required revision with a prosthesis with higher constriction. No thromboembolic or infectious events were observed during postoperative follow-up. CONCLUSION: Following a standardized technique, UKA revision surgery can be achieved with TKA in almost every case despite bone stock loss and lack of anatomic landmarks.

Predictors of contraction and expansion of area of occupancy for British birds.

Geographical range dynamics are driven by the joint effects of abiotic factors, human ecosystem modifications, biotic interactions and the intrinsic organismal responses to these. However, the relative contribution of each component remains largely unknown. Here, we compare the contribution of life-history attributes, broad-scale gradients in climate and geographical context of species' historical ranges, as predictors of recent changes in area of occupancy for 116 terrestrial British breeding birds (74 contractors, 42 expanders) between the early 1970s and late 1990 s. Regional threat classifications demonstrated that the species of highest conservation concern showed both the largest contractions and the smallest expansions. Species responded differently to climate depending on geographical distribution-northern species changed their area of occupancy (expansion or contraction) more in warmer and drier regions, whereas southern species changed more in colder and wetter environments. Species with slow life history (larger body size) tended to have a lower probability of changing their area of occupancy than species with faster life history, whereas species with greater natal dispersal capacity resisted contraction and, counterintuitively, expansion. Higher geographical fragmentation of species' range also increased expansion probability, possibly indicating a release from a previously limiting condition, for example through agricultural abandonment since the 1970s. After accounting statistically for the complexity and nonlinearity of the data, our results demonstrate two key aspects of changing area of occupancy for British birds: (i) climate is the dominant driver of change, but direction of effect depends on geographical context, and (ii) all of our predictors generally had a similar effect regardless of the direction of the change (contraction versus expansion). Although we caution applying results from Britain's highly modified and well-studied bird community to other biogeographic regions, our results do indicate that a species' propensity to change area of occupancy over decadal scales can be explained partially by a combination of simple allometric predictors of life-history pace, average climate conditions and geographical context.

Pancreatic T cell protein-tyrosine phosphatase deficiency ameliorates cerulein-induced acute pancreatitis.

BACKGROUND: Acute pancreatitis (AP) is a common clinical problem whose incidence has been progressively increasing in recent years. Onset of the disease is trigged by intra-acinar cell activation of digestive enzyme zymogens that induce autodigestion, release of pro-inflammatory cytokines and acinar cell injury. T-cell protein tyrosine phosphatase (TCPTP) is implicated in inflammatory signaling but its significance in AP remains unclear. RESULTS: In this study we assessed the role of pancreatic TCPTP in cerulein-induced AP. TCPTP expression was increased at the protein and messenger RNA levels in the early phase of AP in mice and rats. To directly determine whether TCPTP may have a causal role in AP we generated mice with pancreatic TCPTP deletion (panc-TCPTP KO) by crossing TCPTP floxed mice with Pdx1-Cre transgenic mice. Amylase and lipase levels were lower in cerulein-treated panc-TCPTP KO mice compared with controls. In addition, pancreatic mRNA and serum concentrations of the inflammatory cytokines TNFα and IL-6 were lower in panc-TCPTP KO mice. At the molecular level, panc-TCPTP KO mice exhibited enhanced cerulein-induced STAT3 Tyr705 phosphorylation accompanied by a decreased cerulein-induced NF-κB inflammatory response, and decreased ER stress and cell death. CONCLUSION: These findings revealed a novel role for pancreatic TCPTP in the progression of cerulein-induced AP.