Brewermahoney3725

Together, we describe two unique variants with extreme effects on channel function. We employ protein-stability measures to explain why current (and future) LBD mutations in GluN2B primarily instigate Loss-of-Function.The Drosophila polarity protein Crumbs is essential for the establishment and growth of the apical domain in epithelial cells. The protein Yurt limits the ability of Crumbs to promote apical membrane growth, thereby defining proper apical/lateral membrane ratio that is crucial for forming and maintaining complex epithelial structures such as tubes or acini. Here, we show that Yurt also increases Myosin-dependent cortical tension downstream of Crumbs. Yurt overexpression thus induces apical constriction in epithelial cells. The kinase aPKC phosphorylates Yurt, thereby dislodging the latter from the apical domain and releasing apical tension. In contrast, the kinase Pak1 promotes Yurt dephosphorylation through activation of the phosphatase PP2A. The Pak1-PP2A module thus opposes aPKC function and supports Yurt-induced apical constriction. Hence, the complex interplay between Yurt, aPKC, Pak1, and PP2A contributes to the functional plasticity of Crumbs. Overall, our data increase our understanding of how proteins sustaining epithelial cell polarization and Myosin-dependent cell contractility interact with one another to control epithelial tissue architecture.The development of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) has been a critical in vitro advance in the study of patient-specific physiology, pathophysiology, and pharmacology. We designed a new deep learning multitask network approach intended to address the low throughput, high variability, and immature phenotype of the iPSC-CM platform. The rationale for combining translation and classification tasks is because the most likely application of the deep learning technology we describe here is to translate iPSC-CMs following application of a perturbation. The deep learning network was trained using simulated action potential (AP) data and applied to classify cells into the drug-free and drugged categories and to predict the impact of electrophysiological perturbation across the continuum of aging from the immature iPSC-CMs to the adult ventricular myocytes. The phase of the AP extremely sensitive to perturbation due to a steep rise of the membrane resistance was found to contain the key information required for successful network multitasking. We also demonstrated successful translation of both experimental and simulated iPSC-CM AP data validating our network by prediction of experimental drug-induced effects on adult cardiomyocyte APs by the latter.Disillusioned with conducting chemistry experiments in a basement, a new graduate student decides instead to dedicate her PhD to improving the culture of her research environment.Neural control of muscle function is fundamental to animal behavior. Many muscles can generate multiple distinct behaviors. Nonetheless, individual muscle cells are generally regarded as the smallest units of motor control. We report that muscle cells can alter behavior by contracting subcellularly. We previously discovered that noxious tastes reverse the net flow of particles through the C. elegans pharynx, a neuromuscular pump, resulting in spitting. We now show that spitting results from the subcellular contraction of the anterior region of the pm3 muscle cell. Subcellularly localized calcium increases accompany this contraction. Spitting is controlled by an 'hourglass' circuit motif parallel neural pathways converge onto a single motor neuron that differentially controls multiple muscles and the critical subcellular muscle compartment. We conclude that subcellular muscle units enable modulatory motor control and propose that subcellular muscle contraction is a fundamental mechanism by which neurons can reshape behavior.Mannose-sensitive hemagglutinin (MSHA) pili and flagellum are critical for the surface attachment of Vibrio cholerae, the first step of V. cholerae colonization on host surfaces. However, the cell landing mechanism remains largely unknown, particularly in viscoelastic environments such as the mucus layers of intestines. Here, combining the cysteine-substitution-based labeling method with single-cell tracking techniques, we quantitatively characterized the landing of V. cholerae by directly observing both pili and flagellum of cells in a viscoelastic non-Newtonian solution consisting of 2% Luria-Bertani and 1% methylcellulose (LB+MC). The results show that MSHA pili are evenly distributed along the cell length and can stick to surfaces at any point along the filament. With such properties, MSHA pili are observed to act as a brake and anchor during cell landing which includes three phases running, lingering, and attaching. Importantly, loss of MSHA pili results in a more dramatic increase in mean path length in LB+MC than in 2% LB only or in 20% Ficoll solutions, indicating that the role of MSHA pili during cell landing is more apparent in viscoelastic non-Newtonian fluids than viscous Newtonian ones. Our work provides a detailed picture of the landing dynamics of V. check details cholerae under viscoelastic conditions, which can provide insights into ways to better control V. cholerae infections in a real mucus-like environment.The causative agent of Chagas disease undergoes drastic morphological and biochemical modifications as it passes between hosts and transitions from extracellular to intracellular stages. The osmotic and mechanical aspects of these cellular transformations are not understood. Here we identify and characterize a novel mechanosensitive channel in Trypanosoma cruzi (TcMscS) belonging to the superfamily of small-conductance