Let's talk about sex: Mechanisms of neural sexual differentiation in Bilateria.

In multicellular organisms, sexed gonads have evolved that facilitate release of sperm versus eggs, and bilaterian animals purposefully combine their gametes via mating behaviors. Distinct neural circuits have evolved that control these physically different mating events for animals producing eggs from ovaries versus sperm from testis. In this review, we will describe the developmental mechanisms that sexually differentiate neural circuits across three major clades of bilaterian animals-Ecdysozoa, Deuterosomia, and Lophotrochozoa. While many of the mechanisms inducing somatic and neuronal sex differentiation across these diverse organisms are clade-specific rather than evolutionarily conserved, we develop a common framework for considering the developmental logic of these events and the types of neuronal differences that produce sex-differentiated behaviors. This article is categorized under: Congenital Diseases > Stem Cells and Development Neurological Diseases > Stem Cells and Development.

LAMP1 targeting of the large T antigen of Merkel cell polyomavirus results in potent CD4 T cell responses and tumor inhibition.

Introduction: Most cases of Merkel cell carcinoma (MCC), a rare and highly aggressive type of neuroendocrine skin cancer, are associated with Merkel cell polyomavirus (MCPyV) infection. MCPyV integrates into the host genome, resulting in expression of oncoproteins including a truncated form of the viral large T antigen (LT) in infected cells. These oncoproteins are an attractive target for a therapeutic cancer vaccine. Methods: We designed a cancer vaccine that promotes potent, antigen-specific CD4 T cell responses to MCPyV-LT. To activate antigen-specific CD4 T cells in vivo, we utilized our nucleic acid platform, UNITE™ (UNiversal Intracellular Targeted Expression), which fuses a tumor-associated antigen with lysosomal-associated membrane protein 1 (LAMP1). This lysosomal targeting technology results in enhanced antigen presentation and potent antigen-specific T cell responses. LTS220A, encoding a mutated form of MCPyV-LT that diminishes its pro-oncogenic properties, was introduced into the UNITE™ platform. Results: Vaccination with LTS220A-UNITE™ DNA vaccine (ITI-3000) induced antigen-specific CD4 T cell responses and a strong humoral response that were sufficient to delay tumor growth of a B16F10 melanoma line expressing LTS220A. This effect was dependent on the CD4 T cells' ability to produce IFNγ. Moreover, ITI-3000 induced a favorable tumor microenvironment (TME), including Th1-type cytokines and significantly enhanced numbers of CD4 and CD8 T cells as well as NK and NKT cells. Additionally, ITI-3000 synergized with an α-PD-1 immune checkpoint inhibitor to further slow tumor growth and enhance survival. Conclusions: These findings strongly suggest that in pre-clinical studies, DNA vaccination with ITI-3000, using the UNITE™ platform, enhances CD4 T cell responses to MCPyV-LT that result in significant anti-tumor immune responses. These data support the initiation of a first-in-human (FIH) Phase 1 open-label study to evaluate the safety, tolerability, and immunogenicity of ITI-3000 in patients with polyomavirus-positive MCC (NCT05422781).

The influence of water content on the longitudinal modulus of elasticity of maize stalk pith and rind tissues.

BACKGROUND: Modern computational modeling could provide the key to obtaining new insights into the mechanisms of maize stalk failure as well as suggesting new ways to improve stalk strength. However, a complete set of mechanical properties of maize tissues is required to enable computational modeling of maize stems. This study developed two compression test methods for obtaining the longitudinal modulus of elasticity of both rind and pith tissues, assessed the influence of water content on tissue properties, and investigated the relationship between rind modulus and pith modulus. These methods involved uniform 5-7 cm segments of maize stems which were scanned using a flatbed scanner then tested in compression using a universal testing machine in both intact and dissected (rind-only and pith-only) states. RESULTS: The modulus of elasticity of pith tissues was highest for fully turgid specimens and decreased as water was removed from the specimens. Water content was negatively correlated with the modulus of elasticity of the rind. Rind and pith tissues were found to be weakly correlated. The median ratio of rind modulus to pith modulus was found to be 17. Of the two methods investigated, the pith-only specimen preparation was found to be simple reliable while the rind-only method was found to be adversely affected by lateral bowing of the specimen. CONCLUSIONS: Researchers can use the information in this paper to improve computational models of maize stems in three ways: (1) by incorporating realistic values of the longitudinal modulus of elasticity of pith and rind tissues; (2) by selecting pith and rind properties that match empirically observed ratios; and (3) by incorporating appropriate dependencies between these material properties and water content. From an experimental perspective, the intact/pith-only experimental method outlined in this paper is simpler than previously reported methods and provides reliable estimates of both pith and rind modulus of elasticity values. Further research using this measurement method is recommended to more clearly understand the influence of water content and turgor pressure on tissue properties.

