We examined whether adult stress reactivity accounts for the relationship between early life adversity (ELA) and psychological, physical, and cognitive outcomes.
We examined the relationship between ...ELA, stress reactivity, psychological well-being, physical health, and cognitive function in two separate datasets - a cross-sectional community sample of older adults (N = 510) aged 60 and older, and waves I-III of the Midlife in the United States (MIDUS) dataset. Age, sex, and income served as covariates in all analyses. Bootstrapped mediation models were used to assess recent stress as a mediator between ELA and mid- to late-life outcomes.
ELA was significantly associated with adult stress, anxiety, depression, health conditions, and object cognitive assessments. Adult stress partially accounted for the relationships between ELA and depression, anxiety, health conditions, and memory problems.
Our findings demonstrate that ELA may influence increased stress in older age, which confers additional risks for developing depression, anxiety, health problems, and cognitive decline. It is possible that intervening on adult stress may reduce risk for both psychological and physical pathology across the lifespan. Further research is needed to develop targeted interventions for mid and late-life stress to improve overall health as individuals age.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Emotion dysregulation emerges from an interaction between individual factors and environmental factors. Changes in biological, cognitive, and social systems that characterize adolescence create a ...complex array of environmental factors contributing to emotion dysregulation during this developmental period. In particular, peer victimization (PV) has long-term consequences for emotion dysregulation. Yet, previous research has also indicated that emotion dysregulation can be both an antecedent to and outcome of PV. The present study evaluated reciprocal associations between longitudinal changes within repeated measures of PV and emotion dysregulation across adolescence and into young adulthood. The sample included 167 adolescents (53% male,
= 14.07 years at Time 1) who participated in a longitudinal study across five time points, with approximately 1 year between each assessment. Latent change score modeling was used to examine reciprocal associations between PV and emotion dysregulation. Results emphasize bidirectional associations between PV and emotion dysregulation. Consistent with social information processing theory, greater emotion dysregulation predicted greater relational and overt victimization over time. Moreover, higher overt victimization predicted increases in emotion dysregulation. Our results offer insights toward developmentally informed longitudinal, transactional models linking negative social environments, and emotion dysregulation development across adolescence and into young adulthood. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Cancer results from a breakdown of normal gene expression control, so the study of gene regulation is critical to cancer research. To gain insight into the transcriptional and epigenetic factors ...regulating abnormal gene expression patterns in cancers, we developed the Cistrome Cancer web resource (http://cistrome.org/CistromeCancer/). We conducted the systematic integration and modeling of over 10,000 tumor molecular profiles from The Cancer Genome Atlas (TCGA) with over 23,000 ChIP-seq and chromatin accessibility profiles from our Cistrome collection. The results include reconstruction of functional enhancer profiles, "super-enhancer" target genes, as well as predictions of active transcription factors and their target genes for each TCGA cancer type. Cistrome Cancer reveals novel insights from integrative analyses combining chromatin profiles with tumor molecular profiles and will be a useful resource to the cancer gene regulation community.
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Which restorative material is best suited for treating the posterior molar region is unclear. As dentists presumably choose the most appropriate restoration, German dentists were asked how their own ...molars were treated.
The purpose of this survey study was to examine molar restorations and their durability in German dentists.
In the official journal of the Federal Dental Association, German dentists were asked to participate in an online survey that gathered demographic data and information on the type and durability of their molar restorations. To reduce selection bias, the data were weighted for region, sex, and age of the dentist.
The data set consisted of 1719 molars from 288 dentists. Restorations included gold inlays (25%), composite resin (24.3%), amalgam (11.8%), ceramic inlays (5.4%), glass ionomer cement or compomer (0.8%), gold crowns (21.8%), ceramic crowns (6.6%), and metal-ceramic crowns (4.3%). Notable differences were identified based on the sex, age, and region of the dentist. Women selected increased esthetic options, as did young dentists. Restorations made of gold, amalgam, and base metal had the highest longevity, at more than 20 years
Among German dentists, restorations with metallic materials dominated in molars, with gold accounting for the largest share. In recent years, the proportion of tooth-colored restorations has increased, and in particular, young dentists use composite resin and ceramics.
