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Lisa Dwyer Orr,1 Dee Lin,1 Bingcao Wu,1 Thomas W LeBlanc,2 Beth Faiman,3 Jenny Ahlstrom,4 Margaret Yung,5 Kathleen L Deering,5 Victoria Kulbokas,5 Joshua L Feldman,6 Erika Kline,6 Noa Biran7 1Janssen Scientific Affairs LLC, Titusville, NJ, USA; 2Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA; 3Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH, USA; 4HealthTree Foundation, Draper, UT, USA; 5EPI-Q Inc, Chicago, IL, USA; 6Inspire Insights, Arlington, VA, USA; 7Hackensack Meridian Health, John Theurer Cancer Center, Hackensack, NJ, USACorrespondence: Lisa Dwyer Orr, Janssen Scientific Affairs LLC, Titusville, NJ, USA, Tel +1 561 290-9901, Email LDwyer2@ITS.JNJ.comIntroduction: Treatment decision-making for multiple myeloma (MM) is complex. Individuals involved in decision-making may value treatment attributes differently based on their role as a patient, care partner, or physician. This study describes those attributes, and what is most important by role.Methods: We conducted a cross-sectional online survey with consenting adult patients with MM, MM care partners, and physicians treating MM. Respondents were recruited from US panels (Inspire and M3 Global Research) between September and December 2022. Survey items were informed by a targeted literature review, qualitative interviews, and a steering committee comprising clinical experts, a patient advocate, patient, and care partner. Descriptive statistics were generated and reported in aggregate.Results: Email invitations were sent to 8071 Inspire members interested in or posting about MM. Of these, 4427 viewed the invitation, 941 responded, and 156 patients and care partners completed the survey (17% of respondents). For physicians, 5588 were invited via Email by M3 Global Research, with 761 viewing the invitation, 214 accessing the survey link, and 137 completing the survey (64% of respondents). Duration of response, side effects, and patients’ quality-of-life (QoL) were the top three treatment attributes selected across the three cohorts; alignment of these attributes was consistent among patients regardless of disease severity. Separately, patients rated QoL and the amount of caregiving needed during/after treatment as the most important factors for future treatment decisions. If more effective MM treatments were offered, care partners were more willing to assume greater family burden (77%) compared to patients (49%), and patients were more accepting of potential serious side effects (50%) than were care partners (34%).Conclusion: Patients with MM, care partners, and physicians consider and value various treatment decision-making factors. Recognizing and addressing these differences is critical to meeting patients’ preferences, needs, and optimizing patient outcomes.Keywords: Decision-making, treatment choice, cross-sectional survey, multiple myeloma

Respiratory neurobiology has been a lead discipline in the field of neuroscience for almost a century. Despite this, research studies on the fundamental synaptic and cellular processes underlying the generation and modulation of breathing movements suffered a significant decline during the last decade. We still believe that respiratory neurobiology is one of the most exciting and imperative fields of neuroscience. With the first white paper concerned with the central control of breathing, we want to celebrate the global importance of breathing research.

Inhibitory neurons make up a substantial fraction of the neurons in the preBötzinger complex (preBötC), a site that is critical for mammalian eupneic breathing. We investigated the role of glycinergic preBötC neurons in respiratory rhythmogenesis in mice using optogenetically targeted excitation and inhibition. Channelrhodopsin-2 (ChR2) or Archaerhodopsin (Arch) were expressed in glycinergic preBötC neurons of glycine transporter 2 (Glyt2, also known as Slc6a5)-Cre mice. In ChR2-transfected mice, brief inspiratory-phase bilateral photostimulation targeting the preBötC prematurely terminated inspiration, whereas expiratory-phase photostimulation delayed the onset of the next inspiration. Prolonged photostimulation produced apneas lasting as long as the light pulse. Inspiratory-phase photoinhibition in Arch-transfected mice during inspiration increased tidal volume without altering inspiratory duration, whereas expiratory-phase photoinhibition shortened the latency until the next inspiration. During persistent apneas, prolonged photoinhibition restored rhythmic breathing. We conclude that glycinergic preBötC neurons modulate inspiratory pattern and are important for reflex apneas, but that the rhythm can persist after substantial dampening of their activity.

