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Microglia, the immune cells of the central nervous system, play critical roles in brain physiology and pathology. selleck inhibitor We report a novel approach that produces, within 10 days, the differentiation of human induced pluripotent stem cells (hiPSCs) into microglia (iMG) by forced expression of both SPI1 and CEBPA. High-level expression of the main microglial markers and the purity of the iMG cells were confirmed by RT-qPCR, immunostaining, and flow cytometry analyses. Whole-transcriptome analysis demonstrated that these iMGs resemble human fetal/adult microglia but not human monocytes. Moreover, these iMGs exhibited appropriate physiological functions, including various inflammatory responses, ADP/ATP-evoked migration, and phagocytic ability. When co-cultured with hiPSC-derived neurons, the iMGs respond and migrate toward injured neurons. This study has established a protocol for the rapid conversion of hiPSCs into functional iMGs, which should facilitate functional studies of human microglia using different disease models and also help with drug discovery.Interaction of the SARS-CoV-2 Spike receptor binding domain (RBD) with the receptor ACE2 on host cells is essential for viral entry. RBD is the dominant target for neutralizing antibodies, and several neutralizing epitopes on RBD have been molecularly characterized. Analysis of circulating SARS-CoV-2 variants has revealed mutations arising in the RBD, N-terminal domain (NTD) and S2 subunits of Spike. To understand how these mutations affect Spike antigenicity, we isolated and characterized >100 monoclonal antibodies targeting epitopes on RBD, NTD, and S2 from SARS-CoV-2-infected individuals. Approximately 45% showed neutralizing activity, of which ∼20% were NTD specific. NTD-specific antibodies formed two distinct groups the first was highly potent against infectious virus, whereas the second was less potent and displayed glycan-dependant neutralization activity. Mutations present in B.1.1.7 Spike frequently conferred neutralization resistance to NTD-specific antibodies. This work demonstrates that neutralizing antibodies targeting subdominant epitopes should be considered when investigating antigenic drift in emerging variants.Many diseases, including cancer, stem from aberrant activation or overexpression of oncoproteins that are associated with multiple signaling pathways. Although proteins with catalytic activity can be successfully drugged, the majority of other protein families, such as transcription factors, remain intractable due to their lack of ligandable sites. In this study, we report the development of TRAnscription Factor TArgeting Chimeras (TRAFTACs) as a generalizable strategy for targeted transcription factor degradation. We show that TRAFTACs, which consist of a chimeric oligonucleotide that simultaneously binds to the transcription factor of interest (TOI) and to HaloTag-fused dCas9 protein, can induce degradation of the former via the proteasomal pathway. Application of TRAFTACs to two oncogenic TOIs, NF-κB and brachyury, suggests that TRAFTACs can be successfully employed for the targeted degradation of other DNA-binding proteins. Thus, TRAFTAC technology is potentially a generalizable strategy to induce degradation of other transcription factors both in vitro and in vivo.Climate change is increasing the frequency and intensity of weather-related disasters such as hurricanes, wildfires, floods, and droughts. Understanding resilience and vulnerability to these intense stressors and their aftermath could reveal adaptations to extreme environmental change. In 2017, Puerto Rico suffered its worst natural disaster, Hurricane Maria, which left 3,000 dead and provoked a mental health crisis. Cayo Santiago island, home to a population of rhesus macaques (Macaca mulatta), was devastated by the same storm. We compared social networks of two groups of macaques before and after the hurricane and found an increase in affiliative social connections, driven largely by monkeys most socially isolated before Hurricane Maria. Further analysis revealed monkeys invested in building new relationships rather than strengthening existing ones. Social adaptations to environmental instability might predispose rhesus macaques to success in rapidly changing anthropogenic environments.In genome-wide association studies, ordinal categorical phenotypes are widely used to measure human behaviors, satisfaction, and preferences. However, because of the lack of analysis tools, methods designed for binary or quantitative traits are commonly used inappropriately to analyze categorical phenotypes. To accurately model the dependence of an ordinal categorical phenotype on covariates, we propose an efficient mixed model association test, proportional odds logistic mixed model (POLMM). POLMM is computationally efficient to analyze large datasets with hundreds of thousands of samples, can control type I error rates at a stringent significance level regardless of the phenotypic distribution, and is more powerful than alternative methods. In contrast, the standard linear mixed model approaches cannot control type I error rates for rare variants when the phenotypic distribution is unbalanced, although they performed well when testing common variants. We applied POLMM to 258 ordinal categorical phenotypes on array genotypes and imputed samples from 408,961 individuals in UK Biobank. In total, we identified 5,885 genome-wide significant variants, of which, 424 variants (7.2%) are rare variants with MAF less then 0.01.

