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1.
Environ Sci Technol ; 58(26): 11822-11832, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38899941

RESUMO

The potential of Ru(III)-mediated advanced oxidation processes has attracted attention due to the recyclable catalysis, high efficiency at circumneutral pHs, and robust resistance against background anions (e.g., phosphate). However, the reactive species in Ru(III)-peracetic acid (PAA) and Ru(III)-ferrate(VI) (FeO42-) systems have not been rigorously examined and were tentatively attributed to organic radicals (CH3C(O)O•/CH3C(O)OO•) and Fe(IV)/Ru(V), representing single electron transfer (SET) and double electron transfer (DET) mechanisms, respectively. Herein, the reaction mechanisms of both systems were investigated by chemical probes, stoichiometry, and electrochemical analysis, revealing different reaction pathways. The negligible contribution of hydroxyl (HO•) and organic (CH3C(O)O•/CH3C(O)OO•) radicals in the Ru(III)-PAA system clearly indicated a DET reaction via oxygen atom transfer (OAT) that produces Ru(V) as the only reactive species. Further, the Ru(III)-performic acid (PFA) system exhibited a similar OAT oxidation mechanism and efficiency. In contrast, the 1:2 stoichiometry and negligible Fe(IV) formation suggested the SET reaction between Ru(III) and ferrate(VI), generating Ru(IV), Ru(V), and Fe(V) as reactive species for micropollutant abatement. Despite the slower oxidation rate constant (kinetically modeled), Ru(V) could contribute comparably as Fe(V) to oxidation due to its higher steady-state concentration. These reaction mechanisms are distinctly different from the previous studies and provide new mechanistic insights into Ru chemistry and Ru(III)-based AOPs.


Assuntos
Oxirredução , Rutênio , Rutênio/química , Transporte de Elétrons , Catálise , Ferro/química
2.
AIDS Educ Prev ; 36(3): 182-197, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38917302

RESUMO

This analysis examined correlates of HIV testing among Asian immigrant female sex workers in massage parlors. We interviewed 69 Chinese and Korean immigrant women who provided sexual services in massage parlors in New York City or Los Angeles County (2014-2016). Multivariable logistic regression results showed that participants who were younger, have lived in the U.S. for a longer period of time, had greater English proficiency, perceived higher HIV risk, or were living with an intimate partner were more likely to have had an HIV test. Disclosing sex work to a close friend was also positively associated with HIV testing at p < .1. These correlates may reflect differential access to information, systems, and social networks that would facilitate HIV testing, highlighting the importance of reducing social isolation and increasing HIV education, especially for older women who have come to the U.S. more recently. As the literature has indicated that Asian immigrant female sex workers experience high rates of intersectional stigma, efforts to mitigate these intersecting stigmas could further these objectives.


Assuntos
Asiático , Emigrantes e Imigrantes , Infecções por HIV , Teste de HIV , Profissionais do Sexo , Estigma Social , Humanos , Feminino , Profissionais do Sexo/estatística & dados numéricos , Profissionais do Sexo/psicologia , Emigrantes e Imigrantes/estatística & dados numéricos , Emigrantes e Imigrantes/psicologia , Cidade de Nova Iorque/epidemiologia , Los Angeles , Adulto , Asiático/psicologia , Asiático/estatística & dados numéricos , Infecções por HIV/etnologia , Infecções por HIV/diagnóstico , Infecções por HIV/psicologia , Teste de HIV/estatística & dados numéricos , Pessoa de Meia-Idade , Adulto Jovem , Trabalho Sexual/estatística & dados numéricos , Parceiros Sexuais , Entrevistas como Assunto
3.
Nat Cancer ; 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38816660

RESUMO

Dose-limiting toxicity poses a major limitation to the clinical utility of targeted cancer therapies, often arising from target engagement in nonmalignant tissues. This obstacle can be minimized by targeting cancer dependencies driven by proteins with tissue-restricted and/or tumor-restricted expression. In line with another recent report, we show here that, in acute myeloid leukemia (AML), suppression of the myeloid-restricted PIK3CG/p110γ-PIK3R5/p101 axis inhibits protein kinase B/Akt signaling and compromises AML cell fitness. Furthermore, silencing the genes encoding PIK3CG/p110γ or PIK3R5/p101 sensitizes AML cells to established AML therapies. Importantly, we find that existing small-molecule inhibitors against PIK3CG are insufficient to achieve a sustained long-term antileukemic effect. To address this concern, we developed a proteolysis-targeting chimera (PROTAC) heterobifunctional molecule that specifically degrades PIK3CG and potently suppresses AML progression alone and in combination with venetoclax in human AML cell lines, primary samples from patients with AML and syngeneic mouse models.

