Meiotic drivers bias gametogenesis to ensure their transmission into more than half the offspring of a heterozygote. In Schizosaccharomyces pombe, wtf meiotic drivers destroy the meiotic products ...(spores) that do not inherit the driver from a heterozygote, thereby reducing fertility. wtf drivers encode both a Wtfpoison protein and a Wtfantidote protein using alternative transcriptional start sites. Here, we analyze how the expression and localization of the Wtf proteins are regulated to achieve drive. We show that transcriptional timing and selective protein exclusion from developing spores ensure that all spores are exposed to Wtf4poison, but only the spores that inherit wtf4 receive a dose of Wtf4antidote sufficient for survival. In addition, we show that the Mei4 transcription factor, a master regulator of meiosis, controls the expression of the wtf4poison transcript. This transcriptional regulation, which includes the use of a critical meiotic transcription factor, likely complicates the universal suppression of wtf genes without concomitantly disrupting spore viability. We propose that these features contribute to the evolutionary success of the wtf drivers.
The centromere components cohesin, CENP-A, and centromeric DNA are essential for biorientation of sister chromatids on the mitotic spindle and accurate sister chromatid segregation. Insight into the ...3D organization of centromere components would help resolve how centromeres function on the mitotic spindle. We use ChIP-seq and super-resolution microscopy with single particle averaging to examine the geometry of essential centromeric components on human chromosomes. Both modalities suggest cohesin is enriched at pericentromeric DNA. CENP-A localizes to a subset of the α-satellite DNA, with clusters separated by ~562 nm and a perpendicular intervening ~190 nM wide axis of cohesin in metaphase chromosomes. Differently sized α-satellite arrays achieve a similar core structure. Here we present a working model for a common core configuration of essential centromeric components that includes CENP-A nucleosomes, α-satellite DNA and pericentromeric cohesion. This configuration helps reconcile how centromeres function and serves as a foundation to add components of the chromosome segregation machinery.
Introduction
Millions of children and youth live on city streets across the globe, vulnerable to substance use, abuse, material and structural neglect. Structural resilience, the re-establishment of ...access to structural goods within a society such as housing, education, and healthcare following some interruption, provides an orientation for research and interventional efforts with street-involved children and youth (SICY). Further, a structural resilience framework supports organizing interactions between levels and sectors of a socio-ecology.
Methods
Following the expressed interests of Kenyan SICY, and consistent with emerging policy interests at national and global levels, we assess reintegration trajectories of Kenyan SICY (
n
= 227) participating in a new program intervention and model. The intervention combines two coordinated, parallel programs – one focused on the rescue, rehabilitation, reintegration and resocialization of SICY, and the other focused on empowering families and communities to provide better care for children and youth who are reintegrating from life on the streets to the broader community. Data were collected and analyzed from multiple stages across SICY involvement with the intervention.
Results
We found 79% of SICY participants reintegrated with the broader community, and 50% reintegrated with families of origin and returned to school. Twenty-five percent of participants reintegrated to a boarding school, polytechnical school, or began a business. Probability of reintegrating successfully was significantly improved among participants whose families participated in the family- and community-oriented program, who were younger, with less street-exposure, expressed more personal interests, and desired to reintegrate with family.
Discussion
To our knowledge, these are the first quantitative data published of successful reintegration of SICY to the broader, non-institutionalized community in any low- or middle-income country. Future research should (1) identify factors across socio-ecological levels and sectors contributing to health and developmental outcomes of reintegrated children and youth, (2) mechanisms to support SICY for whom the interventional strategy did not work, (3) methods to prevent street-migration by children and youth, and (4) system development to coordinate follow-up and relevant investment by institutions, organizations and community leaders to continue reintegration work.
Diffuse intrinsic pontine glioma (DIPG) remains a fatal brainstem tumor demanding innovative therapies. As B7-H3 (CD276) is expressed on central nervous system (CNS) tumors, we designed ...B7-H3-specific chimeric antigen receptor (CAR) T cells, confirmed their preclinical efficacy, and opened BrainChild-03 (NCT04185038), a first-in-human phase I trial administering repeated locoregional B7-H3 CAR T cells to children with recurrent/refractory CNS tumors and DIPG. Here, we report the results of the first three evaluable patients with DIPG (including two who enrolled after progression), who received 40 infusions with no dose-limiting toxicities. One patient had sustained clinical and radiographic improvement through 12 months on study. Patients exhibited correlative evidence of local immune activation and persistent cerebrospinal fluid (CSF) B7-H3 CAR T cells. Targeted mass spectrometry of CSF biospecimens revealed modulation of B7-H3 and critical immune analytes (CD14, CD163, CSF-1, CXCL13, and VCAM-1). Our data suggest the feasibility of repeated intracranial B7-H3 CAR T-cell dosing and that intracranial delivery may induce local immune activation.
This is the first report of repeatedly dosed intracranial B7-H3 CAR T cells for patients with DIPG and includes preliminary tolerability, the detection of CAR T cells in the CSF, CSF cytokine elevations supporting locoregional immune activation, and the feasibility of serial mass spectrometry from both serum and CSF. This article is highlighted in the In This Issue feature, p. 1.