Trait Loss in Evolution: What Cavefish Have Taught Us about Mechanisms Underlying Eye Regression.

Reduction or complete loss of traits is a common occurrence throughout evolutionary history. In spite of this, numerous questions remain about why and how trait loss has occurred. Cave animals are an excellent system in which these questions can be answered, as multiple traits, including eyes and pigmentation, have been repeatedly reduced or lost across populations of cave species. This review focuses on how the blind Mexican cavefish, Astyanax mexicanus, has been used as a model system for examining the developmental, genetic, and evolutionary mechanisms that underlie eye regression in cave animals. We focus on multiple aspects of how eye regression evolved in A. mexicanus, including the developmental and genetic pathways that contribute to eye regression, the effects of the evolution of eye regression on other traits that have also evolved in A. mexicanus, and the evolutionary forces contributing to eye regression. We also discuss what is known about the repeated evolution of eye regression, both across populations of A. mexicanus cavefish and across cave animals more generally. Finally, we offer perspectives on how cavefish can be used in the future to further elucidate mechanisms underlying trait loss using tools and resources that have recently become available.

Associations of adverse and protective childhood experiences with thwarted belongingness, perceived burdensomeness, and suicide risk among sexual minority men.

BACKGROUND: Sexual minority men (SMM) experience higher suicidal ideation and suicide attempts than the general population. We examined the associations of adverse childhood experiences (ACES) and protective and compensatory childhood experiences (PACES) with suicidal ideation and suicide attempts in adulthood via thwarted belongingness and perceived burdensomeness among SMM. METHODS: Data are from the UNITE study, a national longitudinal cohort study of HIV-negative SMM from the 50 U.S. states and Puerto Rico. Between 2017 and 2019, participants (N = 6303) completed web-based assessments at baseline and 12-month follow-up. ACES and PACES occurring before the age of 18, and current symptoms of thwarted belongingness and perceived burdensomeness were assessed at baseline. Past-week suicidal ideation and past-year suicide attempt were assessed at follow-up. RESULTS: 424 (6.7%) participants reported past-week suicidal ideation and 123 (2.0%) reported a past-year suicide attempt. The results of our multivariate model suggest that each additional adverse childhood experience was prospectively associated with 14% higher odds of past-week suicidal ideation (AOR = 1.14, 95% CI 1.09-1.19) and 19% higher odds of past-year suicide attempt (AOR = 1.19, 95% CI 1.11-1.29). Each additional protective childhood experience was prospectively associated with 15% lower odds of past-week suicidal ideation (AOR = 0.85, 95% CI 0.81-0.90) and 11% lower odds of past-year suicide attempt (AOR = 0.89, 95% CI 0.82-0.98). Perceived burdensomeness partially mediated these prospective associations. CONCLUSION: To reduce suicide, screening and treating perceived burdensomeness among SMM with high ACES may be warranted. PACES may decrease perceived burdensomeness and associated suicide risk.

PEDOT:PSS Conductivity Enhancement through Addition of the Surfactant Tween 80.

Replacement of indium tin oxide with the intrinsically conducting polymer poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) has been of significant interest in recent years as a result of lower processing and material costs. In addition, the inclusion of additives has been reported to further enhance the conductivity, rheology, and wettability of PEDOT:PSS. In this study, Tween 80 was shown to decrease the sheet resistance of PEDOT:PSS films from approximately 1000 to 76 Ω□-1 at a 2.67 wt% surfactant concentration. Through X-ray diffraction, Raman spectroscopy, and atomic force microscopy, it was shown that the surfactant caused phase separation and structural ordering of the PEDOT and PSS components, leading to this improvement in conductivity. Furthermore, Tween 80 altered the rheological properties and decreased the surface tension of PEDOT:PSS, making coating common commodity polymers, often used as flexible substrates, more viable.

B Cell Responses upon Human Papillomavirus (HPV) Infection and Vaccination.