4.
NAR Genom Bioinform ; 6(2): lqae059, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38800827

RESUMO

Recent advancements in shRNA and Cas protein technologies have enabled functional screening methods targeting genes or non-coding regions using single or pooled shRNA and sgRNA. CRISPR-based systems have also been developed for modulating DNA accessibility, resulting in CRISPR-mediated interference (CRISPRi) or activation (CRISPRa) of targeted genes or genomic DNA elements. However, there is still a lack of software tools for integrating diverse array of functional genomics screening outputs that could offer a cohesive framework for comprehensive data integration. Here, we developed PitViper, a flexible and interactive open-source software designed to fill this gap, providing reliable results for the type of elements being screened. It is an end-to-end automated and reproducible bioinformatics pipeline integrating gold-standard methods for functional screening analysis. Our sensitivity analyses demonstrate that PitViper is a useful tool for identifying potential super-enhancer liabilities in a leukemia cell line through genome-wide CRISPRi-based screening. It offers a robust, flexible, and interactive solution for integrating data analysis and reanalysis from functional screening methods, making it a valuable resource for researchers in the field.

5.
Elife ; 122024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38687678

RESUMO

Internalization from the cell membrane and endosomal trafficking of receptor tyrosine kinases (RTKs) are important regulators of signaling in normal cells that can frequently be disrupted in cancer. The adrenal tumor pheochromocytoma (PCC) can be caused by activating mutations of the rearranged during transfection (RET) receptor tyrosine kinase, or inactivation of TMEM127, a transmembrane tumor suppressor implicated in trafficking of endosomal cargos. However, the role of aberrant receptor trafficking in PCC is not well understood. Here, we show that loss of TMEM127 causes wildtype RET protein accumulation on the cell surface, where increased receptor density facilitates constitutive ligand-independent activity and downstream signaling, driving cell proliferation. Loss of TMEM127 altered normal cell membrane organization and recruitment and stabilization of membrane protein complexes, impaired assembly, and maturation of clathrin-coated pits, and reduced internalization and degradation of cell surface RET. In addition to RTKs, TMEM127 depletion also promoted surface accumulation of several other transmembrane proteins, suggesting it may cause global defects in surface protein activity and function. Together, our data identify TMEM127 as an important determinant of membrane organization including membrane protein diffusability and protein complex assembly and provide a novel paradigm for oncogenesis in PCC where altered membrane dynamics promotes cell surface accumulation and constitutive activity of growth factor receptors to drive aberrant signaling and promote transformation.


Assuntos
Membrana Celular , Proteínas de Membrana , Proteínas Proto-Oncogênicas c-ret , Proteínas Proto-Oncogênicas c-ret/metabolismo , Proteínas Proto-Oncogênicas c-ret/genética , Humanos , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Membrana Celular/metabolismo , Transdução de Sinais , Transporte Proteico , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Proliferação de Células , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/patologia
6.
Lancet Planet Health ; 8(4): e270-e283, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38580428

RESUMO

The concurrent pressures of rising global temperatures, rates and incidence of species decline, and emergence of infectious diseases represent an unprecedented planetary crisis. Intergovernmental reports have drawn focus to the escalating climate and biodiversity crises and the connections between them, but interactions among all three pressures have been largely overlooked. Non-linearities and dampening and reinforcing interactions among pressures make considering interconnections essential to anticipating planetary challenges. In this Review, we define and exemplify the causal pathways that link the three global pressures of climate change, biodiversity loss, and infectious disease. A literature assessment and case studies show that the mechanisms between certain pairs of pressures are better understood than others and that the full triad of interactions is rarely considered. Although challenges to evaluating these interactions-including a mismatch in scales, data availability, and methods-are substantial, current approaches would benefit from expanding scientific cultures to embrace interdisciplinarity and from integrating animal, human, and environmental perspectives. Considering the full suite of connections would be transformative for planetary health by identifying potential for co-benefits and mutually beneficial scenarios, and highlighting where a narrow focus on solutions to one pressure might aggravate another.


