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In many physical situations in which many-body assemblies exist at temperature T, a characteristic quantum-mechanical time scale of approximately [Formula: see text] can be identified in both theory and experiment, leading to speculation that it may be the shortest meaningful time in such circumstances. This behavior can be investigated by probing the scattering rate of electrons in a broad class of materials often referred to as "strongly correlated metals". It is clear that in some cases only electron-electron scattering can be its cause, while in others it arises from high-temperature scattering of electrons from quantized lattice vibrations, i.e., phonons. In metallic oxides, which are among the most studied materials, analysis of electrical transport does not satisfactorily identify the relevant scattering mechanism at "high" temperatures near room temperature. We therefore employ a contactless optical method to measure thermal diffusivity in two Ru-based layered perovskites, Sr3Ru2O7 and Sr2RuO4, and use the measurements to extract the dimensionless Lorenz ratio. By comparing our results to the literature data on both conventional and unconventional metals, we show how the analysis of high-temperature thermal transport can both give important insight into dominant scattering mechanisms and be offered as a stringent test of theories attempting to explain anomalous scattering.
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Transient receptor potential canonical (TRPC) proteins assemble to form homo- or heterotetrameric, nonselective cation channels permeable to K+, Na+, and Ca2+. TRPC channels are thought to act as complex integrators of physical and chemical environmental stimuli. Although the understanding of essential physiological roles of TRPC channels is incomplete, their implication in various pathological mechanisms and conditions of the nervous system, kidneys, and cardiovascular system in combination with the lack of major adverse effects of TRPC knockout or TRPC channel inhibition is driving the search of TRPC channel modulators as potential therapeutics. Here, we review the most promising small-molecule TRPC channel modulators, the understanding of their mode of action, and their potential in the study and treatment of cardiovascular and metabolic disease.
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Sistema Cardiovascular , Canais de Potencial de Receptor Transitório , Sistema Cardiovascular/metabolismo , Humanos , Canais de Potencial de Receptor Transitório/metabolismoRESUMO
BACKGROUND: Transitions from sexual to asexual reproduction are common in eukaryotes, but the underlying mechanisms remain poorly known. The pea aphid-Acyrthosiphon pisum-exhibits reproductive polymorphism, with cyclical parthenogenetic and obligate parthenogenetic lineages, offering an opportunity to decipher the genetic basis of sex loss. Previous work on this species identified a single 840 kb region controlling reproductive polymorphism and carrying 32 genes. With the aim of identifying the gene(s) responsible for sex loss and the resulting consequences on the genetic programs controlling sexual or asexual embryogenesis, we compared the transcriptomic response to photoperiod shortening-the main sex-inducing cue-of a sexual and an obligate asexual lineage of the pea aphid, focusing on heads (where the photoperiodic cue is detected) and embryos (the final target of the cue). RESULTS: Our analyses revealed that four genes (one expressed in the head, and three in the embryos) of the region responded differently to photoperiod in the two lineages. We also found that the downstream genetic programs expressed during embryonic development of a future sexual female encompass â¼1600 genes, among which miRNAs, piRNAs and histone modification pathways are overrepresented. These genes mainly co-localize in two genomic regions enriched in transposable elements (TEs). CONCLUSIONS: Our results suggest that the causal polymorphism(s) in the 840 kb region somehow impair downstream epigenetic and post-transcriptional regulations in obligate asexual lineages, thereby sustaining asexual reproduction.
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Afídeos , Feminino , Animais , Afídeos/fisiologia , Pisum sativum , Partenogênese/genética , Reprodução Assexuada/genética , Perfilação da Expressão GênicaRESUMO
PURPOSE: This study aims to assess the diagnostic utility and provide reporting recommendations for clinical DNA methylation episignature testing based on the cohort of patients tested through the EpiSign Clinical Testing Network. METHODS: The EpiSign assay utilized unsupervised clustering techniques and a support vector machine-based classification algorithm to compare each patient's genome-wide DNA methylation profile with the EpiSign Knowledge Database, yielding the result that was reported. An international working group, representing distinct EpiSign Clinical Testing Network health jurisdictions, collaborated to establish recommendations for interpretation and reporting of episignature testing. RESULTS: Among 2399 cases analyzed, 1667 cases underwent a comprehensive screen of validated episignatures, imprinting, and promoter regions, resulting in 18.7% (312/1667) positive reports. The remaining 732 referrals underwent targeted episignature analysis for assessment of sequence or copy-number variants (CNVs) of uncertain significance or for assessment of clinical diagnoses without confirmed molecular findings, and 32.4% (237/732) were positive. Cases with detailed clinical information were highlighted to describe various utility scenarios for episignature testing. CONCLUSION: Clinical DNA methylation testing including episignatures, imprinting, and promoter analysis provided by an integrated network of clinical laboratories enables test standardization and demonstrates significant diagnostic yield and clinical utility beyond DNA sequence analysis in rare diseases.