Morphogenesis and pattern formation are vital processes in any organism, whether unicellular or multicellular. But in contrast to the developmental biology of plants and animals, the principles of morphogenesis and pattern formation in single cells remain

© 2014 Kannegaard et al.Flagellar length control in Chlamydomonas reinhardtii provides a simple model system in which to investigate the general question of how cells regulate organelle size. Previous work demonstrated that Chlamydomonas cytoplasm contains

Rationale: In adult rats, bilateral ablation of pre-Bötzinger complex (preBötC) neurokinin 1-expressing (NK1R) neurons leads to a progressive and irreversible disruption in breathing pattern, initially during sleep, eventually resulting in an ataxic breathing pattern during wakefulness.Objectives: Here we determine whether ablation of fewer preBötC NK1R neurons leads to a persistent pattern of disordered breathing during sleep but not during wakefulness.Methods: Adult male Sprague-Dawley rats (n = 12) were instrumented to record diaphragmatic, abdominal, and neck EMG, and EEG. Fourteen days later, a second surgery was performed to stereotaxically microinject into the preBötC on one side the toxin saporin conjugated to substance P (SP-SAP), which selectively ablates NK1R neurons.Measurements and Main Results: Postinjection, rats were monitored within a plethysmograph until they were killed (Days 21-51). At Days 6-9 post-unilateral SP-SAP injection, respiratory pattern during sleep, particularly REM sleep, became increasingly disordered, characterized by an increase in frequency of central sleep apnea and hypopneas (36.8 +/- 7.4 episodes/h of REM vs. 6 +/- 2.0 episodes/h in preinjection controls; P < 0.05), whereas breathing during resting wakefulness remained stable. Unlike bilateral SP-SAP-injected rats, an ataxic breathing pattern did not develop during wakefulness. Rats that were monitored up to 51 days post-SP-SAP injection continued to have sleep-disordered breathing; breathing during wakefulness remained relatively stable. Histologic analysis of the ventrolateral medulla confirmed that NK1R neurons within the preBötC on the injected but not on the contralateral side of the medulla were ablated.Conclusions: Gradual loss of preBötC NK1R neurons may be an underlying factor of sleep-disordered breathing, in particular of central sleep apnea. [ABSTRACT FROM AUTHOR]

The goal of transgender endocrine therapy is to change secondary sex characteristics to reduce gender dysphoria and/or facilitate gender presentation that is consistent with the felt sense of self. To maximize desired effects and minimize adverse effects, endocrine therapy must he individualized based on the patient's goals, the risk/benefit ratio of medications, the presence of other medical conditions, and consideration of social and economic issues. In this article we suggest protocols for the prescribing clinician relating to physical assessment, prescription planning, initiation of endocrine therapy, and ongoing maintenance in transgender adults. [ABSTRACT FROM AUTHOR]

Transgender medical care involves addressing general medical conditions and those related specifically to transgender issues. This article summarizes existing research in transgender medicine and provides guidance for family physicians and nurses in adapting standard primary care protocols relating to health maintenance, acute illness, and chronic disease management to ad-dress trans-specific clinical concerns. Trans-specific issues in physical examination, health history, interpretation of laboratory tests, vaccination, screening, and treatment are explored, and the role of the primary care provider in caring for patients undergoing hormonal or surgical change is discussed. [ABSTRACT FROM AUTHOR]

Using a mouse equivalent of FDA-approved cannabidiol (CBD) dosing, we found high dose CBD affects opioid induced persistent apnea (OIPA), the principal cause of opioid related fatalities. CBD pretreatment mitigated respiratory depression from fentanyl in awake mice and significantly delayed OIPA onset in anesthetized mice, effective as the opioid antagonist naloxone. The powerful effect of CBD pretreatment on OIPA suggests a novel therapeutic strategy to reduce fatal opioid overdose incidence.

We explored neural mechanisms underlying sighing. Photostimulation of parafacial (pF) neuromedin B ( NMB) or gastrin releasing peptide (GRP), or preBötzinger Complex (preBötC) NMBR or GRPR neurons elicited ectopic sighs with latency inversely related to time from preceding endogenous sigh. Of particular note, ectopic sighs could be produced without involvement of these peptides or their receptors in preBötC. Moreover, chemogenetic or optogenetic activation of preBötC SST neurons induced sighing, even in the presence of NMBR and/or GRPR antagonists. We propose that an increase in the excitability of preBötC NMBR or GRPR neurons not requiring activation of their peptide receptors activates partially overlapping pathways to generate sighs, and that preBötC SST neurons are a downstream element in the sigh generation circuit that converts normal breaths into sighs.