Infection with human papillomavirus (HPV) is the necessary cause of cervical cancer. Availability of vaccines against HPV makes it a highly preventable disease. HPV vaccines act through type-specific neutralizing antibodies produced by antigen-specific plasma cells known as long-lived plasma cells (LLPC). However, just as any other vaccine, success of HPV vaccine is attributed to the immunologic memory that it builds, which is largely attained through generation and maintenance of a class of B cells named memory B cells (Bmem). Both LLPCs and Bmems are important in inducing and maintaining immune memory and it is therefore necessary to understand their role after HPV vaccination to better predict outcomes. This review summarizes current knowledge of B-cell responses following HPV vaccination and natural infection, including molecular signatures associated with these responses.

Methods in HIV-Related Intersectional Stigma Research: Core Elements and Opportunities.

Researchers are increasingly recognizing the importance of studying and addressing intersectional stigma within the field of HIV. Yet, researchers have, arguably, struggled to operationalize intersectional stigma. To ensure that future research and methodological innovation is guided by frameworks from which this area of inquiry has arisen, we propose a series of core elements for future HIV-related intersectional stigma research. These core elements include multidimensional, multilevel, multidirectional, and action-oriented methods that sharpen focus on, and aim to transform, interlocking and reinforcing systems of oppression. We further identify opportunities for advancing HIV-related intersectional stigma research, including reducing barriers to and strengthening investments in resources, building capacity to engage in research and implementation of interventions, and creating meaningful pathways for HIV-related intersectional stigma research to produce structural change. Ultimately, the expected payoff for incorporating these core elements is a body of HIV-related intersectional stigma research that is both better aligned with the transformative potential of intersectionality and better positioned to achieve the goals of Ending the HIV Epidemic in the United States and globally. (Am J Public Health. 2022;112(S4):S413-S419. https://doi.org/10.2105/AJPH.2021.306710).

Intersecting Structural Oppression and Suicidality Among Black Sexual Minority Male Adolescents and Emerging Adults.

This study examined associations between structural racism, anti-LGBTQ policies, and suicide risk among young sexual minority men (SMM). Participants were a 2017-2018 Internet-based U.S. national sample of 497 Black and 1536 White SMM (ages 16-25). Structural equation modeling tested associations from indicators of structural racism, anti-LGBTQ policies, and their interaction to suicide risk factors. For Black participants, structural racism and anti-LGBTQ policies were significantly positively associated with depressive symptoms, heavy drinking, perceived burdensomeness, thwarted belongingness, self-harm, and suicide attempt. There were significant interaction effects: Positive associations between structural racism and several outcomes were stronger for Black participants in high anti-LGBTQ policy states. Structural racism, anti-LGBTQ policies, and their interaction were not significantly associated with suicide risk for White SMM.

Construction of C-C bonds via photoreductive coupling of ketones and aldehydes in the metal-organic-framework MFM-300(Cr).

Construction of C-C bonds via reductive coupling of aldehydes and ketones is hindered by the highly negative reduction potential of these carbonyl substrates, particularly ketones, and this renders the formation of ketyl radicals extremely endergonic. Here, we report the efficient activation of carbonyl compounds by the formation of specific host-guest interactions in a hydroxyl-decorated porous photocatalyst. MFM-300(Cr) exhibits a band gap of 1.75 eV and shows excellent catalytic activity and stability towards the photoreductive coupling of 30 different aldehydes and ketones to the corresponding 1,2-diols at room temperature. Synchrotron X-ray diffraction and electron paramagnetic resonance spectroscopy confirm the generation of ketyl radicals via confinement within MFM-300(Cr). This protocol removes simultaneously the need for a precious metal-based photocatalyst or for amine-based sacrificial agents for the photochemical synthesis.

Intersecting Structural Oppression and Black Sexual Minority Men's Health.

