Electron beam and thermal stabilities of MFM-300(M) metal-organic frameworks.

This work reports the thermal and electron beam stabilities of a series of isostructural metal-organic frameworks (MOFs) of type MFM-300(M) (M = Al, Ga, In, Cr). MFM-300(Cr) was most stable under the electron beam, having an unusually high critical electron fluence of 1111 e- Å-2 while the Group 13 element MOFs were found to be less stable. Within Group 13, MFM-300(Al) had the highest critical electron fluence of 330 e- Å-2, compared to 189 e- Å-2 and 147 e- Å-2 for the Ga and In MOFs, respectively. For all four MOFs, electron beam-induced structural degradation was independent of crystal size and was highly anisotropic, although both the length and width of the channels decreased during electron beam irradiation. Notably, MFM-300(Cr) was found to retain crystallinity while shrinking up to 10%. Thermal stability was studied using in situ synchrotron X-ray diffraction at elevated temperature, which revealed critical temperatures for crystal degradation to be 605, 570, 490 and 480 °C for Al, Cr, Ga, and In, respectively. The pore channel diameters contracted by ≈0.5% on desorption of solvent species, but thermal degradation at higher temperatures was isotropic. The observed electron stabilities were found to scale with the relative inertness of the cations and correlate well to the measured lifetime of the materials when used as photocatalysts.

Polyomavirus ALTOs, but not MTs, downregulate viral early gene expression by activating the NF-κB pathway.

Polyomaviruses are small, circular dsDNA viruses that can cause cancer. Alternative splicing of polyomavirus early transcripts generates large and small tumor antigens (LT, ST) that play essential roles in viral replication and tumorigenesis. Some polyomaviruses also express middle tumor antigens (MTs) or alternate LT open reading frames (ALTOs), which are evolutionarily related but have distinct gene structures. MTs are a splice variant of the early transcript whereas ALTOs are overprinted on the second exon of the LT transcript in an alternate reading frame and are translated via an alternative start codon. Merkel cell polyomavirus (MCPyV), the only human polyomavirus that causes cancer, encodes an ALTO but its role in the viral lifecycle and tumorigenesis has remained elusive. Here, we show MCPyV ALTO acts as a tumor suppressor and is silenced in Merkel cell carcinoma (MCC). Rescuing ALTO in MCC cells induces growth arrest and activates NF-κB signaling. ALTO activates NF-κB by binding SQSTM1 and TRAF2&3 via two N-Terminal Activating Regions (NTAR1+2), resembling Epstein-Barr virus (EBV) Latent Membrane Protein 1 (LMP1). Following activation, NF-κB dimers bind the MCPyV noncoding control region (NCCR) and downregulate early transcription. Beyond MCPyV, NTAR motifs are conserved in other polyomavirus ALTOs, which activate NF-κB signaling, but are lacking in MTs that do not. Furthermore, polyomavirus ALTOs downregulate their respective viral early transcription in an NF-κB- and NTAR-dependent manner. Our findings suggest that ALTOs evolved to suppress viral replication and promote viral latency and that MCPyV ALTO must be silenced for MCC to develop.

Polyomavirus ALTOs, but not MTs, downregulate viral early gene expression by activating the NF-κB pathway.

Polyomaviruses are small, circular dsDNA viruses that can cause cancer. Alternative splicing of polyomavirus early transcripts generates large and small tumor antigens (LT, ST) that play essential roles in viral replication and tumorigenesis. Some polyomaviruses also express middle tumor antigens (MTs) or Alternate LT ORFs (ALTOs), which are evolutionarily related but have distinct gene structures. MTs are a splice variant of the early transcript whereas ALTOs are overprinted on the second exon of the LT transcript in an alternate reading frame and are translated via an alternative start codon. Merkel cell polyomavirus (MCPyV), the only human polyomavirus that causes cancer, encodes an ALTO but its role in the viral lifecycle and tumorigenesis has remained elusive. Here, we show MCPyV ALTO acts as a tumor suppressor and is silenced in Merkel cell carcinoma (MCC). Rescuing ALTO in MCC cells induces growth arrest and activates NF-κB signaling. ALTO activates NF-κB by binding SQSTM1 and TRAF2&3 via two N-Terminal Activating Regions (NTAR1+2), resembling Epstein-Barr virus (EBV) Latent Membrane Protein 1 (LMP1).. Following activation, NF-κB dimers bind the MCPyV non-coding control region (NCCR) and downregulate early transcription. Beyond MCPyV, NTAR motifs are conserved in other polyomavirus ALTOs, which activate NF-κB signaling, but are lacking in MTs that do not. Furthermore, polyomavirus ALTOs downregulate their respective viral early transcription in an NF-κB and NTAR dependent manner. Our findings suggest that ALTOs evolved to suppress viral replication and promote viral latency and that MCPyV ALTO must be silenced for MCC to develop.

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.

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.

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.

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.