Microtubule doublets (MTDs) comprise an incomplete microtubule (B-tubule) attached to the side of a complete cylindrical microtubule. These compound microtubules are conserved in cilia across the tree of life; however, the mechanisms by which MTDs form and are maintained in vivo remain poorly understood. Here, we identify microtubule-associated protein 9 (MAP9) as an MTD-associated protein. We demonstrate that C. elegans MAPH-9, a MAP9 homolog, is present during MTD assembly and localizes exclusively to MTDs, a preference that is in part mediated by tubulin polyglutamylation. We find that loss of MAPH-9 causes ultrastructural MTD defects, including shortened and/or squashed B-tubules with reduced numbers of protofilaments, dysregulated axonemal motor velocity, and perturbed cilia function. Because we find that the mammalian ortholog MAP9 localizes to axonemes in cultured mammalian cells and mouse tissues, we propose that MAP9/MAPH-9 plays a conserved role in regulating ciliary motors and supporting the structure of axonemal MTDs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Tissue-wide patterning is essential to multicellular development, requiring cells to individually generate polarity axes and coordinate them in space and time with neighbors. Using the C. elegans intestinal epithelium, we identified a patterning mechanism that is informed by cell contact lifetime asymmetry and executed via the scaffolding protein PAR-3 and the transmembrane protein E-cadherin/HMR-1. Intestinal cells break symmetry as PAR-3 and HMR-1 recruit apical determinants into punctate "local polarity complexes" (LPCs) at homotypic contacts. LPCs undergo an HMR-1-based migration to a common midline, thereby establishing tissue-wide polarity. Thus, symmetry breaking results from PAR-3-dependent intracellular polarization coupled to HMR-1-based tissue-level communication, which occurs through a non-adhesive signaling role for HMR-1. Differential lifetimes between homotypic and heterotypic cell contacts are created by neighbor exchanges and oriented divisions, patterning where LPCs perdure and thereby breaking symmetry. These cues offer a logical and likely conserved framework for how epithelia without obvious molecular asymmetries can polarize., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Sirtuin 6 (SIRT6) is a multifaceted protein deacetylase/deacylase and a major target for small-molecule modulators of longevity and cancer. In the context of chromatin, SIRT6 removes acetyl groups from histone H3 in nucleosomes, but the molecular basis for its nucleosomal substrate preference is unknown. Our cryo-electron microscopy structure of human SIRT6 in complex with the nucleosome shows that the catalytic domain of SIRT6 pries DNA from the nucleosomal entry-exit site and exposes the histone H3 N-terminal helix, while the SIRT6 zinc-binding domain binds to the histone acidic patch using an arginine anchor. In addition, SIRT6 forms an inhibitory interaction with the C-terminal tail of histone H2A. The structure provides insights into how SIRT6 can deacetylate both H3 K9 and H3 K56.

The preBötzinger Complex (preBötC) encodes inspiratory time as rhythmic bursts of activity underlying each breath. Spike synchronization throughout a sparsely connected preBötC microcircuit initiates bursts that ultimately drive the inspiratory motor patterns. Using minimal microcircuit models to explore burst initiation dynamics, we examined the variability in probability and latency to burst following exogenous stimulation of a small subset of neurons, mimicking experiments. Among various physiologically plausible graphs of 1000 excitatory neurons constructed using experimentally determined synaptic and connectivity parameters, directed Erdős-Rényi graphs with a broad (lognormal) distribution of synaptic weights best captured the experimentally observed dynamics. preBötC synchronization leading to bursts was regulated by the efferent connectivity of spiking neurons that are optimally tuned to amplify modest preinspiratory activity through input convergence. Using graph-theoretic and machine learning-based analyses, we found that input convergence of efferent connectivity at the next-nearest neighbor order was a strong predictor of incipient synchronization. Our analyses revealed a crucial role of synaptic heterogeneity in imparting exceptionally robust yet flexible preBötC attractor dynamics. Given the pervasiveness of lognormally distributed synaptic strengths throughout the nervous system, we postulate that these mechanisms represent a ubiquitous template for temporal processing and decision-making computational motifs. SIGNIFICANCE STATEMENT Mammalian breathing is robust, virtually continuous throughout life, yet is inherently labile: to adapt to rapid metabolic shifts (e.g., fleeing a predator or chasing prey); for airway reflexes; and to enable nonventilatory behaviors (e.g., vocalization, breathholding, laughing). Canonical theoretical frameworks-based on pacemakers and intrinsic bursting-cannot account for the observed robustness and flexibility of the preBötzinger Complex rhythm. Experiments reveal that network synchronization is the key to initiate inspiratory bursts in each breathing cycle. We investigated preBötC synchronization dynamics using network models constructed with experimentally determined neuronal and synaptic parameters. We discovered that a fat-tailed (non-Gaussian) synaptic weight distribution-a manifestation of synaptic heterogeneity-augments neuronal synchronization and attractor dynamics in this vital rhythmogenic network, contributing to its extraordinary reliability and responsiveness., (Copyright © 2023 the authors.)

