Pore dilation occurs in TRPA1 but not in TRPM8 channels

Abundantly expressed in pain-sensing neurons, TRPV1, TRPA1 and TRPM8 are major cellular sensors of thermal, chemical and mechanical stimuli. The function of these ion channels has been attributed to their selective permeation of small cations (e.g., Ca2+, Na+ and K+), and the ion selectivity has been assumed to be an invariant fingerprint to a given channel. However, for TRPV1, the notion of invariant ion selectivity has been revised recently. When activated, TRPV1 undergoes time and agonist-dependent pore dilation, allowing permeation of large organic cations such as Yo-Pro and NMDG+. The pore dilation is of physiological importance, and has been exploited to specifically silence TRPV1-positive sensory neurons. It is unknown whether TRPA1 and TRPM8 undergo pore dilation. Here we show that TRPA1 activation by reactive or non-reactive agonists induces Yo-Pro uptake, which can be blocked by TRPA1 antagonists. In outside-out patch recordings using NMDG+ as the sole external cation and Na+ as the internal cation, TRPA1 activation results in dynamic changes in permeability to NMDG+. In contrast, TRPM8 activation does not produce either Yo-Pro uptake or significant change in ion selectivity. Hence, pore dilation occurs in TRPA1, but not in TRPM8 channels

The Nature of Infrared Emission in the Local Group Dwarf Galaxy NGC 6822 As Revealed by Spitzer

We present Spitzer imaging of the metal-deficient (Z ~30% Z_sun) Local Group dwarf galaxy NGC 6822. On spatial scales of ~130 pc, we study the nature of IR, H alpha, HI, and radio continuum emission. Nebular emission strength correlates with IR surface brightness; however, roughly half of the IR emission is associated with diffuse regions not luminous at H alpha (as found in previous studies). The global ratio of dust to HI gas in the ISM, while uncertain at the factor of ~2 level, is ~25 times lower than the global values derived for spiral galaxies using similar modeling techniques; localized ratios of dust to HI gas are about a factor of five higher than the global value in NGC 6822. There are strong variations (factors of ~10) in the relative ratios of H alpha and IR flux throughout the central disk; the low dust content of NGC 6822 is likely responsible for the different H alpha/IR ratios compared to those found in more metal-rich environments. The H alpha and IR emission is associated with high-column density (> ~1E21 cm^-2) neutral gas. Increases in IR surface brightness appear to be affected by both increased radiation field strength and increased local gas density. Individual regions and the galaxy as a whole fall within the observed scatter of recent high-resolution studies of the radio-far IR correlation in nearby spiral galaxies; this is likely the result of depleted radio and far-IR emission strengths in the ISM of this dwarf galaxy.Comment: ApJ, in press; please retrieve full-resolution version from http://www.astro.wesleyan.edu/~cannon/pubs.htm

Anti-inflammatory effects of antidepressant and atypical antipsychotic medication for the treatment of major depression and comorbid arthritis: a case report

Extent: 4p.Introduction: This case report describes the effects of psychotropic treatment, quetiapine in particular, on systemic inflammation, pain, general functioning and major depression in the treatment of a woman with arthritis. Case presentation: A 49-year-old Caucasian Australian woman with arthritis, pain and depression was treated with a course of escitalopram, mirtazapine and quetiapine. Pain levels, general functioning and degree of depressive symptoms were evaluated with a visual analogue scale. Systemic inflammation had been assessed by C-reactive protein serum levels since 2003. C-reactive protein levels, physical pain, symptoms of arthritis and depression decreased significantly during the past 12 months of treatment with quetiapine, while treatment with selective serotonin reuptake inhibitors and mirtazapine remained the same. Conclusions: We suggest that the treatment particularly with quetiapine may have anti-inflammatory effects in arthritis and comorbid major depression, which eventually led to a remission of pain and depression and to normal general function.Bernhard T Baune, Harris Eyr

Global gene expression profile progression in Gaucher disease mouse models

<p>Abstract</p> <p>Background</p> <p>Gaucher disease is caused by defective glucocerebrosidase activity and the consequent accumulation of glucosylceramide. The pathogenic pathways resulting from lipid laden macrophages (Gaucher cells) in visceral organs and their abnormal functions are obscure.</p> <p>Results</p> <p>To elucidate this pathogenic pathway, developmental global gene expression analyses were conducted in distinct <it>Gba1 </it>point-mutated mice (V394L/V394L and D409 V/null). About 0.9 to 3% of genes had altered expression patterns (≥ ± 1.8 fold change), representing several categories, but particularly macrophage activation and immune response genes. Time course analyses (12 to 28 wk) of INFγ-regulated pro-inflammatory (13) and IL-4-regulated anti-inflammatory (11) cytokine/mediator networks showed tissue differential profiles in the lung and liver of the <it>Gba1 </it>mutant mice, implying that the lipid-storage macrophages were not functionally inert. The time course alterations of the INFγ and IL-4 pathways were similar, but varied in degree in these tissues and with the <it>Gba1 </it>mutation.</p> <p>Conclusions</p> <p>Biochemical and pathological analyses demonstrated direct relationships between the degree of tissue glucosylceramides and the gene expression profile alterations. These analyses implicate IFNγ-regulated pro-inflammatory and IL-4-regulated anti-inflammatory networks in differential disease progression with implications for understanding the Gaucher disease course and pathophysiology.</p

The Contribution of Religiosity to Ideology:Empirical Evidences From Five Continents

The current study examines the extent to which religiosity account for ideological orientations in 16 countries from five continents (Australia, Brazil, Chile, Germany, Greece, Finland, Israel, Italy, Japan, Poland, Slovakia, Spain, Turkey, Ukraine, the United Kingdom, and the United States). Results showed that religiosity was consistently related to right and conservative ideologies in all countries, except Australia. This relation held across different religions, and did not vary across participant’s demographic conditions (i.e., gender, age, income, and education). After controlling for basic personal values, the contribution of religiosity on ideology was still significant. However, the effect was substantial only in countries where religion has played a prominent role in the public sphere, such as Spain, Poland, Greece, Italy, Slovakia, and Turkey. In the other countries, the unique contribution of religiosity was marginal or small

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Studies of new Higgs boson interactions through nonresonant HH production in the b¯bγγ fnal state in pp collisions at √s = 13 TeV with the ATLAS detector

A search for nonresonant Higgs boson pair production in the b ¯bγγ fnal state is performed using 140 fb−1 of proton-proton collisions at a centre-of-mass energy of 13 TeV recorded by the ATLAS detector at the CERN Large Hadron Collider. This analysis supersedes and expands upon the previous nonresonant ATLAS results in this fnal state based on the same data sample. The analysis strategy is optimised to probe anomalous values not only of the Higgs (H) boson self-coupling modifer κλ but also of the quartic HHV V (V = W, Z) coupling modifer κ2V . No signifcant excess above the expected background from Standard Model processes is observed. An observed upper limit µHH &lt; 4.0 is set at 95% confdence level on the Higgs boson pair production cross-section normalised to its Standard Model prediction. The 95% confdence intervals for the coupling modifers are −1.4 &lt; κλ &lt; 6.9 and −0.5 &lt; κ2V &lt; 2.7, assuming all other Higgs boson couplings except the one under study are fxed to the Standard Model predictions. The results are interpreted in the Standard Model efective feld theory and Higgs efective feld theory frameworks in terms of constraints on the couplings of anomalous Higgs boson (self-)interactions