Assuntos
Doenças Transmissíveis , Ecossistema , Animais , Humanos , Mudança Climática , Biodiversidade , Modelos Teóricos , Doenças Transmissíveis/epidemiologia
7.
Am J Obstet Gynecol ; 230(5): 544.e1-544.e13, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38191019

RESUMO

BACKGROUND: Few studies have evaluated the role of cytoreductive surgery in patients with recurrent adult granulosa cell tumors of the ovary. Despite a multitude of treatment modalities in the recurrent setting, the optimal management strategy is not known. Cytoreductive surgery offers an attractive option for disease confined to the abdomen/pelvis. However, few studies have evaluated the role of surgery compared with systemic therapy alone following the first recurrence and subsequent disease progressions. OBJECTIVE: This study aimed to determine the impact of secondary, tertiary, and quaternary cytoreductive surgery on survival outcomes in recurrent adult granulosa cell tumors of the ovary. STUDY DESIGN: This is a multicenter, retrospective cohort study evaluating patients with recurrent adult granulosa cell tumors of the ovary enrolled in the MD Anderson Rare Gynecologic Malignancy Registry from 1970 to 2022. Study inclusion criteria consisted of histology-proven recurrent disease, at least 1 documented recurrence, and treatment/treatment planning at the MD Anderson Cancer Center or Lyndon B. Johnson General Hospital. The primary exposure was cytoreductive surgery, and the outcomes of interest were progression-free survival and overall survival. Survival analyses were restricted to eligible patients with resectable disease without medical barriers to surgery at each progression episode. Demographic and clinicopathologic characteristics were summarized using descriptive statistics. Progression-free survival (after first, second, and third progression) and overall survival were estimated with methods of Kaplan and Meier, and were modeled via Cox proportional hazards regression. Multivariable analyses were performed for progression-free survival after first progression and overall survival. RESULTS: Among the 369 patients with adult granulosa cell tumors of the ovary in the registry, 149 patients met the study inclusion criteria. Secondary cytoreductive surgery was associated with a significant improvement in progression-free survival on univariable (hazard ratio, 0.37; 95% confidence interval, 0.17-0.81, P=.01) and multivariable analyses (hazard ratio, 0.42; 95% confidence interval, 0.19-0.92; P=.03). Those who underwent secondary cytoreductive surgery had a significantly improved median overall survival compared with those who did not undergo cytoreductive surgery (181.92 vs 61.56 months, respectively; P=.002). Overall survival benefit remained statistically significant on multivariable analysis (hazard ratio, 0.28; 95% confidence interval, 0.11-0.67; P=.004). Tertiary cytoreductive surgery was similarly associated with a significant improvement in progression-free survival (hazard ratio, 0.43; 95% confidence interval, 0.26-0.70; P=.001). Despite a similar trend, quaternary cytoreductive surgery was not associated with a significant improvement in progression-free survival (hazard ratio, 0.74; 95% confidence interval, 0.42-1.26; P=.27). CONCLUSION: Among those with resectable disease and no medical contraindications to surgery, cytoreductive surgery may have a beneficial impact on progression-free survival and overall survival in patients with recurrent adult granulosa cell tumors of the ovary.


Assuntos
Procedimentos Cirúrgicos de Citorredução , Tumor de Células da Granulosa , Recidiva Local de Neoplasia , Neoplasias Ovarianas , Humanos , Feminino , Tumor de Células da Granulosa/cirurgia , Tumor de Células da Granulosa/mortalidade , Tumor de Células da Granulosa/patologia , Estudos Retrospectivos , Pessoa de Meia-Idade , Adulto , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Idoso , Intervalo Livre de Progressão , Estudos de Coortes , Sistema de Registros , Taxa de Sobrevida
8.
J Lipid Res ; 65(3): 100503, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38246235