Epithelia are tissues with diverse morphologies and functions across metazoans, ranging from vast cell sheets encasing internal organs to internal tubes facilitating nutrient uptake, all of which require establishment of apical-basolateral polarity axes. While all epithelia tend to polarize the same components, how these components are deployed to drive polarization is largely context-dependent and likely shaped by tissue-specific differences in development and ultimate functions of polarizing primordia. The nematode Caenorhabditis elegans (C. elegans) offers exceptional imaging and genetic tools and possesses unique epithelia with well-described origins and roles, making it an excellent model to investigate polarity mechanisms. In this review, we highlight the interplay between epithelial polarization, development, and function by describing symmetry breaking and polarity establishment in a particularly well-characterized epithelium, the C. elegans intestine. We compare intestinal polarization to polarity programs in two other C. elegans epithelia, the pharynx and epidermis, correlating divergent mechanisms with tissue-specific differences in geometry, embryonic environment, and function. Together, we emphasize the importance of investigating polarization mechanisms against the backdrop of tissue-specific contexts, while also underscoring the benefits of cross-tissue comparisons of polarity., (Copyright © 2023. Published by Elsevier Inc.)

Apico-basolateral polarization is essential for epithelial cells to function as selective barriers and transporters, and to provide mechanical resilience to organs. Epithelial polarity is established locally, within individual cells to establish distinct apical, junctional and basolateral domains, and globally, within a tissue where cells coordinately orient their apico-basolateral axes. Using live imaging of endogenously tagged proteins and tissue-specific protein depletion in the Caenorhabditiselegans embryonic intestine, we found that local and global polarity establishment are temporally and genetically separable. Local polarity is initiated prior to global polarity and is robust to perturbation. PAR-3 is required for global polarization across the intestine but local polarity can arise in its absence, as small groups of cells eventually established polarized domains in PAR-3-depleted intestines in a HMR-1 (E-cadherin)-dependent manner. Despite the role of PAR-3 in localizing PKC-3 to the apical surface, we additionally found that PAR-3 and PKC-3/aPKC have distinct roles in the establishment and maintenance of local and global polarity. Taken together, our results indicate that different mechanisms are required for local and global polarity establishment in vivo., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Background: Transgender healthcare is a rapidly evolving interdisciplinary field. In the last decade, there has been an unprecedented increase in the number and visibility of transgender and gender diverse (TGD) people seeking support and gender-affirming medical treatment in parallel with a significant rise in the scientific literature in this area. The World Professional Association for Transgender Health (WPATH) is an international, multidisciplinary, professional association whose mission is to promote evidence-based care, education, research, public policy, and respect in transgender health. One of the main functions of WPATH is to promote the highest standards of health care for TGD people through the Standards of Care (SOC). The SOC was initially developed in 1979 and the last version (SOC-7) was published in 2012. In view of the increasing scientific evidence, WPATH commissioned a new version of the Standards of Care, the SOC-8. Aim: The overall goal of SOC-8 is to provide health care professionals (HCPs) with clinical guidance to assist TGD people in accessing safe and effective pathways to achieving lasting personal comfort with their gendered selves with the aim of optimizing their overall physical health, psychological well-being, and self-fulfillment. Methods: The SOC-8 is based on the best available science and expert professional consensus in transgender health. International professionals and stakeholders were selected to serve on the SOC-8 committee. Recommendation statements were developed based on data derived from independent systematic literature reviews, where available, background reviews and expert opinions. Grading of recommendations was based on the available evidence supporting interventions, a discussion of risks and harms, as well as the feasibility and acceptability within different contexts and country settings. Results: A total of 18 chapters were developed as part of the SOC-8. They contain recommendations for health care professionals who provide care and treatment for TGD people. Each of the recommendations is followed by explanatory text with relevant references. General areas related to transgender health are covered in the chapters Terminology, Global Applicability, Population Estimates, and Education. The chapters developed for the diverse population of TGD people include Assessment of Adults, Adolescents, Children, Nonbinary, Eunuchs, and Intersex Individuals, and people living in Institutional Environments. Finally, the chapters related to gender-affirming treatment are Hormone Therapy, Surgery and Postoperative Care, Voice and Communication, Primary Care, Reproductive Health, Sexual Health, and Mental Health. Conclusions: The SOC-8 guidelines are intended to be flexible to meet the diverse health care needs of TGD people globally. While adaptable, they offer standards for promoting optimal health care and guidance for the treatment of people experiencing gender incongruence. As in all previous versions of the SOC, the criteria set forth in this document for gender-affirming medical interventions are clinical guidelines; individual health care professionals and programs may modify these in consultation with the TGD person., Competing Interests: Conflict of interests were reviewed as part of the selection process for committee members and at the end of the process before publication. No conflicts of interest were deemed significant or consequential., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Breathing is a vital rhythmic motor behavior with a surprisingly broad influence on the brain and body. The apparent simplicity of breathing belies a complex neural control system, the breathing central pattern generator (bCPG), that exhibits diverse operational modes to regulate gas exchange and coordinate breathing with an array of behaviors. In this review, we focus on selected advances in our understanding of the bCPG. At the core of the bCPG is the preBötzinger complex (preBötC), which drives inspiratory rhythm via an unexpectedly sophisticated emergent mechanism. Synchronization dynamics underlying preBötC rhythmogenesis imbue the system with robustness and lability. These dynamics are modulated by inputs from throughout the brain and generate rhythmic, patterned activity that is widely distributed. The connectivity and an emerging literature support a link between breathing, emotion, and cognition that is becoming experimentally tractable. These advances bring great potential for elucidating function and dysfunction in breathing and other mammalian neural circuits.