mechanosensitive channels (MscS). TcMscS is activated by membrane tension and forms a large pore permeable to anions, cations, and small osmolytes. The channel changes its location from the contractile vacuole complex in epimastigotes to the plasma membrane as the parasites develop into intracellular amastigotes. TcMscS knockout parasites show significant fitness defects, including increased cell volume, calcium dysregulation, impaired differentiation, and a dramatic decrease in infectivity. Our work provides mechanistic insights into components supporting pathogen adaptation inside the host, thus opening the exploration of mechanosensation as a prerequisite for protozoan infectivity.Cell cycle duration changes dramatically during development, starting out fast to generate cells quickly and slowing down over time as the organism matures. The cell cycle can also act as a transcriptional filter to control the expression of long gene transcripts, which are partially transcribed in short cycles. Using mathematical simulations of cell proliferation, we identify an emergent property that this filter can act as a tuning knob to control gene transcript expression, cell diversity, and the number and proportion of different cell types in a tissue. Our predictions are supported by comparison to single-cell RNA-seq data captured over embryonic development. Additionally, evolutionary genome analysis shows that fast-developing organisms have a narrow genomic distribution of gene lengths while slower developers have an expanded number of long genes. Our results support the idea that cell cycle dynamics may be important across multicellular animals for controlling gene transcript expression and cell fate.This graphic narrative explores struggles with underinsurance, compromised access to indicated care, and intergenerational health inequity.Native American peoples' health is impacted by structural legacies of settler colonialism, including land dispossession, racism, and poverty. Responding with care to individuals and communities experiencing past and present traumatic stress from genocide and deeply entrenched structural violence means navigating ongoing grief, restoring self-community and human-ecological relationships, and generating cultural vibrancy.Because multiple Asian American and Pacific Islander (AAPI) communities in the United States have experienced historical trauma (HT), it is important to understand HT's impact on the well-being of members of subsequent generations. This article addresses intergenerational trauma transmission, focusing primarily on Japanese American and Southeast Asian American communities. Research on these groups illuminates strategies for future empirical investigations of intergenerational trauma in other AAPI populations and suggests implications for care.Transgenerational trauma is a potential barrier to achieving a healthy and holistic patient-physician relationship, particularly for Black Americans. Examination of deeply rooted historical injustices that Black patients suffer in health care and how they undermine trust can help clarify connections between historical trauma, distrust, and health outcomes. Furthering clinicians' understanding of how daily practice can respond to Black patients' experiences can help restore trust and mitigate racial and ethnic health inequity.Pharmacists have the same duty as prescribers to prevent inappropriate use of dangerous drugs. Loperamide, for example, is an over-the-counter medication that has been reported to be potentially misused for euphoric effects. Pharmacists and prescribers alike face challenges in providing optimal care for patients and protecting communities from drug misuse. These challenges include cognitive bias, underdeveloped safety culture, and differing expectations of responsibilities of the other party in ensuring safe prescribing. This commentary explores legal, ethical, and practical considerations for pharmacists and prescribers working together to address uncertainty in drug prescribing.Pediatricians have obligations to respond with care to all children's clinical and social vulnerabilities. Finding and addressing causes of children's stress (ie, family separation, child abuse, and trauma) are also obligations. Preventive and rescue interventions should be implemented to address potential short- and long-term harms of toxic stress and their short- and long-term consequences.The "model minority" myth (MMM) has far-reaching implications for Asian Americans in many settings, including medicine. For clinicians working with first-generation Asian American college students, this article considers 3 factors that affect how the MMM plays out in clinical care clinicians' racial identity awareness, cross-racial dynamics, and the extent to which a patient has internalized racism or oppression.Addressing intergenerational trauma remains a public health priority in Native American (NA) communities. Clinicians working with NA patients must express humility, understand local culture, collaborate, and develop an insider's perspective on NA past and present life in order to earn trust. This case considers an NA adolescent suffering from mental distress, possible substance use, and multiple traumas. The commentary argues that trauma-informed therapies are lacking in some current psychiatric and primary care practices in the Indian Health Service and that an interprofessional, trauma-informed approach that considers the interplay between relevant somatic and psychological factors can better motivate patient-centered care. Cultivating safe environments in which interventions are pursued within the patient-clinician therapeutic alliance is key to generating optimal outcomes and healing among NA patients.