The organic anion transporting polypeptide (OATP) 2B1 is considered an emerging drug transporter that is found expressed in pharmacokinetically relevant organs such as the liver, small intestine, and ...kidney. Despite its interaction with various substrate drugs, the understanding of its in vivo relevance is still limited. In this study, we first validated the interaction of atorvastatin with rat OATP2B1 using transiently transfected HeLa cells. Moreover, we characterized our rSlco2b1-knockout and SLCO2B1-knockin rats for mRNA, protein expression, and localization of OATP2B1 in the liver, small intestine, and kidney. The transporter showed the highest expression in the liver followed by the small intestine. In humanized rats, human OATP2B1 is localized on the sinusoidal membrane of hepatocytes. In enterocytes of wild-type and humanized rats, the transporter was detected in the luminal membrane with the vast majority being localized subapical. Subsequently, we assessed atorvastatin pharmacokinetics in male wild-type, rSlco2b1-knockout, and SLCO2B1-knockin rats after a single-dose administration (orally and intravenously). Investigating the contribution of rat OATP2B1 or human OATP2B1 to oral atorvastatin pharmacokinetics revealed no differences in concentration-time profiles or pharmacokinetic parameters. However, when comparing the pharmacokinetics of atorvastatin after intravenous administration in SLCO2B1-humanized rats and knockout animals, notable differences were observed. In particular, the systemic exposure (area under the curve) decreased by approximately 40% in humanized animals, whereas the clearance was 57% higher in animals expressing human OATP2B1. These findings indicate that human OATP2B1 influences pharmacokinetics of atorvastatin after intravenous administration, most likely by contributing to the hepatic uptake. SIGNIFICANCE STATEMENT: Wild-type, rSlco2b1-knockout, and SLCO2B1-humanized Wistar rats were characterized for the expression of rat and human SLCO2B1/OATP2B1. Pharmacokinetic studies of atorvastatin over 24 hours were conducted in male wild-type, rSlco2b1-knockout, and SLCO2B1-humanized rats. After a single-dose intravenous administration, a lower systemic exposure and an increase in clearance were observed in SLCO2B1-humanized rats compared with knockout animals indicating a contribution of OATP2B1 to the hepatic clearance.The organic anion transporting polypeptide (OATP) 2B1 is considered an emerging drug transporter that is found expressed in pharmacokinetically relevant organs such as the liver, small intestine, and kidney. Despite its interaction with various substrate drugs, the understanding of its in vivo relevance is still limited. In this study, we first validated the interaction of atorvastatin with rat OATP2B1 using transiently transfected HeLa cells. Moreover, we characterized our rSlco2b1-knockout and SLCO2B1-knockin rats for mRNA, protein expression, and localization of OATP2B1 in the liver, small intestine, and kidney. The transporter showed the highest expression in the liver followed by the small intestine. In humanized rats, human OATP2B1 is localized on the sinusoidal membrane of hepatocytes. In enterocytes of wild-type and humanized rats, the transporter was detected in the luminal membrane with the vast majority being localized subapical. Subsequently, we assessed atorvastatin pharmacokinetics in male wild-type, rSlco2b1-knockout, and SLCO2B1-knockin rats after a single-dose administration (orally and intravenously). Investigating the contribution of rat OATP2B1 or human OATP2B1 to oral atorvastatin pharmacokinetics revealed no differences in concentration-time profiles or pharmacokinetic parameters. However, when comparing the pharmacokinetics of atorvastatin after intravenous administration in SLCO2B1-humanized rats and knockout animals, notable differences were observed. In particular, the systemic exposure (area under the curve) decreased by approximately 40% in humanized animals, whereas the clearance was 57% higher in animals expressing human OATP2B1. These findings indicate that human OATP2B1 influences pharmacokinetics of atorvastatin after intravenous administration, most likely by contributing to the hepatic uptake. SIGNIFICANCE STATEMENT: Wild-type, rSlco2b1-knockout, and SLCO2B1-humanized Wistar rats were characterized for the expression of rat and human SLCO2B1/OATP2B1. Pharmacokinetic studies of atorvastatin over 24 hours were conducted in male wild-type, rSlco2b1-knockout, and SLCO2B1-humanized rats. After a single-dose intravenous administration, a lower systemic exposure and an increase in clearance were observed in SLCO2B1-humanized rats compared with knockout animals indicating a contribution of OATP2B1 to the hepatic clearance.
