Rare manifestation of a c.290 C\u3eT, p.Gly97Glu VCP mutation

Introduction. The valosin-containing protein (VCP) regulates several distinct cellular processes. Consistent with this, VCP mutations manifest variable clinical phenotypes among and within families and are a diagnostic challenge. Methods. A 60-year-old man who played ice hockey into his 50’s was evaluated by electrodiagnostics, muscle biopsy, and molecular genetics. Results. With long-standing pes cavus and toe walking, our patient developed progressive weakness, cramps, memory loss, and paresthesias at age 52. An axonal sensorimotor neuropathy was found upon repeated testing at age 58. Neuropathic histopathology was present in the quadriceps, and exome sequencing revealed the VCP mutation c.290 C>T, p.Gly97Glu. Conclusions. Our patient reflects the clinical heterogeneity of VCP mutations, as his neurological localization is a spectrum between a lower motor neuron disorder and a hereditary axonal peripheral neuropathy such as CMT2. Our case demonstrates a rare manifestation of the c.290 C>T, pGly97Glu VCP mutation

Notch activation is required for downregulation of HoxA3-dependent endothelial cell phenotype during blood formation.

Hemogenic endothelium (HE) undergoes endothelial-to-hematopoietic transition (EHT) to generate blood, a process that requires progressive down-regulation of endothelial genes and induction of hematopoietic ones. Previously, we have shown that the transcription factor HoxA3 prevents blood formation by inhibiting Runx1 expression, maintaining endothelial gene expression and thus blocking EHT. In the present study, we show that HoxA3 also prevents blood formation by inhibiting Notch pathway. HoxA3 induced upregulation of Jag1 ligand in endothelial cells, which led to cis-inhibition of the Notch pathway, rendering the HE nonresponsive to Notch signals. While Notch activation alone was insufficient to promote blood formation in the presence of HoxA3, activation of Notch or downregulation of Jag1 resulted in a loss of the endothelial phenotype which is a prerequisite for EHT. Taken together, these results demonstrate that Notch pathway activation is necessary to downregulate endothelial markers during EHT

Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment

Background: Global but predictable changes impact the DNA methylome as we age, acting as a type of molecular clock. This clock can be hastened by conditions that decrease lifespan, raising the question of whether it can also be slowed, for example, by conditions that increase lifespan. Mice are particularly appealing organisms for studies of mammalian aging; however, epigenetic clocks have thus far been formulated only in humans. Results: We first examined whether mice and humans experience similar patterns of change in the methylome with age. We found moderate conservation of CpG sites for which methylation is altered with age, with both species showing an increase in methylome disorder during aging. Based on this analysis, we formulated an epigenetic-aging model in mice using the liver methylomes of 107 mice from 0.2 to 26.0 months old. To examine whether epigenetic aging signatures are slowed by longevity-promoting interventions, we analyzed 28 additional methylomes from mice subjected to lifespan-extending conditions, including Prop1df/df dwarfism, calorie restriction or dietary rapamycin. We found that mice treated with these lifespan-extending interventions were significantly younger in epigenetic age than their untreated, wild-type age-matched controls. Conclusions: This study shows that lifespan-extending conditions can slow molecular changes associated with an epigenetic clock in mice livers

Notochordal cells protect nucleus pulposus cells from degradation and apoptosis: implications for the mechanisms of intervertebral disc degeneration

