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Cisapride is a synthetic drug which binds, in vitro, to type 2 serotonin receptors. We examined the influence of serotonin and cisapride on ion transport across intestinal mucosa in vitro and studied the effect of cisapride on the response to serotonin. Segments of ileum of male Sprague-Dawley rats were stripped of muscle layers and mounted in flux chambers. The addition of serotonin (10(-8) to 10(-4) M) to the serosal aspect of the mucosa caused a rapid, dose-dependent rise in short circuit current and transmural potential difference. Cisapride alone (5 X 10(-5) M), when added to the mucosal and serosal surfaces, had no effect on the short circuit current, transmural potential difference, resistance, or sodium and chloride fluxes across the mucosa. It did, however, inhibit the response of the mucosa to serotonin (10(-5) M) in a dose dependent manner and blocked it completely at a concentration of 5 X 10(-5) M. Serotonin (5 X 10(-5) M) increased serosal to mucosal flux of chloride from 12.6 +/- 0.8 to 15.2 +/- 0.6 mumol/cm2/h (p less than 0.025), thus reducing net chloride absorption from 4.65 +/- 0.81 to 1.49 +/- 1.04 mumol/cm2/h (p less than 0.05). This effect was completely blocked by cisapride (5 X 10(-5) M). In summary, cisapride inhibits the effect of serotonin on rat ileal ion transport, probably by blocking type 2 serotonin receptors. [ABSTRACT FROM PUBLISHER]

Michael R Woodford1, Amy R Krentzman2, Maurice N Gattis31School of Social Work, University of Michigan, Ann Arbor, MI, USA; 2Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA; 3School of Social Work, University of Wisconsin-Madison, Madison, WI, USAPurpose: Research suggests that discrimination contributes to increased substance use among sexual minorities. Subtle discrimination and witnessing mistreatment, however, have received little attention. Using minority stress theory as a conceptual framework the authors examined the intersection of sexual orientation, experiencing and witnessing incivility and hostility, and students' alcohol and drug use. The authors hypothesized that experiencing/witnessing incivility/hostility would mediate the relationship between sexual minority status and drinking and drug use, as well as problematic use of these substances.Methods: Data were taken from a campus climate survey (n = 2497; age mean [M] = 23.19 years; 61% female; 17% sexual minorities). Controlling for demographics, logistic regressions depicted specifications for each path of the mediation analysis and bootstrapping was used to assess the significance of each sexual minority-mistreatment-drinking/drug use path.Results: Experiencing incivility mediated the relationship between sexual minority status and problematic drinking. Sexual minority college students were more likely to personally experience incivility (adjusted odds ratio [AOR] = 1.87; 95% confidence interval [CI] = 1.51–2.33), which was associated with greater odds of problematic drinking (AOR = 1.64; 95% CI = 1.35–2.00). The mediation path was significant at P < 0.001. Further, witnessing hostility mediated the relationship between sexual minority status and problematic drinking. Sexual minority college students were more likely to witness hostility (AOR = 1.87, 95% CI = 1.48–2.36), which was associated with greater odds of problematic drinking (AOR = 1.53; 95% CI = 1.24–1.90). The mediation path was significant at P < 0.01.Conclusion: The results provide further evidence for minority stress theory and suggest that clinical alcohol use interventions with sexual minorities need to assess personal incivilities and witnessing interpersonal mistreatment, especially hostility. Campus climate interventions that address subtle discrimination as well as harassment and violence may help reduce problematic drinking.Keywords: sexual orientation, discrimination, minority stress, campus climate, drinking, substance use

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Abstract Background The purpose of Abbreviated Injury Scale (AIS) is to code various types of Traumatic Brain Injuries (TBI) based on their anatomical location and severity. The Marshall CT Classification is used to identify those subgroups of brain injured patients at higher risk of deterioration or mortality. The purpose of this study is to determine whether and how AIS coding can be translated to the Marshall Classification Methods Initially, a Marshall Class was allocated to each AIS code through cross-tabulation. This was agreed upon through several discussion meetings with experts from both fields (clinicians and AIS coders). Furthermore, in order to make this translation possible, some necessary assumptions with regards to coding and classification of mass lesions and brain swelling were essential which were all approved and made explicit. Results The proposed method involves two stages: firstly to determine all possible Marshall Classes which a given patient can attract based on allocated AIS codes; via cross-tabulation and secondly to assign one Marshall Class to each patient through an algorithm. Conclusion This method can be easily programmed in computer softwares and it would enable future important TBI research programs using trauma registry data.