Background and Purpose
Coproporphyrin (CP) I and III are byproducts of haem synthesis currently investigated as biomarkers for drug–drug interactions involving hepatic organic anion transporting ...polypeptide (OATP) 1B transporters. Another hepatically expressed OATP‐member is OATP2B1. The aim of this study was to test the impact of OATP2B1, which specifically transports CPIII, on CP serum levels, applying novel rat models.
Experimental Approach
CPIII transport kinetics and the interplay between OATP2B1 and multidrug resistance‐associated proteins (MRPs) were determined in vitro using the vTF7 expression system. Novel rSlco2b1−/− and SLCO2B1+/+ rat models were characterized for physiological parameters and for CP serum levels. Hepatic and renal expression of transporters involved in CP disposition were determined by real‐time qPCR, Western blot analysis, and immunohistochemistry.
Key Results
In vitro experiments revealed differences in transport kinetics comparing human and rat OATP2B1 and showed a consistent, species‐specific interplay with hMRP3/rMRP3. Deletion of rOATP2B1 was associated with a trend towards lower CPI serum levels compared with wildtype rats, while CPIII remained unchanged. Comparing SLCO2B1+/+ with knockout rats revealed an effect of sex: only in females the genetic modification influenced CP serum levels. Analysis of hepatic and renal transporters revealed marginal, but in part, statistically significant differences in rMRP2 abundance, which may contribute to the observed changes in CP serum levels.
Conclusion and Implications
Our findings support that factors other than OATP1B transporters are of relevance for basal CP levels. Only in female rats, humanization of SLCO2B1 affects basal CPI and CPIII serum levels, despite isomer selectivity of OATP2B1.
Prognostication has become central to medical practice, offering clinicians and patients views of particular futures enabled by biomedical expertise and technologies. Drawing on research on diabetes ...care and sleep medicine in the United States, in this article we suggest that subjectivity is increasingly modeled on medical understandings of chronic illness. These chronic conceptions of the self and society instill in individuals an anxiety about future health outcomes that, in turn, motivate practices oriented at self-care to avoid negative health outcomes and particular medical futures. At its most extreme, these anxieties of self-care trouble conceptions of self and social belonging, particularly in the future tense, leading patients and clinicians to consider intergenerational and public health based on the threats that individual patients pose for others.
This work describes the heterologous expression and enzymatic activity of NTPDase-1, which is ubiquitously expressed in epimastigotes, participating in the T. cruzi adhesion to host cells and ...infection.
•Heterologous TcNTPDase-1 showed a greater capacity to hydrolyze NDPs than NTPs.•TcNTPDase1 Km for ATP would permit it to influence host purinergic signaling.•TcNTPDase-1 showed a ubiquitous localization in epimastigotes.•TcNTPDase-1 may be involved in a number of different biological processes.•TcNTPDase-1 acts as a pro-adhesion molecule.
Previous work has suggested that Trypanosoma cruzi diphosphohydrolase 1 (TcNTPDase-1) may be involved in the infection of mammalian cells and serve as a potential target for rational drug design. In this work, we produced recombinant TcNTPDase-1 and evaluated its nucleotidase activity, cellular localization and role in parasite adhesion to mammalian host cells. TcNTPDase-1 was able to utilize a broad range of triphosphate and diphosphate nucleosides. The enzyme's Km for ATP (0.096mM) suggested a capability to influence the host's ATP-dependent purinergic signaling. The use of specific polyclonal antibodies allowed us to confirm the presence of TcNTPDase-1 at the surface of parasites by confocal and electron microscopy. In addition, electron microscopy revealed that TcNTPDase-1 was also found in the flagellum, flagellum insertion region, kinetoplast, nucleus and intracellular vesicles. The presence of this enzyme in the flagellum insertion region and vesicles suggests that it may have a role in nutrient acquisition, and the widespread distribution of TcNTPDase-1 within the parasite suggests that it may be involved in other biological process. Adhesion assays using anti-TcNTPDase-1 polyclonal antibodies as a blocker or purified recombinant TcNTPDase-1 as a competitor revealed that the enzyme has a role in parasite–host cell adhesion. These data open new frontiers to future studies on this specific parasite–host interaction and other unknown functions of TcNTPDase-1 related to its ubiquitous localization.