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Metilação de DNA , Testes Genéticos , Doenças Raras , Humanos , Metilação de DNA/genética , Doenças Raras/genética , Doenças Raras/diagnóstico , Testes Genéticos/normas , Testes Genéticos/métodos , Feminino , Regiões Promotoras Genéticas/genética , Masculino , Variações do Número de Cópias de DNA/genética , Criança , Adulto , Pré-Escolar , Impressão Genômica/genéticaRESUMO
vonHoldt et al. ((2024), Molecular Ecology, 33, e17231) (vH24) used low-coverage (average ~ 7X read depth) restriction site-associated DNA sequence data to estimate individual inbreeding and heterozygosity, and recent effective population size (Ne), in Great Lakes (GL) and Northern Rocky Mountain (RM) wolves. They concluded that RM heterozygosity rapidly declined between 1991 and 2020, and that Ne declined substantially in GL and RM over the last 50 generations. Here, we evaluate the effects of low sequence coverage and sampling strategy on vH24's findings and provide general recommendations for using sequence data to evaluate inbreeding, heterozygosity and Ne. Low-coverage sequencing resulted in downwardly biased estimates of individual inbreeding and heterozygosity, and an erroneous large temporal decline in RM heterozygosity due to declining read depth through time. Additionally, vH24's sampling strategy-which combined individuals from several genetically differentiated populations and across at least eight wolf generations-is expected to have resulted in severe downward bias in estimates of recent Ne for RM. We recommend using high-coverage sequence data ( ≥ $$ \ge $$ 15-20X) to estimate inbreeding and heterozygosity. Carefully filtering individuals, loci and genotypes, and using genotype imputation or likelihoods can help to minimise bias when low-coverage sequence data must be used. For estimation of contemporary Ne, the marginal benefits of using more than 103-104 loci are small, so aggressive filtering of loci with low average read depth potentially can retain most individuals without sacrificing much precision. Individuals are relatively more valuable than loci because analyses of contemporary Ne should focus on roughly single-generation samples from local breeding populations.
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OBJECTIVES: Several measures have been used or developed to capture the health and well-being of caregivers, including the EQ Health and Well-being (EQ-HWB) and its short form, EQ-HWB-S. This study aimed to evaluate the psychometric properties and construct validity of the EQ-HWB/EQ-HWB-S in a US caregiver population. METHODS: A cross-sectional survey was conducted involving 504 caregivers. Eligible participants were 18+ years old, provided unpaid care to a relative/friend aged 18+ in the past 6 months, and spent on average of at least 1 hour per week caregiving. Survey included the following measures: EQ-HWB, Adult Social Care Outcomes Toolkit for Carers-Carer, CarerQol, and EQ-5D-5L. Psychometric properties were assessed using response distributions, floor/ceiling effects, Spearman's correlation for convergent validity, and effect sizes (ES) for known-group validity based on caregiving situations and intensity. RESULTS: The average age of caregivers was 49.2 (SD = 15.4), with 57.5% being female. More than half (54.4%) reported high caregiving intensity, and 68.3% lived with the care recipient. The EQ-HWB-S index showed a strong positive correlation with the EQ-5D-5L (rs = 0.72), Adult Social Care Outcomes Toolkit for Carers (rs = 0.54), and CarerQol (rs = 0.54) indices. Notably, the EQ-HWB-S index showed the largest ES among measures in differentiating caregiving scenarios with a large ES for caregiver's general health (d = 1.00) and small ES for caregiving intensity (d = 0.39). CONCLUSIONS: Results support construct validity of EQ-HWB and EQ-HWB-S as measures for assessing health and well-being of adult informal caregivers in comparison with other validated instruments. Differing levels of known-group validity across anchors emphasize the importance of selecting appropriate measures for caregivers, depending on research question and/or intervention aims.