Epithelial tissues form continuous barriers to protect against external environments. Within these tissues, epithelial cells build environment-facing apical membranes, junction complexes that anchor neighbors together, and basolateral surfaces that face other cells. Critically, to form a continuous apical barrier, neighboring epithelial cells must align their apico-basolateral axes to create global polarity along the entire tissue. Here, we will review mechanisms of global tissue-level polarity establishment, with a focus on how neighboring epithelial cells of different origins align their apical surfaces. Epithelial cells with different developmental origins and/or that polarize at different times and places must align their respective apico-basolateral axes. Connecting different epithelial tissues into continuous sheets or tubes, termed epithelial fusion, has been most extensively studied in cases where neighboring cells initially dock at an apical-to-apical interface. However, epithelial cells can also meet basal-to-basal, posing several challenges for apical continuity. Pre-existing basement membrane between the tissues must be remodeled and/or removed, the cells involved in docking are specialized, and new cell-cell adhesions are formed. Each of these challenges can involve changes to apico-basolateral polarity of epithelial cells. This minireview highlights several in vivo examples of basal docking and how apico-basolateral polarity changes during epithelial fusion. Understanding the specific molecular mechanisms of basal docking is an area ripe for further exploration that will shed light on complex morphogenetic events that sculpt developing organisms and on the cellular mechanisms that can go awry during diseases involving the formation of cysts, fistulas, atresias, and metastases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cote and Feldman.)