RESUMO

Circulating levels of the soluble ligand-binding ectodomain of the LDL receptor (sLDLR) that is proteolytically cleaved from the cell surface have been shown to correlate with plasma triglycerides, but the lipid and lipoprotein effects of longitudinal changes in sLDLR have not been examined. We sought to assess associations between changes in sLDLR and detailed lipoprotein measurements between baseline and 6 months in participants in the DIETFITS (Diet Intervention Examining The Factors Interacting with Treatment Success) weight loss trial who were randomly assigned to the low-fat (n = 225) or low-carbohydrate (n = 236) diet arms. sLDLR was assayed using a proteomic procedure, lipids and apoprotein (apo) B and apoAI were measured by standard assays, and lipoprotein particle subfractions were quantified by ion mobility methodology. Changes in sLDLR were significantly positively associated with changes in plasma cholesterol, triglycerides, apoB, large-sized and medium-sized VLDL, and small and very small LDL, and inversely with changes in large LDL and HDL. The lipoprotein subfraction associations with sLDLR were independent of age, sex, diet, and BMI, but all except for large LDL were reduced to insignificance when adjusted for triglyceride change. Principal component analysis identified three independent clusters of changes in lipoprotein subfractions that accounted for 78% of their total variance. Change in sLDLR was most strongly correlated with change in the principal component that was loaded positively with large VLDL and small and very small LDL and negatively with large LDL and HDL. In conclusion, sLDLR is a component of a cluster of lipids and lipoproteins that are characteristic of atherogenic dyslipidemia.


Assuntos
Lipoproteínas , Proteômica , Humanos , Triglicerídeos , Receptores de LDL , Dieta , Redução de Peso , Lipoproteínas LDL , Lipoproteínas VLDL
9.
Sci Total Environ ; 915: 169863, 2024 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-38190906

RESUMO

Decentralised wastewater treatment is becoming a suitable strategy to reduce cost and environmental impact. In this research, the performance of two technologies treating black water (BW) and grey water (GW) fractions of urban sewage is carried out in a decentralised treatment of the wastewater produced in three office buildings. An Anaerobic Membrane Bioreactor (AnMBR) treating BW and a Hybrid preanoxic Membrane Bioreactor (H-MBR) containing small plastic carrier elements, treating GW were operated at pilot scale. Their potential on reducing the release of contaminants of emerging concern (CECs) such as Organic Micropollutants (OMPs), Antibiotic Resistance Genes (ARGs) and pathogens was studied. After 226 d of operation, a stable operation was achieved in both systems: the AnMBR removed 92.4 ± 2.5 % of influent COD, and H-MBR removed 89.7 ± 3.5 %. Regarding OMPs, the profile of compounds differed between BW and GW, being BW the matrix with more compounds detected at higher concentrations (up to µg L-1). For example, in the case of ibuprofen the concentrations in BW were 23.63 ± 3.97 µg L-1, 3 orders of magnitude higher than those detected in GW. The most abundant ARGs were sulfonamide resistant genes (sul1) and integron class 1 (intl1) in both BW and GW. Pathogenic bacteria counts were reduced between 1 and 3 log units in the AnMBR. Bacterial loads in GW were much lower than in BW, being no bacterial re-growth observed for the GW effluents after treatment in the H-MBR. None of the selected enteric viruses was detected in GW treatment line.


Assuntos
Antibacterianos , Purificação da Água , Água , Águas Residuárias , Esgotos/microbiologia , Resistência Microbiana a Medicamentos/genética , Genes Bacterianos , Reatores Biológicos/microbiologia , Eliminação de Resíduos Líquidos
10.
bioRxiv ; 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-37425958

RESUMO

Internalization from the cell membrane and endosomal trafficking of receptor tyrosine kinases (RTK) are important regulators of signaling in normal cells that can frequently be disrupted in cancer. The adrenal tumour pheochromocytoma (PCC) can be caused by activating mutations of the RET receptor tyrosine kinase, or inactivation of TMEM127, a transmembrane tumour suppressor implicated in trafficking of endosomal cargos. However, the role of aberrant receptor trafficking in PCC is not well understood. Here, we show that loss of TMEM127 causes wildtype RET protein accumulation on the cell surface, where increased receptor density facilitates constitutive ligand-independent activity and downstream signaling, driving cell proliferation. Loss of TMEM127 altered normal cell membrane organization and recruitment and stabilization of membrane protein complexes, impaired assembly, and maturation of clathrin coated pits, and reduced internalization and degradation of cell surface RET. In addition to RTKs, TMEM127 depletion also promoted surface accumulation of several other transmembrane proteins, suggesting it may cause global defects in surface protein activity and function. Together, our data identify TMEM127 as an important determinant of membrane organization including membrane protein diffusability, and protein complex assembly and provide a novel paradigm for oncogenesis in PCC where altered membrane dynamics promotes cell surface accumulation and constitutive activity of growth factor receptors to drive aberrant signaling and promote transformation.