Abstract Introduction The relative resistance of non-chondrodystrophic (NCD) canines to degenerative disc disease (DDD) may be due to a combination of anabolic and anti-catabolic factors secreted by notochordal cells within the intervertebral disc (IVD) nucleus pulposus (NP). Factors known to induce DDD include interleukin-1 beta (IL-1ß) and/or Fas-Ligand (Fas-L). Therefore we evaluated the ability of notochordal cell conditioned medium (NCCM) to protect NP cells from IL-1ß and IL-1ß +FasL-mediated cell death and degeneration. Methods We cultured bovine NP cells with IL-1ß or IL-1ß+FasL under hypoxic serum-free conditions (3.5% O2) and treated the cells with either serum-free NCCM or basal medium (Advanced DMEM/F-12). We used flow cytometry to evaluate cell death and real-time (RT-)PCR to determine the gene expression of aggrecan, collagen 2, and link protein, mediators of matrix degradation ADAMTS-4 and MMP3, the matrix protection molecule TIMP1, the cluster of differentiation (CD)44 receptor, the inflammatory cytokine IL-6 and Ank. We then determined the expression of specific apoptotic pathways in bovine NP cells by characterizing the expression of activated caspases-3, -8 and -9 in the presence of IL-1ß+FasL when cultured with NCCM, conditioned medium obtained using bovine NP cells (BCCM), and basal medium all supplemented with 2% FBS. Results NCCM inhibits bovine NP cell death and apoptosis via suppression of activated caspase-9 and caspase-3/7. Furthermore, NCCM protects NP cells from the degradative effects of IL-1ß and IL-1ß+Fas-L by up-regulating the expression of anabolic/matrix protective genes (aggrecan, collagen type 2, CD44, link protein and TIMP-1) and down-regulating matrix degrading genes such as MMP-3. Expression of ADAMTS-4, which encodes a protein for aggrecan remodeling, is increased. NCCM also protects against IL-1+FasL-mediated down-regulation of Ank expression. Furthermore, NP cells treated with NCCM in the presence of IL-1ß+Fas-L down-regulate the expression of IL-6 by almost 50%. BCCM does not mediate cell death/apoptosis in target bovine NP cells. Conclusions Notochordal cell-secreted factors suppress NP cell death by inhibition of activated caspase-9 and -3/7 activity and by up-regulating genes contributing anabolic activity and matrix protection of the IVD NP. Harnessing the restorative powers of the notochordal cell could lead to novel cellular and molecular strategies in the treatment of DDD

Demand satisfied by modern contraceptive among married women of reproductive age in Kenya

Background: Demand for family planning met/satisfied with modern contraceptive methods (mDFPS) has been proposed to track progress in Family Planning (FP) programs for Sustainable Development Goals. This study measured mDFPS among married women of reproductive age (MWRA) in Kenya to identify which groups were not being reached by FP programs. Materials and methods: Performance, Monitoring and Accountability 2020 (PMA2020) survey data from 2014–2018 was used. PMA2020 surveys are cross-sectional including women 15–49 years. PMA2020 used a 2-stage cluster design with urban/rural regions as strata with random selection of households. Univariate and multivariate analysis was done using stata V15. Results: Of the 34,832 respondents interviewed from 2014 to 2018, 60.2% were MWRA. There was a significant decrease in demand for FP from 2014 to 2018, p = 0.012. Lowest demand was among 15–19 and 45–49 years old women. Overall, modern contraceptive prevalence rate increased significantly from 54.6% to 60.8%, p = 0.004, being higher for women from urban areas, home visits by health care worker (HCW), educated, wealthy, visited health facilities and exposed to mass media. Unmet need for FP decreased from 23.0–13.8% over the 5-years, p\u3c0.001. Married adolescent 15–19 had the highest unmet need and those from rural areas, poor, uneducated and not exposed to mass media. mDFPS increased significantly from 69.7–79.4% over the 5-years, p\u3c0.001, with increase in long acting reversible contraception/permanent methods from 19.9–37.2% and decrease in short acting methods from 49.9–42.2%. Significant determinants of mDFPS were age, rural/urban residence, education, wealth, health facility visitation, exposure to FP messages via mass media in the last 12 months, year of study and county of residence. Conclusions: Results show a good progress in key FP indicators. However, not all MWRA are being reached and should be reached if Kenya is to achieve the desired universal health coverage as well as Sustainable Development Goals. Targeted home visits by HCW as well increase in mass media coverage could be viable interventions

Trinucleating Copper: Synthesis and Magnetostructural Characterization of Complexes Supported by a Hexapyridyl 1,3,5-Triarylbenzene Ligand