INTRODUCTION: Although evidence indicates that Black gay, bisexual, and other sexual minority men experience vast psychological and behavioral health inequities, most research has focused on individual rather than structural drivers of these inequities. This study examines the associations between structural racism and anti-lesbian, gay, bisexual, transgender, and queer policies and the psychological and behavioral health of Black and White sexual minority men. METHODS: Participants were an Internet-based U.S. national sample of 1,379 Black and 5,537 White sexual minority men during 2017-2018. Analysis occurred in 2019-2020. Structural equation modeling tested the associations from indicators of structural racism, anti‒lesbian, gay, bisexual, transgender, and queer policies, and their interaction to anxiety symptoms, depressive symptoms, perceived burdensomeness, heavy drinking, and HIV testing frequency. Separate models for Black and White sexual minority men adjusted for contextual and individual covariates. RESULTS: For Black participants, structural racism was positively associated with anxiety symptoms (ß=0.20, SE=0.10, p=0.04), perceived burdensomeness (ß=0.42, SE=0.09, p<0.001), and heavy drinking (ß=0.23, SE=0.10, p=0.01). Anti‒lesbian, gay, bisexual, transgender, and queer policies were positively associated with anxiety symptoms (ß=0.08, SE=0.04, p=0.03), perceived burdensomeness (ß=0.20, SE=0.04, p<0.001), and heavy drinking (ß=0.10, SE=0.04, p=0.01) and were negatively associated with HIV testing frequency (ß= -0.14, SE=0.07, p=0.04). Results showed significant interaction effects, such that the positive associations between structural racism and both perceived burdensomeness (ß=0.38, SE=0.08, p≤0.001) and heavy drinking (ß=0.22, SE=0.07, p=0.003) were stronger for individuals living in states with high levels of anti‒lesbian, gay, bisexual, transgender, and queer policies. Neither of the oppression variables nor their interaction was significantly associated with outcomes for White sexual minority men. CONCLUSIONS: Results highlight the intersectional nature of structural oppression and suggest that racist and anti-lesbian, gay, bisexual, transgender, and queer policies must be repealed to rectify health inequities facing Black sexual minority men.

The Origin of Catalytic Benzylic C-H Oxidation over a Redox-Active Metal-Organic Framework.

Selective oxidation of benzylic C-H compounds to ketones is important for the production of a wide range of fine chemicals, and is often achieved using toxic or precious metal catalysts. Herein, we report the efficient oxidation of benzylic C-H groups in a broad range of substrates under mild conditions over a robust metal-organic framework material, MFM-170, incorporating redox-active [Cu2 II (O2 CR)4 ] paddlewheel nodes. A comprehensive investigation employing electron paramagnetic resonance (EPR) spectroscopy and synchrotron X-ray diffraction has identified the critical role of the paddlewheel moiety in activating the oxidant t BuOOH (tert-butyl hydroperoxide) via partial reduction to [CuII CuI (O2 CR)4 ] species.

Control of zeolite microenvironment for propene synthesis from methanol.

Optimising the balance between propene selectivity, propene/ethene ratio and catalytic stability and unravelling the explicit mechanism on formation of the first carbon-carbon bond are challenging goals of great importance in state-of-the-art methanol-to-olefin (MTO) research. We report a strategy to finely control the nature of active sites within the pores of commercial MFI-zeolites by incorporating tantalum(V) and aluminium(III) centres into the framework. The resultant TaAlS-1 zeolite exhibits simultaneously remarkable propene selectivity (51%), propene/ethene ratio (8.3) and catalytic stability (>50 h) at full methanol conversion. In situ synchrotron X-ray powder diffraction, X-ray absorption spectroscopy and inelastic neutron scattering coupled with DFT calculations reveal that the first carbon-carbon bond is formed between an activated methanol molecule and a trimethyloxonium intermediate. The unprecedented cooperativity between tantalum(V) and Brønsted acid sites creates an optimal microenvironment for efficient conversion of methanol and thus greatly promotes the application of zeolites in the sustainable manufacturing of light olefins.

Generation of a cost-effective cell line for support of high-throughput isolation of primary human B cells and monoclonal neutralizing antibodies.

The isolation of human monoclonal antibodies (mAbs) arising from natural infection with human pathogens has proven to be a powerful technology, facilitating the understanding of the host response to infection at a molecular level. mAbs can reveal sites of vulnerability on pathogens and illuminate the biological function of the antigenic targets. Moreover, mAbs have the potential to be used directly for therapeutic applications such as passive delivery to prevent infection in susceptible target populations, and as treatment of established infection. The isolation of antigen-specific B cells from vaccine trials can also assist in deciphering whether the desired B cells are being targeted by a given vaccine. Several different processes have been developed to isolate mAbs, but all are generally labor-intensive and result in varying degrees of efficiency. Here, we describe the development of a cost-effective feeder cell line that stably expresses CD40-ligand, interleukin-2 and interleukin-21. Sorting of single B cells onto a layer of irradiated feeder cells sustained antibody production that permits functional screening of secreted antibodies in a manner that enables subsequent recovery of B cells for recombinant antibody cloning. As a proof of concept, we show that this approach can be used to isolate B cells that secrete antibodies that neutralize human papilloma virus (HPV) from participants of an HPV vaccine study.