11.
Cult Health Sex ; 26(2): 159-173, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36995142

RESUMO

Transgender women face a disproportionate burden of carceral violence, or violence related to policing and the criminal legal system, with transgender women of colour experiencing even greater disparities. Several frameworks conceptualise the mechanisms through which violence impacts transgender women. However, none of them directly explore the role of carceral violence, particularly as it is experienced by transgender women themselves. Sixteen in-depth interviews were conducted with a racially/ethnically diverse sample of transgender women in Los Angeles between May and July 2020. Participants were between 23 - 67 years old. Participants identified as Black (n = 4), Latina (n = 4), white (n = 2), Asian (n = 2), and Native American (n = 2). Interviews assessed experiences of multilevel violence, including from police and law enforcement. Deductive and inductive coding methods were used to identify and explore common themes concerning carceral violence. Experiences of law enforcement-perpetrated interpersonal violence were common and included physical, sexual and verbal abuse. Participants also highlighted structural violence, including misgendering, the non-acceptance of transgender identities, and police intentionally failing to uphold laws that could protect transgender women. These results demonstrate the pervasive, multilevel nature of carceral violence perpetrated against transgender women and suggest avenues for future framework development, trans-specific expansions of carceral theory, and system-wide institutional change.


Assuntos
Pessoas Transgênero , Transexualidade , Humanos , Feminino , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Los Angeles , Violência , Comportamento Sexual
12.
J Nerv Ment Dis ; 212(3): 159-165, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38113933

RESUMO

ABSTRACT: The present study explores the relationship between bullying victimization and suicidal thoughts among African American adolescents in urban neighborhoods. The study, which was guided by the general strain theory, proposed and tested potential pathways that link bullying victimization with suicidal thoughts through the mediators including emotional distress, low future orientation, hopelessness, and drug use. The study sample included 414 African American adolescents who were between ages 12 and 22 years and residing in low-income Chicago's South Side neighborhoods. Descriptive statistics, bivariate correlation, and path analyses were conducted. Bullying victimization was not significantly related to suicidal thoughts, although it was positively associated with emotional distress and drug use. The association between low future orientation and hopelessness was bidirectional. The study findings have implications for practice, which is important as resources to assist adolescents who are affected by violence tend to be limited.


Assuntos
Bullying , Vítimas de Crime , Transtornos Relacionados ao Uso de Substâncias , Adolescente , Humanos , Negro ou Afro-Americano , Bullying/psicologia , Vítimas de Crime/psicologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Ideação Suicida , Violência , Criança , Adulto Jovem
13.
mBio ; : e0267123, 2023 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-38032204

RESUMO

IMPORTANCE: Hypochlorous acid (HOCl), commonly known as bleach, is generated during the respiratory burst by phagocytes and is a key weapon used to attack Candida albicans and other microbial pathogens. However, the effects of hypochlorous acid on C. albicans have been less well studied than H2O2, a different type of oxidant produced by phagocytes. HOCl kills C. albicans more effectively than H2O2 and results in disruption of the plasma membrane. HOCl induced a very different transcriptional response than H2O2, and there were significant differences in the susceptibility of mutant strains of C. albicans to these oxidants. Altogether, these results indicate that HOCl has distinct effects on cells that could be targeted in novel therapeutic strategies to enhance the killing of C. albicans and other pathogens.

14.
Behav Sci (Basel) ; 13(10)2023 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-37887484

RESUMO

The present study investigates whether less computer access is associated with an increase or decrease in cyberbullying and face-to-face bullying victimization. Data were derived from the 2009-2010 Health Behavior in School-Aged Children U.S. Study, consisting of 12,642 adolescents aged 11, 13, and 15 years (Mage = 12.95). We found that less computer usage was negatively associated with cyberbullying victimization and face-to-face bullying victimization. The findings from the study have implications for research and practice.