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Cuidadores , Psicometria , Qualidade de Vida , Humanos , Cuidadores/psicologia , Pessoa de Meia-Idade , Masculino , Feminino , Estudos Transversais , Adulto , Estados Unidos , Inquéritos e Questionários , Idoso , Reprodutibilidade dos Testes , Nível de Saúde , Adulto JovemRESUMO
AIM: This study describes the process of updating the cerebral palsy (CP) common data elements (CDEs), specifically identifying tools that capture the impact of chronic pain on children's functioning. METHOD: Through a partnership between the American Academy for Cerebral Palsy and Developmental Medicine and the National Institute of Neurological Disorders and Stroke (NINDS), the CP CDEs were developed as data standards for clinical research in neuroscience. Chronic pain was underrepresented in the NINDS CP CDEs version 1.0. A multi-step methodology was applied by an interdisciplinary professional team. Following an adapted CP chronic pain tools' rating system, and a review of psychometric properties, clinical utility, and compliance with inclusion/exclusion criteria, a set of recommended pain tools was posted online for external public comment in May 2022. RESULTS: Fifteen chronic pain tools met inclusion criteria, representing constructs across all components of the International Classification of Functioning, Disability and Health. INTERPRETATION: This paper describes the first condition-specific pain CDEs for a pediatric population. The proposed set of chronic pain tools complement and enhance the applicability of the existing pediatric CP CDEs. The novel CP CDE pain tools harmonize the assessment of chronic pain, addressing not only intensity of chronic pain, but also the functional impact of experiencing it in everyday activities.
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Pesquisa Biomédica , Paralisia Cerebral , Dor Crônica , Criança , Humanos , Estados Unidos , Elementos de Dados Comuns , National Institute of Neurological Disorders and Stroke (USA) , Dor Crônica/diagnóstico , Dor Crônica/terapia , Paralisia Cerebral/complicaçõesRESUMO
OBJECTIVE: Suboptimal nutritional adherence in adolescents with cystic fibrosis (awCF) has been associated with lower lung function. AwCF often have more independence in dietary decisions than younger children, yet little research has examined how adolescent decision-making relates to nutritional adherence. This study explored whether components of adolescent decision-making involvement facilitate enzyme and caloric adherence in awCF. METHODS: 37 families participated and completed study procedures. AwCF and caregivers completed electronic surveys, including the Decision-Making Involvement Scale (DMIS). The DMIS evaluated awCF behaviors during nutrition-related decision-making/discussions with caregivers using DMIS subscales: Child Seek (asking for help/advice from caregivers), Child Express (awCF stating opinions) and Joint/Options (awCF participating in joint decision-making or caregiver providing options). AwCF completed 2, 24-hr diet recalls via videoconferencing/phone to estimate adherence. Chart reviews collected medical information. DMIS subscales were regressed onto enzyme and caloric adherence. RESULTS: 43% of awCF met calorie recommendations; 48.6% took all enzymes as prescribed. Caloric adherence was positively correlated with adolescent- and parent-reported Child Seek (r = 0.53; r = 0.36) and adolescent-reported Joint/Options (r = 0.41). Per adolescent-report, the caloric adherence regression model was significant, with Child Seek contributing unique variance in caloric adherence (ß = .62, p = .03). Parent-reported adolescent-decision-making involvement significantly predicted caloric adherence, but none of the subscales contributed unique variance. No other regressions were significant. CONCLUSIONS: When awCF participated in nutrition-related discussions with a caregiver, especially with questions, caloric adherence was better. Future research should examine whether family factors influence these results. AwCF are encouraged to ask questions in nutrition discussions.