Data on immune reconstitution inflammatory syndrome (IRIS), despite being a widely recognized complication of antiretroviral therapy, remain limited. The objective of the present study was to evaluate the time-to-onset and factors affecting clinical outcomes of IRIS in people living with HIV (PLWH) using data from the Japanese Adverse Drug Event Report (JADER) database.

Data of PLWH who developed IRIS as an adverse event were extracted from the JADER database. Cases with the data of both the start date of anti-HIV drug therapy and date of IRIS onset were included in the study. The survey items included sex, age, anti-HIV drug use, IRIS-compatible events, time-to-onset of IRIS, and clinical outcome. The time-to-onset of IRIS was evaluated in relation to anchor drug use. Overall, 79 cases were included in the analysis.

The median (range) time-to-onset of IRIS was 29 (1-365) days, and it differed significantly between IRIS-compatible events (P = 0.029). In particular, the time-to-onset of Pneumocystis pneution/AIDS and for the management of IRIS.In recent years, self-sampling has emerged as a compelling way of increasing cervical cancer screening rates within First Nations, Inuit and Métis communities. By allowing women to take their own samples in private, when and where they are most comfortable, home testing kits have been framed as a new, unequivocally feminist technology, and a panacea in Indigenous health. But are these techniques really as ethical and empowering as they have been made out to be? To answer this question, this article traces the history of the uptake and use of cervical cancer screening technologies in Canada. By tracing the mechanics and motivations of two state-sponsored cervical cancer screening studies carried out by Canada's Department of Indian Health Services during the mid to late twentieth century, this piece explores the settler-colonial roots of cancer surveillance, and shows how the implementation of both Pap-testing and DIY forms of screening within Indigenous communities has, at least historically, been more about enacting biopolitical regimes than promoting feminist ideals or improving health outcomes.After the Second World War, health prevention work in Canada shifted from a focus on sanitation and hygiene to illness prevention and health promotion. Canada became a significant global leader, beginning with the Lalonde Report of 1974. Yet less is known about the provincial public health associations and how their work differed from that of the national body. The purpose of this article is to examine the Saskatchewan Public Health Association's (SPHA) policy work from 1954 to 1986. Utilizing meeting minutes and newsletters, we found that while both national and provincial associations made efforts to prevent accidents, reduce tobacco use, and fluoridate water, the SPHA tended to advocate more for child health, and the cautious use of nuclear power. At the same time, the SPHA's resolutions tended to ignore emerging factors shaping health, including the social determinants of health, regional inequities, lack of public trust in experts, misinformation, and human psychology. Examining the SPHA's records revealed that region mattered in preventative policy work.

Three Words-Three Shapes (3W3S) is a bedside test that assesses verbal and non-verbal memory and has proven useful in staging memory decline in amnestic disorders and primary progressive aphasia. Given its simple structure, the 3W3S can be easily adapted to other languages maintaining the original shapes and only modifying the words. We aim to validate a Spanish version of the 3W3S test and establish whether memory loss patterns present in amnesic disorders associated with Alzheimer's etiology and PPA were correctly characterized.

The translation and adaptation of the 3W3S were performed according to standardized guidelines and applied to a cohort of patients with Dementia of Alzheimer's type (DAT = 20), mild cognitive impairment (aMCI= 20), primary progressive aphasia (PPA = 20), and healthy controls (HC = 20).

In verbal memory performance, PPA patients' score was lower than that of MCI and HC and similar to DAT's in the effortless encoding (

 < 0.001), delayed recall (

 < 0.001), and recognition (

 < 0.012). For non-verbal performance, PPA patients performed better than DAT and similar to HC and MCI subjects (

 < 0.001).

Results show good applicability of 3W3S to determine memory function in PPA patients, independently from language ability. Visual and verbal components of memory are dissociated in PPA.

Results show good applicability of 3W3S to determine memory function in PPA patients, independently from language ability. Visual and verbal components of memory are dissociated in PPA.

This study sought to quantify physical activity and sedentary time among older adults during a skilled nursing facility (SNF) stay and after the transition home, a critical period when patients are at high risk for adverse events.

We performed an observational cohort study of physical activity and sedentary behavior during the last 3-5 days before discharge from SNF and the initial 3-5 days at home using accelerometers. Participants answered questions about perceived physical activity in the SNF and at home.

A convenience sample of thirty-one residents from two SNFs were included. Participants spent a median 12.2% (interquartile range [IQR], 17.3%) of time upright in the SNF and 16.8% (IQR, 15.2%) of their time upright at home (

 = 0.002) and took a median of 849 steps (IQR, 1772) in the SNF and 922 steps (IQR, 1906) at home (

 = 0.57), per day. Participants averaged fewer sitting bouts at home (

 = 0.03), but there was no difference in sit-to-stand transitions (

 = 0.32) or activity scores (

 = 0.