Summary
Over the past four decades, group-based microfinance programs have spread rapidly throughout south Asia, sub-Saharan Africa and Latin America. Recent evaluations of the programs have ...identified social capital as a common byproduct of frequent association by members, increasing trust, belonging and normative influence. Concurrently, social capital is increasingly recognized as an important health determinant. We present an overview of a program intervention operating in Kenya that utilizes a microfinance approach to produce social capital, and seeks to leverage that social capital to promote health at three levels—the village, group, and individual. A theory of change is presented for each of these three levels, demonstrating conceptually and with program examples how social capital can be applied to promote health. Related social theories and approaches, further research and program directions are given for each of the three levels. We identify potential to improve a broad range of health outcomes through this innovative model, which requires engagement with health promotion researchers and planners in low- and middle-income countries for further refinement and validation.
Millions of children sleep on the streets every night, separated from family and reliable shelter. Research over the past decades has established risk factors and health outcomes of street-involved ...children and youth (SICY), which in turn have led to the development of multiple frameworks to guide policy and programming for working with SICY. However, research is also needed to define and evaluate effective interventions to help children caught in homelessness and separated from families. Through a review of implemented programs to reunite SICY with their families as well as relevant formative research on family-level risk factors for street migration, we explore family-level factors relevant to successful family reintegration of SICY. This scoping literature review is structured following a typical timeline of street-migration to reintegration (migration, rescue, reintegration, and follow-up) and uses a family capital framework to explore forms of capital (economic, social, cultural, and health) pertinent to family-level well-being. Associations between stages of street-migration and forms of capital are discussed as well as implications for not only the structure and design of interventions but also their evaluation. The current body of research on SICY, though lacking in evaluation, provides key findings to inform interventions to prevent street-migration and support family and community reintegration.
Reactivation of the varicella zoster virus (VZV) increases during aging. Although the effects of VZV reactivation are observed in the skin (shingles), the number and functional capacity of cutaneous ...VZV-specific T cells have not been investigated. The numbers of circulating IFN-γ-secreting VZV-specific CD4+ T cells are significantly decreased in old subjects. However, other measures of VZV-specific CD4+ T cells, including proliferative capacity to VZV antigen stimulation and identification of VZV-specific CD4+ T cells with an major histocompatibility complex class II tetramer (epitope of IE-63 protein), were similar in both age groups. The majority of T cells in the skin of both age groups expressed CD69, a characteristic of skin-resident T cells. VZV-specific CD4+ T cells were significantly increased in the skin compared with the blood in young and old subjects, and their function was similar in both age groups. In contrast, the number of Foxp3+ regulatory T cells and expression of the inhibitory receptor programmed cell death -1 PD-1 on CD4+ T cells were significantly increased in the skin of older humans. Therefore, VZV-specific CD4+ T cells in the skin of older individuals are functionally competent. However, their activity may be restricted by multiple inhibitory influences in situ.
Multisystem, multi-level interventions are required to enable resilient, nurturing environments for children facing adversity. This study assesses parenting behavior associated with participation in ...a community-based, adapted microfinance program, and mediated by program-affiliated social capital, maternal depression and self-esteem among Kenyan women. Participants in the intervention, Kuja Pamoja kwa Jamii (KPJ, Swahili for “Come Together to Belong”), gather weekly to engage in trainings and group-based microfinance. Groups selected for the study had participated in the program for 0–15 months at the time of the first interview. Women (n = 400) completed surveys in June 2018 and June 2019. Measures included duration of program exposure, group-affiliated social capital (i.e. trust, belonging, cohesion, and expectation of mutual benefit), depression, self-esteem, and conflict tactics. We used regression analyses and generalized structural equation models to explore associations between program exposure, social capital, psychosocial variables and child maltreatment. Each standard deviation increase in duration of program exposure decreased odds of child physical abuse by 40% and child neglect by 35%. Each standard deviation in the social capital index predicted a significant reduction in odds of child physical abuse (aOR: 0.67), and child neglect (aOR: 0.71). Self-esteem and depression fully mediated observed associations between social capital and child maltreatment. Findings recommend further investigation of the potential for adapted microfinance programs to deliver parenting interventions, improve mental health and foster resilience-enabling social capital. A randomized control trial is required to validate the potential of the assessed intervention to improve parenting behaviors and supportive social conditions.
Abstract Globally, study of factors contributing to the street-migration of the tens of millions of street-involved children focus almost exclusively on children’s perspectives. In this study, we ...assess household and maternal factors associated with street-migration of children through self-report of 1974 randomly selected women in semi-rural Kenya. Contributing new perspectives on this global phenomenon, data show a statistically significant association between increased maternal childhood adversities and street-migration of children (p < 0.001). Higher household wealth (p < 0.01) and maternal education (p < 0.05) were associated with lower odds of street-migration of children. Social support, reporting HIV+, school enrollment of biologically-related children, overall health, reported alcohol use, and functional literacy significantly mediated these pathways. Protecting children from street-migration in the next generation requires reducing childhood adversities in the present generation.
The first study focused on a three-month chart review containing information on suicide attempts (n = 34) admitted to a local mission hospital in Meru County, Kenya. The second study utilized a ...cross-sectional survey administered to men 18–34 years old (n = 532) residing in rural Kenya. Data posit intimate partnership discord as salient to suicide ideation and behavior. Men who reported their partner status was “divorced” had four-times the odds of reporting suicide ideation than other partnership states, an association significantly mediated by loneliness. Violent conflict tactics predicted suicidal ideation, mediated by loneliness and decreased marital satisfaction.
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