Abstract Background Intracranial bleeding (IB) is a common and serious consequence of traumatic brain injury (TBI). IB can be classified according to the location into: epidural haemorrhage (EDH) subdural haemorrhage (SDH) intraparenchymal haemorrhage (IPH) and subarachnoid haemorrhage (SAH). Studies involving repeated CT scanning of TBI patients have found that IB can develop or expand in the 48 hours after injury. If IB enlarges after hospital admission and larger bleeds have a worse prognosis, this would provide a therapeutic rationale for treatments to prevent increase in the extent of bleeding. We analysed data from the Trauma Audit & Research Network (TARN), a large European trauma registry, to evaluate the association between the size of IB and mortality in patients with TBI. Methods We analysed 13,962 patients presenting to TARN participating hospitals between 2001 and 2008 with a Glasgow Coma Score (GCS) less than 15 at presentation or any head injury with Abbreviated Injury Scale (AIS) severity code 3 and above. The extent of intracranial bleeding was determined by the AIS code. Potential confounders were age, presenting Glasgow Coma Score, mechanism of injury, presence and nature of other brain injuries, and presence of extra-cranial injuries. The outcomes were in-hospital mortality and haematoma evacuation. We conducted a multivariable logistic regression analysis to evaluate the independent effect of large and small size of IB, in comparison with no bleeding, on patient outcomes. We also conducted a multivariable logistic regression analysis to assess the independent effect on mortality of large IB in comparison with small IB. Results Almost 46% of patients had at some type of IB. Subdural haemorrhages were present in 30% of the patients, with epidural and intraparenchymal present in approximately 22% each. After adjusting for potential confounders, we found that large IB, wherever located, was associated with increased mortality in comparison with no bleeding. We also found that large IB was associated with an increased risk of mortality in comparison with small IB. The odds ratio for mortality for large SDH, IPH and EDH, in comparison with small bleeds, were: 3.41 (95% CI: 2.684.33), 3.47 (95% CI: 2.265.33) and 2.86 (95% CI: 1.864.38) respectively. Conclusion Large EDH, SDH and IPH are associated with a substantially higher probability of hospital mortality in comparison with small IB. However, the limitations of our data, such as the large proportion of missing data and lack of data on other confounding factors, such as localization of the bleeding, make the results of this report only explanatory. Future studies should also evaluate the effect of IB size on functional outcomes.

The efficient coding approach proposes that neural systems represent as much sensory information as biological constraints allow. It aims at formalizing encoding as a constrained optimal process. A different approach, that aims at formalizing decoding, proposes that neural systems instantiate a generative model of the sensory world. Here, we put forth a normative framework that characterizes neural systems as jointly optimizing encoding and decoding. It takes the form of a variational autoencoder: sensory stimuli are encoded in the noisy activity of neurons to be interpreted by a flexible decoder; encoding must allow for an accurate stimulus reconstruction from neural activity. Jointly, neural activity is required to represent the statistics of latent features which are mapped by the decoder into distributions over sensory stimuli; decoding correspondingly optimizes the accuracy of the generative model. This framework yields in a family of encoding-decoding models, which result in equally accurate generative models, indexed by a measure of the stimulus-induced deviation of neural activity from the marginal distribution over neural activity. Each member of this family predicts a specific relation between properties of the sensory neurons-such as the arrangement of the tuning curve means (preferred stimuli) and widths (degrees of selectivity) in the population-as a function of the statistics of the sensory world. Our approach thus generalizes the efficient coding approach. Notably, here, the form of the constraint on the optimization derives from the requirement of an accurate generative model, while it is arbitrary in efficient coding models. Moreover, solutions do not require the knowledge of the stimulus distribution, but are learned on the basis of data samples; the constraint further acts as regularizer, allowing the model to generalize beyond the training data. Finally, we characterize the family of models we obtain through alternate measures of performance, such as the error in stimulus reconstruction. We find that a range of models admits comparable performance; in particular, a population of sensory neurons with broad tuning curves as observed experimentally yields both low reconstruction stimulus error and an accurate generative model that generalizes robustly to unseen data., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Blanco Malerba et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