As neuronal subtypes are increasingly categorized, delineating their functional role is paramount. The preBötzinger complex (preBötC) subpopulation expressing the neuropeptide somatostatin (SST) is classified as mostly excitatory, inspiratory-modulated and not rhythmogenic. We further characterized their phenotypic identity: 87% were glutamatergic and the balance were glycinergic and/or GABAergic. We then used optogenetics to investigate their modulatory role in both anaesthetized and freely moving mice. In anaesthetized mice, short photostimulation (100 ms) of preBötC SST + neurons modulated breathing-related variables in a combinatory phase- and state-dependent manner; changes in inspiratory duration, inspiratory peak amplitude (Amp), and phase were different at higher (≥2.5 Hz) vs. lower (<2.5 Hz) breathing frequency (f). Moreover, we observed a biphasic effect of photostimulation during expiration that is probabilistic, that is photostimulation given at the same phase in consecutive cycles can evoke opposite responses (lengthening vs. shortening of the phase). These unexpected probabilistic state- and phase-dependent responses to photostimulation exposed properties of the preBötC that were not predicted and cannot be readily accounted for in current models of preBötC pattern generation. In freely moving mice, prolonged photostimulation decreased f in normoxia, hypoxia or hypercapnia, and increased Amp and produced a phase advance, which was similar to the results in anaesthetized mice when f ≥ 2.5 Hz. We conclude that preBötC SST + neurons are a key mediator of the extraordinary and essential lability of breathing pattern. KEY POINTS: PreBötzinger complex (preBötC) SST + neurons, which modulate respiratory pattern but are not rhythmogenic, were transfected with channelrhodopsin to investigate phase- and state-dependent modulation of breathing pattern in anaesthetized and freely behaving mice in normoxia, hypoxia and hypercapnia. In anaesthetized mice, photostimulation during inspiration increased inspiratory duration and amplitude regardless of baseline f, yet the effects were more robust at higher f. In anaesthetized mice with low f (<2.5 Hz), photostimulation during expiration evoked either phase advance or phase delay, whereas in anaesthetized mice with high f (≥2.5 Hz) and in freely behaving mice in normoxia, hypoxia or hypercapnia, photostimulation always evoked phase advance. Phase- and state-dependency is a function of overall breathing network excitability. The f-dependent probabilistic modulation of breathing pattern by preBötC SST + neurons was unexpected, requiring reconsideration of current models of preBötC function, which neither predict nor can readily account for such responses., (© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society.)

Enzyme-catalyzed proximity labeling (PL) has emerged as a critical approach for identifying protein-protein proximity interactions in cells; however, PL techniques were not historically practical in living multicellular organisms due to technical limitations. Here, we present a protocol for applying PL to living C. elegans using the biotin ligase mutant enzyme TurboID. We demonstrated PL in a tissue-specific and region-specific manner by focusing on non-centrosomal MTOCs (ncMTOCs) of intestinal cells. This protocol is useful for targeted in vivo protein network profiling. For complete details on the use and execution of this protocol, please refer to Sanchez et al. (2021)., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Introduction: Existing data on cardiovascular disease among transgender people are inconsistent and are derived from nonrepresentative samples or population-based data sets that do not include transgender-specific risk factors such as gender-affirming hormone use and gender minority stressors. A nationally representative sample of cisgender and transgender adults aged ≥40 years was used to assess the prevalence and correlates of smoking, select cardiovascular disease conditions, and venous thromboembolism., Methods: Participants were recruited from 2016 to 2018, with analysis conducted in December 2020 with 114 transgender and 964 cisgender individuals. Sample weights and multiple imputations were used for all estimates except for descriptive statistics. Logistic regression models estimated the ORs and 95% CIs expressing the relationship between each outcome variable and a set of independent variables. Each model controlled for race and age., Results: No meaningful differences between cisgender and transgender participants were found in smoking or cardiovascular disease conditions. However, there was an increased odds of venous thromboembolism among transgender women compared with those among cisgender women. Transgender people had greater odds of discrimination, psychological distress, and adverse childhood experiences. These stressors were associated with increased odds of a cardiovascular condition, and everyday discrimination and adverse childhood experiences were associated with increased odds of smoking. Discrimination and psychological distress were associated with venous thromboembolism., Conclusions: Transgender people face disparities in cardiovascular disease risk. This study provides support for the gender minority stress model as a framework for understanding cardiovascular disease disparities. Future research with larger samples and adjudicated outcomes is needed to advance the field., (Copyright © 2021 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Probability and nonprobability-based studies of US transgender persons identify different disparities in health and health care access., Objectives: We used TransPop, the first US national probability survey of transgender persons, to describe and compare measures of health and health access among transgender, nonbinary, and cisgender participants. We directly compared the results with 2015 US Transgender Survey (USTS) data and with previously published analyses from the Behavioral Risk Factor Surveillance System (BRFSS)., Methods: All participants were screened by Gallup Inc., which recruited a probability sample of US adults. Transgender people were identified using a two-step screening process. Eligible participants completed self-administered questionnaires (transgender n = 274, cisgender n = 1162). We obtained weighted proportions/means, then tested for differences between gender groups. Logistic regression was performed to evaluate associations. Bivariate analyses were conducted using the weighted USTS data set for shared variables in USTS and TransPop., Results: Transgender participants were younger and more racially diverse compared to the cisgender group. Despite equally high insurance coverage, transgender people more often avoided care due to cost concerns. Nonbinary persons were less likely to access transgender-related health care providers/clinics than transgender men and women. Transgender respondents more often rated their health as fair/poor, with more frequently occuring poor physical and mental health days compared to cisgender participants. Health conditions including HIV, emphysema, and ulcer were higher among transgender people. TransPop and USTS, unlike BRFSS-based analyses, showed no differences in health or health access., Discussion: Transgender persons experience health access disparities centered on avoidance of care due to cost beyond insured status. Health disparities correspond with models of minority stress, with nonbinary persons having distinct health/health access patterns. Despite different sampling methods, USTS and TransPop appear more similar than BRFSS studies regarding health/health access., Conclusion: Future research should elucidate health care costs for transgender and nonbinary people, while addressing methodology in national studies of transgender health., (© 2021 American Society of Andrology and European Academy of Andrology.)