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Fibrose Cística , Tomada de Decisões , Cooperação do Paciente , Humanos , Fibrose Cística/psicologia , Adolescente , Feminino , Masculino , Cooperação do Paciente/psicologia , Criança , Cuidadores/psicologiaRESUMO
OBJECTIVE: This study tested a randomized controlled trial of RVA Breathes, a community asthma program, in reducing asthma-related healthcare utilization among children living in an area with a high poverty rate. METHODS: Participants included 250 caregivers (78% African American/Black; 73.3% household income<$25,000/year) and their children with asthma (5-11 years). Inclusion criteria included an asthma-related emergency department (ED) visit, hospitalization, unscheduled doctor's visit, or systemic steroids in the past 2 years. Families were randomized to a full active intervention (asthma education with community health workers [CHWs], home remediation with home assessors, and a school nurse component; n = 118), partial active intervention (asthma education and home remediation; n = 69), or a control group (n = 63) for 9 months. Measures on healthcare utilization and asthma-related factors were collected. Follow-up assessments occurred across a 9-month period. RESULTS: Although we did not find any significant effects, there was a trend toward significance for a group by time effect with objective healthcare utilization as the outcome (F4,365 = 2.28, p = .061). The full intervention group experienced a significant decrease from baseline to 9-month follow-up compared with the other groups (p < .001). Only the full intervention group experienced a significant increase in reported asthma action plans across time (no significant group effect). CONCLUSIONS: In the context of the unprecedented COVID-19 pandemic, which led to a substantial global decrease in healthcare utilization, the study's main hypotheses were not supported. Nevertheless, findings support the benefit of community asthma programs that integrate care across multiple settings and connect families with CHWs.
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PURPOSE: Caregiver burden (CB) is typically self-assessed by caregivers. However, an emerging concept is assessment of CB by the recipients of care, i.e., the patient. The specific objectives are (1) to assess the level of agreement between care recipients' and caregivers' view on CB, across financial, physical, emotional, and social domains; (2) to explore two care recipient perspectives: their self-perceived burden (CR-SPB), and their interpretation of the caregiver's view (Proxy-CB). METHODS: Data were collected from 504 caregiver-care recipient dyads in the U.S. using an online Qualtrics panel. The survey assessed caregiver burden using CarerQol and newly developed items. The level of agreement between responses was quantified using weighted kappa (κ) coefficients for individual items and intraclass correlation coefficients (ICC) for index/summary scores. RESULTS: The average age of caregivers was 49.2 years, and 62.7 years for care recipients. Dyads most commonly consisted of spouses/partners (34.5%); 68.3% lived together. Proxy-CB aligned more closely with caregiver's view, with moderate to substantial agreement across CB domains (from κ = 0.48 for emotional to κ = 0.66 for financial). In the same perspective, the CarerQol-7D Index showed moderate agreement (ICC = 0.58) and the summary score of CB items substantial agreement (ICC = 0.76). Care recipients generally overestimated CB in the Proxy-CB perspective, while they underestimated it in the CR-SPB perspective. CONCLUSION: Results demonstrate there is a difference between perspectives. Strong agreement in Proxy-CB perspective suggests that care recipients can potentially substitute for caregivers depending on the domain. CR-SPB agrees less with caregivers and may provide complementary information.
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Sobrecarga do Cuidador , Cuidadores , Qualidade de Vida , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Cuidadores/psicologia , Sobrecarga do Cuidador/psicologia , Inquéritos e Questionários , Adulto , Idoso , Estados Unidos , PsicometriaRESUMO
Perceiving facial attractiveness is an important behaviour across psychological science due to these judgments having real-world consequences. However, there is little consensus on the measurement of this behaviour, and practices differ widely. Research typically asks participants to provide ratings of attractiveness across a multitude of different response scales, with little consideration of the psychometric properties of these scales. Here, we make psychometric comparisons across nine different response scales. Specifically, we analysed the psychometric properties of a binary response, a 0-100 scale, a visual analogue scale, and a set of Likert scales (1-3, 1-5, 1-7, 1-8, 1-9, 1-10) as tools to measure attractiveness, calculating a range of commonly used statistics for each. While certain properties suggested researchers might choose to favour the 1-5, 1-7 and 1-8 scales, we generally found little evidence of an advantage for one scale over any other. Taken together, our investigation provides consideration of currently used techniques for measuring facial attractiveness and makes recommendations for researchers in this field.