More than 99% of the mitochondrial proteome is encoded by the nucleus and requires refolding following import. Therefore, mitochondrial proteins require the coordinated action of molecular chaperones for their folding and activation. Several heat shock protein (Hsp) molecular chaperones, including members of the Hsp27, Hsp40/70, and Hsp90 families, as well as the chaperonin complex Hsp60/10 have an established role in mitochondrial protein import and folding. The "Chaperone Code" describes the regulation of chaperone activity by dynamic post-translational modifications; however, little is known about the post-translational regulation of mitochondrial chaperones. Dissecting the regulation of chaperone function is essential for understanding their differential regulation in pathogenic conditions and the potential development of efficacious therapeutic strategies. Here, we summarize the recent literature on post-translational regulation of mitochondrial chaperones, the consequences for mitochondrial function, and potential implications for disease., Competing Interests: Declarations of interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mark Woodford reports financial support was provided by SUNY Upstate Medical University. Mark Woodford reports financial support was provided by Upstate Foundation Inc. The corresponding author (Mark Woodford) serves as a Senior Editor for Cell Stress & Chaperones. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Base-rate neglect is a pervasive bias in judgment that is conceptualized as underweighting of prior information and can have serious consequences in real-world scenarios. This bias is thought to reflect variability in inferential processes but empirical support for a cohesive theory of base-rate neglect with sufficient explanatory power to account for longer-term and real-world beliefs is lacking. A Bayesian formalization of base-rate neglect in the context of sequential belief updating predicts that belief trajectories should exhibit dynamic patterns of dependence on the order in which evidence is presented and its consistency with prior beliefs. To test this, we developed a novel 'urn-and-beads' task that systematically manipulated the order of colored bead sequences and elicited beliefs via an incentive-compatible procedure. Our results in two independent online studies confirmed the predictions of the sequential base-rate neglect model: people exhibited beliefs that are more influenced by recent evidence and by evidence inconsistent with prior beliefs. We further found support for a noisy-sampling inference model whereby base-rate neglect results from rational discounting of noisy internal representations of prior beliefs. Finally, we found that model-derived indices of base-rate neglect-including noisier prior representation-correlated with propensity for unusual beliefs outside the laboratory. Our work supports the relevance of Bayesian accounts of sequential base-rate neglect to real-world beliefs and hints at strategies to minimize deleterious consequences of this pervasive bias., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Ashinoff et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Even in cases of medical emergency, mistreatment and negative experiences in life or in medical settings can deter trans patients from seeking necessary care. The purpose of this study was to identify factors associated with trans persons' emergency department (ED) avoidance in the mixed urban-rural Region of Waterloo, Ontario, Canada. Methods: The OutLook Study was a community-based partnership that created an online, cross-sectional questionnaire for lesbian, gay, bisexual, transgender, and other sexual and gender minority community members. Participants in this analysis were 16 years of age or older, lived, worked, or attended school in Waterloo Region, and identified as trans ( n =112). Binary logistic regression was used to test associations between sociodemographic, resilience, and risk variables, and ED avoidance. Sociodemographic variables statistically significant at p <0.05 at the bivariate level were included as controls to explore different combinations of resilience and risk factor in multivariable models. Results: Participants reporting complete or partially complete medical transitions were more likely to report ED avoidance, compared to those who had not initiated medical transition. Elevated transphobia was associated with greater likelihood of avoidance. However, increasing levels of social support decreased the likelihood of avoidance. In multivariable models, social support, support from a special person, and transphobia were always significant, regardless of controlled variables. Conclusion: Transphobia-enacted in the contexts of everyday life and health care-can deter patients from seeking care. Patient-centered care requires careful attention to trans identity and health needs, especially in emergency settings. In the absence of structural changes, providers can take steps to mitigate the erasure and discrimination trans patients experience and anticipate when accessing EDs., Competing Interests: No competing financial interests exist., (Copyright 2021, Mary Ann Liebert, Inc., publishers.)

In recent studies of humans estimating non-stationary probabilities, estimates appear to be unbiased on average, across the full range of probability values to be estimated. This finding is surprising given that experiments measuring probability estimation in other contexts have often identified conservatism: individuals tend to overestimate low probability events and underestimate high probability events. In other contexts, repulsive biases have also been documented, with individuals producing judgments that tend toward extreme values instead. Using extensive data from a probability estimation task that produces unbiased performance on average, we find substantial biases at the individual level; we document the coexistence of both conservative and repulsive biases in the same experimental context. Individual biases persist despite extensive experience with the task, and are also correlated with other behavioral differences, such as individual variation in response speed and adjustment rates. We conclude that the rich computational demands of our task give rise to a variety of behavioral patterns, and that the apparent unbiasedness of the pooled data is an artifact of the aggregation of heterogeneous biases., Competing Interests: The authors have declared that no competing interests exist.

Human decisions are based on finite information, which makes them inherently imprecise. But what determines the degree of such imprecision? Here, we develop an efficient coding framework for higher-level cognitive processes in which information is represented by a finite number of discrete samples. We characterize the sampling process that maximizes perceptual accuracy or fitness under the often-adopted assumption that full adaptation to an environmental distribution is possible, and show how the optimal process differs when detailed information about the current contextual distribution is costly. We tested this theory on a numerosity discrimination task, and found that humans efficiently adapt to contextual distributions, but in the way predicted by the model in which people must economize on environmental information. Thus, understanding decision behavior requires that we account for biological restrictions on information coding, challenging the often-adopted assumption of precise prior knowledge in higher-level decision systems., Competing Interests: JH, MW, RP No competing interests declared, (© 2020, Heng et al.)

Protein phosphatase 5 (PP5) is a serine/threonine protein phosphatase that regulates many cellular functions including steroid hormone signaling, stress response, proliferation, apoptosis, and DNA repair. PP5 is also a co-chaperone of the heat shock protein 90 molecular chaperone machinery that assists in regulation of cellular signaling pathways essential for cell survival and growth. PP5 plays a significant role in survival and propagation of multiple cancers, which makes it a promising target for cancer therapy. Though there are several naturally occurring PP5 inhibitors, none is specific for PP5. Here, we review the roles of PP5 in cancer progression and survival and discuss the unique features of the PP5 structure that differentiate it from other phosphoprotein phosphatase (PPP) family members and make it an attractive therapeutic target.