Sex-related differences in the immune pathogenesis of hepatocellular carcinoma (HCC), particularly related to oestrogen-dependent secretion of pro-tumourigenic cytokines, are well-known. Whether sex ...influences the efficacy and safety of immunotherapy is not known.
We performed a restricted maximum likelihood random effects meta-analysis of five phase III trials that evaluated immune checkpoint inhibitors (ICIs) in advanced HCC and reported overall survival (OS) hazard ratios (HRs) stratified by sex to evaluate sex-related differences in OS. In a real-world cohort of 840 patients with HCC from 22 centres included between 2018 and 2023, we directly compared the efficacy and safety of atezolizumab + bevacizumab (A+B) between sexes. Radiological response was reported according to RECIST v1.1. Uni- and multivariable Cox regression analyses were performed for OS and progression-free survival (PFS).
In the meta-analysis, immunotherapy was associated with a significant OS benefit only in male (pooled HR 0.79; 95% CI 0.73–0.86) but not in female (pooled HR 0.85; 95% CI 0.70–1.03) patients with HCC. When directly comparing model estimates, no differences in the treatment effect between sexes were observed. Among 840 patients, 677 (81%) were male (mean age 66 ± 11 years), and 163 (19%) were female (mean age 67 ± 12 years). Type and severity of adverse events were similar between the two groups. OS and PFS were comparable between males and females upon uni- and multivariable analyses (aHR for OS and PFS: 0.79, 95% CI 0.59–1.04; 1.02, 95% CI 0.80–1.30, respectively). Objective response rates (24%/22%) and disease control rates (59%/59%) were also similar between sexes.
Female phase III trial participants experienced smaller OS benefit following ICI therapy for advanced HCC, while outcomes following A+B treatment were comparable between sexes in a large real-world database. Based on the ambiguous sex-related differences in survival observed here, further investigation of sex-specific clinical and biologic determinants of responsiveness and survival following ICIs are warranted.
While immune checkpoint inhibitors have emerged as standard of care for the treatment of hepatocellular carcinoma, there are conflicting reports on whether the efficacy of cancer immunotherapy differs between females and males. Our study suggests ambiguous sex-related differences in outcomes from immunotherapy in hepatocellular carcinoma. Further investigation of sex-specific clustering in clinicopathologic and immunologic determinants of responsiveness to immune checkpoint inhibitor therapy should be prioritised.
PROSPERO CRD42023429625.
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•There are conflicting reports on the efficacy of cancer immunotherapy between sexes.•Female phase III trial patients experienced worse OS following ICI therapy for HCC.•Our study suggests ambiguous sex differences in terms of outcomes after ICI therapy in HCC.•Further investigation of sex-specific clustering should be prioritised.
RESUMO A possibilidade do uso de herbicidas em ecossistema aquático para controle de macrófitas quando em condições de desequilíbrio levou à necessidade de estudos que avaliam a concentração de ...efeito que seja eficiente e ecologicamente equilibrada, sem causar maiores impactos aos organismos não alvo e ao ecossistema aquático. O glifosato é o princípio ativo de alguns herbicidas e é conhecido pela sua eficácia, amplo espectro de ação e baixa toxicidade. Neste trabalho foi investigada a menor concentração de efeito para controle da Eichhornia crassipes e da Salvinia sp em experimentos realizados em triplicata e observados pelo período de 20 dias após aplicações de glifosato nas concentrações de 6,25; 12,5; 25,0; 50,0 e 100 L.ha-1. Como resultado, verificou-se que apenas a concentração de 100 L.ha-1 apresentou diferença significativa de efeito comparada ao controle. O efeito ao final do vigésimo dia foi superior a 90%, tornando-se aparente a partir do décimo dia. Existiu uma pequena diferença na sensibilidade entre as espécies, no entanto, a concentração de efeito foi semelhante. A dose de 100 L.ha-1 impediu a ocorrência de rebrota, no prazo de 30 dias, e causou efeito residual pobre em espécies vegetais inseridas no ambiente após a aplicação do herbicida.
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