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Beleza , Face , Psicometria , Humanos , Adulto , Feminino , Masculino , Adulto Jovem , Julgamento , Reconhecimento Facial/fisiologia , Escala Visual Analógica , AdolescenteRESUMO
INTRODUCTION: The US Food and Drug Administration is poised to restrict the availability of menthol cigarettes and flavored cigars, products disproportionately used by Black/African American (B/AA) individuals. We examined B/AA youth and adult perceptions regarding factors contributing to tobacco use, as well as prevention/cessation resources. METHODS: In 2 mixed-methods studies in Richmond, Virginia, we conducted cross-sectional surveys among youth (n = 201) and adult (n = 212) individuals who were primarily B/AA and reported past 30-day cigar smoking or nontobacco use, followed by focus groups with a subset (youth: n = 30; adults: n = 24). Focus groups were analyzed using a thematic analysis framework, and descriptive survey data provided context to themes. RESULTS: Among focus group participants, 20% of youth and 75% of adults reported current cigar smoking. Six themes emerged across the groups: advertising/brands, sensory experiences, costs, social factors, youth-related factors, and dependence/cessation. Youth and adults perceived cigars as popular; cigar use was attributed to targeted advertising, flavors, affordability, and accessibility. While adults expressed concern regarding youth tobacco use, youth did not perceive tobacco prevention programs as helpful. Adults and youth reported limited access to community tobacco prevention/cessation programs. DISCUSSION: Expanded tobacco prevention and cessation resources for B/AA people who smoke could leverage federal regulatory actions to ban tobacco products targeted toward this group and decrease disparities in tobacco-related morbidity and mortality.
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Negro ou Afro-Americano , Uso de Tabaco , Adulto , Humanos , Adolescente , Virginia , Estudos Transversais , Inquéritos e QuestionáriosRESUMO
Measuring and optimizing a health system is challenging when patient care is split between many independent organizations. For example, patients receive care from their primary care provider, outpatient specialist clinics, hospitals, private providers and, in some instances, family members. These silos are maintained through different funding sources (or lack of funding) which incentivize siloed service delivery. A shift towards prioritizing patient outcomes and keeping the patient at the centre of care is emerging. However, competing philosophies on patient needs, how health is defined and how health is produced and funded is creating and engraining silos in the delivery of health services. Healthcare and health outcomes are produced through a series of activities conducted by diverse teams of health professionals working in concert. Health professionals are continually learning from each patient interaction; however, silos are barriers to information exchange, collaborative evidence generation and health system improvement. This paper presents a systems view of healthcare and provides a systems lens to approach current challenges in health systems. The first part of the paper provides a background on the current state and challenges to healthcare in Canada. The second part presents potential reasons for continued health system underperformance. The paper concludes with a system perspective for addressing these challenges.
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Atenção à Saúde , Humanos , Canadá , Qualidade da Assistência à Saúde , Pessoal de Saúde , Atenção Primária à Saúde/organização & administraçãoRESUMO
Tanshinone IIA (T2A) is a bioactive compound that provides promise in the treatment of glioblastoma multiforme (GBM), with a range of molecular mechanisms including the inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) and the induction of autophagy. Recently, T2A has been demonstrated to function through sestrin 2 (SESN) to inhibit mTORC1 activity, but its possible impact on autophagy through this pathway has not been investigated. Here, the model system Dictyostelium discoideum and GBM cell lines were employed to investigate the cellular role of T2A in regulating SESN to inhibit mTORC1 and activate autophagy through a GATOR2 component MIOS. In D. discoideum, T2A treatment induced autophagy and inhibited mTORC1 activity, with both effects lost upon the ablation of SESN (sesn-) or MIOS (mios-). We further investigated the targeting of MIOS to reproduce this effect of T2A, where computational analysis identified 25 novel compounds predicted to strongly bind the human MIOS protein, with one compound (MIOS inhibitor 3; Mi3) reducing cell proliferation in two GBM cells. Furthermore, Mi3 specificity was demonstrated through the loss of potency in the D. discoideum mios- cells regarding cell proliferation and the induction of autophagy. In GBM cells, Mi3 treatment also reduced mTORC1 activity and induced autophagy. Thus, a potential T2A mimetic showing the inhibition of mTORC1 and induction of autophagy in GBM cells was identified.