Copper threesome: A hexapyridyl ligand based upon a 1,3,5-triphenylbenzene framework coordinates three metal centers in a constrained environment (see picture). The tricopper(I) complex reduces dioxygen to form a tricopper(II) cluster. The capping anions affect the magnetism and EPR spectra of these species and reveal a linear dependence between the antiferromagnetic exchange parameter and the Cu-O-Cu angles

Lack of a Y-Chromosomal Complement in the Majority of Gestational Trophoblastic Neoplasms

Gestational trophoblastic neoplasms (GTNs) are a rare group of neoplastic diseases composed of choriocarcinomas, placental site trophoblastic tumors (PSTTs) and epithelioid trophoblastic tumors (ETTs). Since these tumors are derivatives of fetal trophoblastic tissue, approximately 50% of GTN cases are expected to originate from a male conceptus and carry a Y-chromosomal complement according to a balanced sex ratio. To investigate this hypothesis, we carried out a comprehensive analysis by genotyping a relatively large sample size of 51 GTN cases using three independent sex chromosome genetic markers; Amelogenin, Protein Kinase and Zinc Finger have X and Y homologues that are distinguishable by their PCR product size. We found that all cases contained the X-chromosomal complement while only five (10%) of 51 tumors harbored the Y-chromosomal complement. Specifically, Y-chromosomal signals were detected in one (5%) of 19 choriocarcinomas, one (7%) of 15 PSTTs and three (18%) of 17 ETTs. The histopathological features of those with a Y-chromosome were similar to those without. Our results demonstrate the presence of a Y-chromosomal complement in GTNs, albeit a low 10% of cases. This shortfall of Y-chromosomal complements in GTNs may reinforce the notion that the majority of GTNs are derived from previous molar gestations

Missed opportunities for family planning counselling among postpartum women in eleven counties in Kenya

Background: Mothers may access medical facilities for their babies and miss opportunities to access family planning (FP) services. This study was undertaken to describe missed opportunities for FP among women within the extended (0–11months) postpartum period from counties participating in Performance Monitoring and Accountability 2020 (PMA2020) surveys. Design and setting: This study analysed cross-sectional household survey data from 11 counties in Kenya between 2014 and 2018. PMA2020 uses questions extracted from the Demographic and Health survey (DHS) and DHS defnitions were used. Multivariable logistic regression was used for inferential statistics with p-value of \u3c0.05 considered to be signifcant. Participants: Women aged 15-49 years from the households visited. Primary outcome measure: Missed opportunity for family planning/contraceptives (FP/C) counselling. Results: Of the 34,832 women aged 15-49 years interviewed, 10.9% (3803) and 10.8% (3746) were in the period 0–11months and 12–23months postpartum respectively, of whom, 38.8 and 39.6% respectively had their previous pregnancy unintended. Overall, 50.4% of women 0-23months postpartum had missed opportunities for FP/C counselling. Among women who had contact with health care at the facility, 39.2% of women 0-11months and 44.7% of women 12-23months had missed opportunities for FP/C counselling. Less than half of the women 0-11months postpartum (46.5%) and 64.5% of women 12 – 23months postpartum were using highly efcacious methods. About 27 and 18% of the women 0-11months and 12 – 23months postpartum respectively had unmet need for FP/C. Multivariable analysis showed that being low parity and being from the low wealth quintile signifcantly increased the odds of missed opportunities for FP/C counselling among women in the extended postpartum period, p\u3c0.05. Conclusions: A large proportion of women have missed opportunities for FP/C counselling within 2 years postpartum. Programs should address these missed opportunities

Institutional Polycentrism, Entrepreneurs' Social Networks, and New Venture Growth

International audienceWhat is the interrelationship among formal institutions, social networks, and new venture growth? Drawing on the theory of institutional polycentrism and social network theory, we examine this question using data on 637 entrepreneurs from four different countries. We find the confluence of weak and inefficient formal institutions to be associated with a larger number of structural holes in entrepreneurial social networks. While the effect of this institutional order on the revenue growth of new ventures is negative, a network's structural holes have a positive effect on revenue growth. Furthermore, the positive effect of structural holes on revenue growth is stronger in an environment with a more adverse institutional order (i.e., weaker and more inefficient institutions). The contributions and implications of these findings are discussed.<br/