Effects of Geochemical and Environmental Parameters on Abiotic Organic Chemistry Driven by Iron Hydroxide Minerals

Geological conditions play a significant role in prebiotic/abiotic organic chemistry, especially when reactive minerals are present. Previous studies of the prebiotic synthesis of amino acids and other products in mineral‐containing systems have shown that a diverse array of compounds can be produced, depending on the experimental conditions. However, these previous experiments have not simulated the effects of varying geochemical conditions, in which factors such as pH, iron redox state, or chemical concentrations may vary over time and space in a natural environment. In geochemical systems that contain overlapping gradients, many permutations of individual conditions could exist and affect the outcome of an organic reaction network. We investigated reactions of pyruvate and glyoxylate, two compounds that are central to the emergence of metabolism, in simulated geological gradients of redox, pH, and ammonia concentration. Our results show that the positioning of pyruvate/glyoxylate reactions in this environmental parameter space determines the organic product distribution that results. Therefore, the distribution pattern of amino acids and alpha‐hydroxy acids produced prebiotically in a system reflects the specific reaction conditions, and would be distinct at various locations in an environment depending on local geochemistry. This is significant for origin of life chemistry in which the composition and function of oligomers could be affected by the environmentally driven distribution of monomers available. Also, for astrobiology and planetary science where organic distribution patterns are sometimes considered as a possible biosignature, it is important to consider environmentally driven abiotic organic reactions that might produce similar effects

CD4 Effectors Need to Recognize Antigen Locally to Become Cytotoxic CD4 and Follicular Helper T Cells [preprint]

T follicular helper (TFH) and Cytotoxic CD4 (ThCTL) are tissue-restricted CD4 effector subsets, functionally specialized to mediate optimal Ab production and cytotoxicity of infected cells. Influenza infection generates robust CD4 responses, including lung ThCTL and SLO TFH, that protect against reinfection by variant strains. Antigen (Ag) presentation after infection, lasts through the effector phase of the response. Here, we show that this effector phase Ag presentation, well after priming, is required to drive CD4 effectors to ThCTL and TFH. Using in vivo influenza models, we varied Ag presentation to effectors acutely, just at the effector phase. Ag presentation was required in the tissue of effector residence. We suggest these requirements contain unnecessary or potentially pathogenic CD4 responses, only allowing them if infection is uncleared. The results imply that providing effector phase Ag, would lead to stronger humoral and CD4 tissue immunity and thus can be applied to improve vaccine design

Model-based Bayesian inference of neural activity and connectivity from all-optical interrogation of a neural circuit

Neural information processing systems foundation. All rights reserved. Population activity measurement by calcium imaging can be combined with cellular resolution optogenetic activity perturbations to enable the mapping of neural connectivity in vivo. This requires accurate inference of perturbed and unperturbed neural activity from calcium imaging measurements, which are noisy and indirect, and can also be contaminated by photostimulation artifacts. We have developed a new fully Bayesian approach to jointly inferring spiking activity and neural connectivity from in vivo all-optical perturbation experiments. In contrast to standard approaches that perform spike inference and analysis in two separate maximum-likelihood phases, our joint model is able to propagate uncertainty in spike inference to the inference of connectivity and vice versa. We use the framework of variational autoencoders to model spiking activity using discrete latent variables, low-dimensional latent common input, and sparse spike-and-slab generalized linear coupling between neurons. Additionally, we model two properties of the optogenetic perturbation: off-target photostimulation and photostimulation transients. Using this model, we were able to fit models on 30 minutes of data in just 10 minutes. We performed an all-optical circuit mapping experiment in primary visual cortex of the awake mouse, and use our approach to predict neural connectivity between excitatory neurons in layer 2/3. Predicted connectivity is sparse and consistent with known correlations with stimulus tuning, spontaneous correlation and distance

Differential chloride homeostasis in the spinal dorsal horn locally shapes synaptic metaplasticity and modality-specific sensitization