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Abietanos , Autofagia , Dictyostelium , Glioblastoma , Alvo Mecanístico do Complexo 1 de Rapamicina , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patologia , Abietanos/farmacologia , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Dictyostelium/efeitos dos fármacos , Dictyostelium/metabolismo , Proliferação de Células/efeitos dos fármacos , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/antagonistas & inibidores , SestrinasRESUMO
OBJECTIVE: The purpose of this study was to estimate the behavioral impacts of training police officers in implicit bias awareness and management. HYPOTHESES: Training police in implicit bias reduces racial and ethnic disparities in stops, arrests, summonses, frisks, searches, and/or use of force. METHOD: A cluster randomized controlled trial using the stepped wedge design was applied to 14,471 officers in the New York City Police Department, with a 1-day training delivered to clusters of police commands between May 2018 and April 2019 and outcomes measured with police records of individual events from April 2018 to May 2019. Police records were supplemented with survey data on 1,973 officers matched to administrative data. For each type of enforcement action, the likelihood that the action involved or was taken against Black or Hispanic suspects, respectively, relative to White suspects was estimated, controlling for potential confounders. Additional analysis allowed for estimating training effects of different magnitudes for Black, Hispanic, and White officers and for officers with greater motivation to act without prejudice or greater concern about discrimination. RESULTS: None of the estimated training effects achieved statistical significance at the .05 level. CONCLUSIONS: Isolated and weak evidence of behavioral impacts of the training was detected. Several explanations for the null findings are considered. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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We report a rapid, room-temperature mechanochemical synthesis of 2- and 3-dimensional boroxine covalent organic frameworks (COFs), enabled by using trimethylboroxine as a dehydrating additive to overcome the hydrolytic sensitivity of boroxine-based COFs. The resulting COFs display high porosity and crystallinity, with COF-102 being the first example of a mechanochemically prepared 3D COF, exhibiting a surface area of ca. 2,500 m2 g-1. Mechanochemistry enabled a >20-fold reduction in solvent use and ~100-fold reduction in reaction time compared with solvothermal methods, providing target COFs quantitatively with no additional work-up besides vacuum drying. Real-time Raman spectroscopy permitted the first quantitative kinetic analysis of COF mechanosynthesis, while transferring the reaction design to Resonant Acoustic Mixing (RAM) enabled synthesis of multi-gram amounts of the target COFs (tested up to 10 g).
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The ß-coronavirus SARS-CoV-2 causes severe acute respiratory syndrome (COVID-19) in humans. It enters and infects epithelial airway cells upon binding of the receptor binding domain (RBD) of the virus entry protein spike to the host receptor protein Angiotensin Converting Enzyme 2 (ACE2). Here, we used coimmunoprecipitation coupled with bottom-up mass spectrometry to identify host proteins that engaged with the spike protein in human bronchial epithelial cells (16HBEo-). We found that the spike protein bound to extracellular laminin and thrombospondin and endoplasmatic reticulum (ER)-resident DJB11 and FBX2 proteins. The ER-resident proteins UGGT1, CALX, HSP7A, and GRP78/BiP bound preferentially to the original Wuhan D614 over the mutated G614 spike protein in the more rapidly spreading Alpha SARS-CoV-2 strain. The increase in protein binding to the D614 spike might be explained by higher accessibility of cryptic sites in "RDB open" and "S2 only" D614 spike protein conformations and may enable SARS-CoV-2 to infect additional, ACE2-negative cell types. Moreover, a novel proteome-based cell type set enrichment analysis (pCtSEA) found that host factors like laminin might render additional cell types such as macrophages and epithelial cells in the nephron permissive to SARS-CoV-2 infection.