15.
Cancer Cell ; 41(11): 1945-1962.e11, 2023 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-37863066

RESUMO

Tumor microbiota can produce active metabolites that affect cancer and immune cell signaling, metabolism, and proliferation. Here, we explore tumor and gut microbiome features that affect chemoradiation response in patients with cervical cancer using a combined approach of deep microbiome sequencing, targeted bacterial culture, and in vitro assays. We identify that an obligate L-lactate-producing lactic acid bacterium found in tumors, Lactobacillus iners, is associated with decreased survival in patients, induces chemotherapy and radiation resistance in cervical cancer cells, and leads to metabolic rewiring, or alterations in multiple metabolic pathways, in tumors. Genomically similar L-lactate-producing lactic acid bacteria commensal to other body sites are also significantly associated with survival in colorectal, lung, head and neck, and skin cancers. Our findings demonstrate that lactic acid bacteria in the tumor microenvironment can alter tumor metabolism and lactate signaling pathways, causing therapeutic resistance. Lactic acid bacteria could be promising therapeutic targets across cancer types.


Assuntos
Microbiota , Neoplasias do Colo do Útero , Feminino , Humanos , Ácido Láctico/metabolismo , Neoplasias do Colo do Útero/radioterapia , Lactobacillus/genética , Lactobacillus/metabolismo , Microambiente Tumoral
16.
Ecology ; 104(12): e4183, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37786322

RESUMO

Climate change manifests unevenly across space and time and produces complex patterns of stress for ecological systems. Species can also show substantial among-population variability in response to environmental change across their geographic range due to evolutionary processes. Explanatory factors or their proxies, such as temperature and latitude, help parse these sources of environmental and intraspecific variability; however, overemphasizing latitudinal trends can obscure the role of local environmental conditions in shaping population vulnerability to climate change. Focusing on the geographic center of a species range to disentangle latitude, we test the hypothesis that populations from warmer regions of a species range are more vulnerable to ocean warming. We conducted a mesocosm experiment and field reciprocal transplant with four populations of a marine snail, Nucella lamellosa, from two regions in British Columbia, Canada, that differ in thermal characteristics: the Central Coast, a cool region, and the Strait of Georgia, one of the warmest regions of this species' range and one that is warming faster than the Central Coast. Populations from the Strait of Georgia experienced growth reductions at contemporary summertime seawater temperatures in the laboratory and showed stark reductions in survival and growth under future seawater conditions and when outplanted at their native transplant sites. This indicates a high vulnerability to ocean warming, especially given the faster rate of ocean warming in this region. In contrast, populations from the cooler Central Coast demonstrated high performance at contemporary seawater temperatures and high growth and survival in projected future seawater temperatures and at their native outplant sites. Given their position within the geographic center of N. lamellosa's range, extirpation events in the vulnerable Strait of Georgia populations could compromise connectivity within the metapopulation and lead to gaps across this species' range. Overall, our study supports predictions that populations from warm regions of species ranges are more vulnerable to environmental warming, suggests that the Strait of Georgia and other inland or coastal seas could be focal points for climate change effects and ecological transformation, and emphasizes the importance of analyzing climate change vulnerability in the context of regional environmental data and throughout a species' range.


Assuntos
Mudança Climática , Ecossistema , Temperatura , Água do Mar , Colúmbia Britânica
17.
J Med Chem ; 66(20): 13900-13917, 2023 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-37847244

RESUMO

Most known synthetic toll-like receptor 4 (TLR4) agonists are carbohydrate-based lipid-A mimetics containing several fatty acyl chains, including a labile 3-O-acyl chain linked to the C-3 position of the non-reducing sugar known to undergo cleavage impacting stability and resulting in loss of activity. To overcome this inherent instability, we rationally designed a new class of chemically more stable synthetic TLR4 ligands that elicit robust innate and adaptive immune responses. This new class utilized a diamino allose phosphate (DAP) scaffold containing a nonhydrolyzable 3-amide bond instead of the classical 3-ester. Accordingly, the DAPs have significantly improved thermostability in aqueous formulations and potency relative to other known natural and synthetic TLR4 ligands. Furthermore, the DAP analogues function as potent vaccine adjuvants to enhance influenza-specific antibodies in mice and provide protection against lethal influenza virus challenges. This novel set of TLR4 ligands show promise as next-generation vaccine adjuvants and stand-alone immunomodulators.