Neurons are highly polarized cells with morphologically and functionally distinct dendritic and axonal processes. The molecular mechanisms that establish axon-dendrite polarity in vivo are poorly understood. Here, we describe the initial polarization of posterior deirid (PDE), a ciliated mechanosensory neuron, during development in vivo through 4D live imaging with endogenously tagged proteins. PDE inherits and maintains apicobasal polarity from its epithelial precursor. Its apical domain is directly transformed into the ciliated dendritic tip through apical constriction, which is followed by axonal outgrowth from the opposite basal side of the cell. The apical Par complex and junctional proteins persistently localize at the developing dendritic domain throughout this transition. Consistent with their instructive role in axon-dendrite polarization, conditional depletion of the Par complex and junctional proteins results in robust defects in dendrite and axon formation. During apical constriction, a microtubule-organizing center (MTOC) containing the microtubule nucleator γ-tubulin ring complex (γ-TuRC) forms along the apical junction between PDE and its sister cell in a manner dependent on the Par complex and junctional proteins. This junctional MTOC patterns neuronal microtubule polarity and facilitate the dynein-dependent recruitment of the basal body for ciliogenesis. When non-ciliated neurons are genetically manipulated to obtain ciliated neuronal fate, inherited apicobasal polarity is required for generating ciliated dendritic tips. We propose that inherited apicobasal polarity, together with apical cell-cell interactions drive the morphological and cytoskeletal polarity in early neuronal differentiation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Microtubules are polarized intracellular polymers that play key roles in the cell, including in transport, polarity, and cell division. Across eukaryotic cell types, microtubules adopt diverse intracellular organization to accommodate these distinct functions coordinated by specific cellular sites called microtubule-organizing centers (MTOCs). Over 50 years of research on MTOC biology has focused mainly on the centrosome; however, most differentiated cells employ non-centrosomal MTOCs (ncMTOCs) to organize their microtubules into diverse arrays, which are critical to cell function. To identify essential ncMTOC components, we developed the biotin ligase-based, proximity-labeling approach TurboID for use in C. elegans. We identified proteins proximal to the microtubule minus end protein PTRN-1/Patronin at the apical ncMTOC of intestinal epithelial cells, focusing on two conserved proteins: spectraplakin protein VAB-10B/MACF1 and WDR-62, a protein we identify as homologous to vertebrate primary microcephaly disease protein WDR62. VAB-10B and WDR-62 do not associate with the centrosome and instead specifically regulate non-centrosomal microtubules and the apical targeting of microtubule minus-end proteins. Depletion of VAB-10B resulted in microtubule mislocalization and delayed localization of a microtubule nucleation complex ɣ-tubulin ring complex (γ-TuRC), while loss of WDR-62 decreased the number of dynamic microtubules and abolished γ-TuRC localization. This regulation occurs downstream of cell polarity and in conjunction with actin. As this is the first report for non-centrosomal roles of WDR62 family proteins, we expand the basic cell biological roles of this important disease protein. Our studies identify essential ncMTOC components and suggest a division of labor where microtubule growth and localization are distinctly regulated., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)