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COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Laminina , Ligação Proteica , Proteínas Virais/metabolismo , TropismoRESUMO
Nonsense mutations, which occur in â¼11% of patients with genetic disorders, introduce premature termination codons (PTCs) that lead to truncated proteins and promote nonsense-mediated mRNA decay. Aminoglycosides such as G418 permit PTC readthrough and so may be used to address this problem. However, their effects are variable between patients, making clinical use of aminoglycosides challenging. In this study, we tested whether TRPC nonselective cation channels contribute to the variable PTC readthrough effect of aminoglycosides by controlling their cellular uptake. Indeed, a recently reported selective TRPC5 inhibitor, AC1903, consistently suppressed G418 uptake and G418-induced PTC readthrough in the DMS-114 cancer cell line and junctional epidermolysis bullosa (JEB) patient-derived keratinocytes. Interestingly, the effect of AC1903 in DMS-114 cells was mimicked by nonselective TRPC inhibitors, but not by well-characterized inhibitors of TRPC1/4/5 (Pico145, GFB-8438) or TRPC3/6/7 (SAR7334), suggesting that AC1903 may work through additional or undefined targets. Indeed, in our experiments, AC1903 inhibited multiple TRPC channels including TRPC3, TRPC4, TRPC5, TRPC6, TRPC4-C1, and TRPC5-C1, as well as endogenous TRPC1:C4 channels in A498 renal cancer cells, all with low micromolar IC50 values (1.8-18 µM). We also show that AC1903 inhibited TRPV4 channels, but had weak or no effects on TRPV1 and no effect on the nonselective cation channel PIEZO1. Our study reveals that AC1903 has previously unrecognized targets, which need to be considered when interpreting results from experiments with this compound. In addition, our data strengthen the hypothesis that nonselective calcium channels are involved in aminoglycoside uptake.
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Aminoglicosídeos , Códon sem Sentido , Indazóis , Canais de Cátion TRPC , Aminoglicosídeos/farmacologia , Códon sem Sentido/efeitos dos fármacos , Humanos , Indazóis/farmacologia , Inibidores da Síntese de Proteínas , Canais de Cátion TRPC/antagonistas & inibidores , Canais de Cátion TRPC/genética , Canais de Cátion TRPC/metabolismoRESUMO
The SWY-type aluminosilicate zeolite, STA-30, has been synthesized via different routes to understand its defect chemistry and solid acidity. The synthetic parameters varied were the gel aging, the Al source, and the organic structure directing agent. All syntheses give crystalline materials with similar Si/Al ratios (6-7) that are stable in the activated K,H-form and closely similar by powder X-ray diffraction. However, they exhibit major differences in the crystal morphology and in their intracrystalline porosity and silanol concentrations. The diDABCO-C82+ (1,1'-(octane-1,8-diyl)bis(1,4-diazabicyclo[2.2.2]octan)-1-ium)-templated STA-30 samples (but not those templated by bisquinuclidinium octane, diQuin-C82+) possess hierarchical microporosity, consisting of noncrystallographic extra-large micropores (13 Å) that connect with the characteristic swy and gme cages of the SWY structure. This results in pore volumes up to 30% greater than those measured in activated diQuin-C8_STA-30 as well as higher concentrations of silanols and fewer Brønsted acid sites (BASs). The hierarchical porosity is demonstrated by isopentane adsorption and the FTIR of adsorbed pyridine, which shows that up to 77% of the BASs are accessible (remarkable for a zeolite that has a small-pore crystal structure). A structural model of single can/d6r column vacancies is proposed for the extra-large micropores, which is revealed unambiguously by high-resolution scanning transmission electron microscopy. STA-30 can therefore be prepared as a hierarchically porous zeolite via direct synthesis. The additional noncrystallographic porosity and, subsequently, the amount of SiOHs in the zeolites can be enhanced or strongly reduced by the choice of crystallization conditions.
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AbstractCrow's "opportunity for selection" (I=variance in relative fitness) is an important albeit controversial eco-evolutionary concept, particularly regarding the most appropriate null model(s). Here, we treat this topic in a comprehensive way by considering opportunities for both fertility selection (If) and viability selection (Im) for discrete generations, both seasonal and lifetime reproductive success in age-structured species, and experimental designs that include either a full or partial life cycle, with complete enumeration or random subsampling. For each scenario, a null model that includes random demographic stochasticity can be constructed that follows Crow's initial formulation that I=If+Im. The two components of I are qualitatively different. Whereas an adjusted If (ΔIf) can be computed that accounts for random demographic stochasticity in offspring number, Im cannot be similarly adjusted in the absence of data on phenotypic traits under viability selection. Including as potential parents some individuals that die before reproductive age produces an overall zero-inflated Poisson null model. It is always important to remember that (1) Crow's I represents only the opportunity for selection and not selection itself and (2) the species' biology can lead to random stochasticity in offspring number that is either overdispersed or underdispersed compared with the Poisson (Wright-Fisher) expectation.