Assuntos
Adjuvantes de Vacinas , Receptor 4 Toll-Like , Animais , Camundongos , Fatores Imunológicos , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/química , Ligantes , Anticorpos Antivirais
18.
Cell Rep ; 42(9): 113070, 2023 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-37659079

RESUMO

The TMEM127 gene encodes a transmembrane protein of poorly known function that is mutated in pheochromocytomas, neural crest-derived tumors of adrenomedullary cells. Here, we report that, at single-nucleus resolution, TMEM127-mutant tumors share precursor cells and transcription regulatory elements with pheochromocytomas carrying mutations of the tyrosine kinase receptor RET. Additionally, TMEM127-mutant pheochromocytomas, human cells, and mouse knockout models of TMEM127 accumulate RET and increase its signaling. TMEM127 contributes to RET cellular positioning, trafficking, and lysosome-mediated degradation. Mechanistically, TMEM127 binds to RET and recruits the NEDD4 E3 ubiquitin ligase for RET ubiquitination and degradation via TMEM127 C-terminal PxxY motifs. Lastly, increased cell proliferation and tumor burden after TMEM127 loss can be reversed by selective RET inhibitors in vitro and in vivo. Our results define TMEM127 as a component of the ubiquitin system and identify aberrant RET stabilization as a likely mechanism through which TMEM127 loss-of-function mutations cause pheochromocytoma.


Assuntos
Neoplasias das Glândulas Suprarrenais , Feocromocitoma , Humanos , Animais , Camundongos , Feocromocitoma/genética , Feocromocitoma/metabolismo , Feocromocitoma/patologia , Mutação em Linhagem Germinativa , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/patologia , Mutação/genética , Ubiquitinação , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo
19.
Rand Health Q ; 10(4): 1, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37720068

RESUMO

Opioids play an outsized role in America's drug problems, but they also play a critically important role in medicine. Thus, they deserve special attention. Illegally manufactured opioids (such as fentanyl) are involved in a majority of U.S. drug overdoses, but the problems are broader and deeper than drug fatalities. Depending on the drugs involved, there can be myriad physical and mental health consequences associated with having a substance use disorder. And it is not just those using drugs who suffer. Substance use and related behaviors can significantly affect individuals' families, friends, employers, and wider communities. Efforts to address problems related to opioids are insufficient and sometimes contradictory. Researchers provide a nuanced assessment of America's opioid ecosystem, highlighting how leveraging system interactions can reduce addiction, overdose, suffering, and other harms. At the core of the opioid ecosystem are the individuals who use opioids and their families. Researchers also include detail on ten major components of the opioid ecosystem: substance use disorder treatment, harm reduction, medical care, the criminal legal system, illegal supply and supply control, first responders, the child welfare system, income support and homeless services, employment, and education. The primary audience for this study is policymakers, but it should also be useful for foundations looking for opportunities to create change that have often been overlooked. This study can help researchers better consider the full consequences of policy changes and help members of the media identify the dynamics of interactions that deserve more attention.

20.
iScience ; 26(8): 107380, 2023 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-37575182

RESUMO

Immunization of pregnant women with Group B Streptococcus (GBS) capsular polysaccharide (CPS) conjugate vaccine (CV) could protect young infants against invasive GBS disease. We evaluated the immunogenicity of investigational five GBS monovalent (serotypes Ia, Ib, II, III, and V) CPS-tetanus toxoid (TT)-CV with adjuvant and GBS pentavalent CPS-TT-CV with adjuvant (GBS5-CV-adj) and without adjuvant (GBS5-CV-no-adj), in Balb/c mice. Aluminum phosphate was the adjuvant in the formulations, where included. The homotypic immunoglobulin G (IgG) geometric mean concentration (GMC) and opsonophagocytic activity (OPA) geometric mean titer (GMT) did not differ after the third dose of the GBS5-CV-adj vaccine compared with the monovalent counterparts for all five serotypes. The GBS5-CV-adj induced higher post-vaccination serotype-specific IgG GMCs and OPA GMTs compared to GBS5-CV-no_adj. The GBS5-CV with and without adjuvant should be considered for further development as a potential vaccine for pregnant women to protect their infants against invasive GBS disease.

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