A systematic review of stigma in sexual and gender minority health interventions.

Stigma against sexual and gender minorities is a major driver of health disparities. Psychological and behavioral interventions that do not address the stigma experienced by sexual and gender minorities may be less efficacious. We conducted a systematic review of existing psychological and behavioral health interventions for sexual and gender minorities to investigate how interventions target sexual and gender minority stigma and consider how stigma could affect intervention efficacy. Preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were followed. Eligible studies were peer reviewed and published in English between January 2003 and July 2019 and reported empirical results of behavioral or psychological interventions implemented among sexual and gender minorities. All interventions addressed stigma. We identified 37 eligible interventions. Most interventions targeted sexual minority men. Interventions were frequently developed or adapted for implementation among sexual and gender minorities and addressed multiple levels and types of stigma. Interventions most frequently targeted proximal stressors, including internalized and anticipated stigma. HIV and mental health were the most commonly targeted health outcomes. A limited number of studies investigated the moderating or mediating effects of stigma on intervention efficacy. The application of an intersectional framework was frequently absent and rarely amounted to addressing sources of stigma beyond sexual and gender minority identities. A growing number of interventions address sexual and gender minority stigma in an effort to prevent deleterious health effects. Future research is needed to assess whether stigma modifies the effectiveness of existing psychological and behavioral interventions among sexual and gender minorities. Further, the application of intersectional frameworks is needed to more comprehensively intervene on multiple, intersecting sources of stigma faced by the diverse sexual and gender minority community.

Treatment Is More Than Prevention: Perceived Personal and Social Benefits of Undetectable = Untransmittable Messaging Among Sexual Minority Men Living with HIV.

Research suggests that the science of undetectable viral load (VL) status and HIV transmission-conveyed with the slogan "Undetectable = Untransmittable" or "U = U"-has gaps in acceptance despite robust scientific evidence. Nonetheless, growing acceptance of U = U creates conditions for a shift in the sociopolitical and personal implications of viral suppression. We conducted an online survey over a 23-month period in 2018 and 2019 among 30,361 adolescent and adult (aged 13-99) sexual minority men living with HIV (SMM-LHIV) across the United States. We examined the impact of U = U on self-image, potential for changing societal HIV stigma, whether SMM-LHIV had ever spoken with a provider about viral suppression and HIV transmission, and primary sources of hearing about U = U. Approximately 80% of SMM-LHIV reported that U = U was beneficial for their self-image and societal HIV stigma, 58.6% reported it made them feel "much better" about their own HIV status, and 40.6% reporting it had the potential to make HIV stigma "much better." The most consistent factors associated with these beliefs centered around care engagement, particularly self-reported viral suppression and excellent antiretroviral therapy adherence. Two-thirds reported ever talking to a provider about VL and HIV transmission, although the primary sources for having heard about U = U were HIV and lesbian, gay, bisexual, transgender, and queer (LGBTQ) news media and personal profiles on networking apps. These findings demonstrate the significant personal and social importance of U = U for SMM-LHIV that go above-and-beyond the well-documented health benefits of viral suppression, suggesting that providers should consider routinely initiating conversations with patients around the multifaceted benefits (personal health, sexual safety and intimacy, increased self-image, and reduced social stigma) of viral suppression.

Long-Term Stability of MFM-300(Al) toward Toxic Air Pollutants.

Temperature- or pressure-swing sorption in porous metal-organic framework (MOF) materials has been proposed for new gas separation technologies. The high tunability of MOFs toward particular adsorbates and the relatively low energy penalty for system regeneration indicate that reversible physisorption in MOFs has the potential to create economic and environmental benefits compared with state-of-the-art chemisorption systems. However, for MOF-based sorbents to be commercialized, they have to show long-term stability under the conditions imposed by the application. Here, we demonstrate the structural stability of MFM-300(Al) in the presence of a series of industrially relevant toxic and corrosive gases, including SO2, NO2, and NH3, over 4 years using long-duration synchrotron X-ray powder diffraction. Full structural analysis of gas-loaded MFM-300(Al) confirms the retention of these toxic gas molecules within the porous framework for up to 200 weeks, and cycling adsorption experiments verified the reusability of MFM-300(Al) for the capture of these toxic air pollutants.