Inhibition in spinal nociceptive pathways is weaker and more labile in lamina I —where thermal input is primarily processed— than in lamina II that encodes predominantly high threshold mechanical input. This explains why noxious thermal input makes spinal circuits prone to catastrophic sensitization

Сберегательное поведение в контексте исследования белорусской деловой культуры

Материалы X Международной научной конференции 25–26 мая 2017 г

Organometallic iridium(III) anticancer complexes with new mechanisms of action: NCI-60 screening, mitochondrial targeting, and apoptosis

Platinum complexes related to cisplatin, cis-[PtCl2(NH3)2], are successful anticancer drugs; however, other transition metal complexes offer potential for combating cisplatin resistance, decreasing side effects, and widening the spectrum of activity. Organometallic half-sandwich iridium (IrIII) complexes [Ir(Cpx)(XY)Cl]+/0 (Cpx = biphenyltetramethylcyclopentadienyl and XY = phenanthroline (1), bipyridine (2), or phenylpyridine (3)) all hydrolyze rapidly, forming monofunctional G adducts on DNA with additional intercalation of the phenyl substituents on the Cpx ring. In comparison, highly potent complex 4 (Cpx = phenyltetramethylcyclopentadienyl and XY = N,N-dimethylphenylazopyridine) does not hydrolyze. All show higher potency toward A2780 human ovarian cancer cells compared to cisplatin, with 1, 3, and 4 also demonstrating higher potency in the National Cancer Institute (NCI) NCI-60 cell-line screen. Use of the NCI COMPARE algorithm (which predicts mechanisms of action (MoAs) for emerging anticancer compounds by correlating NCI-60 patterns of sensitivity) shows that the MoA of these IrIII complexes has no correlation to cisplatin (or oxaliplatin), with 3 and 4 emerging as particularly novel compounds. Those findings by COMPARE were experimentally probed by transmission electron microscopy (TEM) of A2780 cells exposed to 1, showing mitochondrial swelling and activation of apoptosis after 24 h. Significant changes in mitochondrial membrane polarization were detected by flow cytometry, and the potency of the complexes was enhanced ca. 5× by co-administration with a low concentration (5 μM) of the γ-glutamyl cysteine synthetase inhibitor L-buthionine sulfoximine (L-BSO). These studies reveal potential polypharmacology of organometallic IrIII complexes, with MoA and cell selectivity governed by structural changes in the chelating ligands

Use of NSAIDs, smoking and lung cancer risk

We investigated the risk of lung cancer in relation to non-steroidal anti-inflammatory drugs (NSAIDs) among 573 cases and 857 sex- and age-matched controls for whom we had information on use of NSAIDs, from a prescription database covering all pharmacies in Denmark since 1995, and self-reported NSAID use, smoking habits and other potential confounders. Associations were expressed as odds ratios, assessed by logistic regression in unmatched analyses. After controlling for smoking habits, length of education and concomitant use of acetaminophen, we found a slightly decreased relative risk of 0.86 (95% confidence intervals, 0.65–1.14) for lung cancer associated with any use of NSAIDs. The risk decreased significantly (P=0.02) with increasing numbers of dispensed prescriptions per year during the 1–3 years before the index date with a relative risk of 0.49 (0.28–0.84) among those with four or more prescriptions per year during this period. Our findings suggest that regular use of NSAIDs is associated with a slightly or moderately reduced risk for lung cancer

Looking both ways

On the occasion of the 25th anniversary of the journal, Psychotherapy Research, three former editors first look back at: (i) the controversial persistence of the Dodo verdict (i.e., the observation that all bona fide therapies seem equally effective); (ii) the connection between process and outcome; (iii) the move toward methodological pluralism; and (iv) the politicization of the field around evidence-based practice and treatment guidelines. We then look forward to the next 25 years, suggesting that it would be promising to focus on three areas: (i) systematic theory-building research; (ii) renewed attention to fine-grained study of therapist techniques; and (iii) politically expedient research on the outcomes of marginalized or emerging therapies