PLZF targets developmental enhancers for activation during osteogenic differentiation of human mesenchymal stem cells

The PLZF transcription factor is essential for osteogenic differentiation of hMSCs; however, its regulation and molecular function during this process is not fully understood. Here, we revealed that the ZBTB16 locus encoding PLZF, is repressed by Polycomb (PcG) and H3K27me3 in naive hMSCs. At the pre-osteoblast stage of differentiation, the locus lost PcG binding and H3K27me3, gained JMJD3 recruitment, and H3K27ac resulting in high expression of PLZF. Subsequently, PLZF was recruited to osteogenic enhancers, influencing H3K27 acetylation and expression of nearby genes important for osteogenic function. Furthermore, we identified a latent enhancer within the ZBTB16/PLZF locus itself that became active, gained PLZF, p300 and Mediator binding and looped to the promoter of the nicotinamide N-methyltransferase (NNMT) gene. The increased expression of NNMT correlated with a decline in SAM levels, which is dependent on PLZF and is required for osteogenic differentiatio

Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Enabling the Voices of Marginalized Groups of People in Theoretical Business Ethics Research

The paper addresses an understudied but highly relevant group of people within corporate organizations and society in general—the marginalized—as well as their narration, and criticism, of personal lived experiences of marginalization in business. They are conventionally perceived to lack traditional forms of power such as public influence, formal authority, education, money, and political positions; however, they still possess the resources to impact their situations, their circumstances, and the structures that determine their situations. Business ethics researchers seldom consider marginalized people’s voices and experiences as resources to understand their lives, as demonstrated through a review of 7500 articles published in the Journal of Business Ethics and Business Ethics Quarterly (2000–2019). Only 78 studies included aspects of marginalized groups. 69 of those studies discussed the topic of marginalized groups of people, but without integrating their explicit voices into the text. Only 9 of the 78 articles featured marginalized people’s explicit voices about their marginalization experiences incorporated into the text as a source for exploration. None of the identified studies discussed the potential for theorizing based on such voices. This paper contributes to business ethics theory by developing four theoretical possibilities vis-à-vis the critical voices of marginalized people’s experiences in business: (a) marginalized theory on critical agency and freedom of speech; (b) the gatekeeping role of academia; (c) primary sources; and (d) a participative perspective. Discussing the theoretical potential of quoting the above voices can enrich business ethics research in terms of the theoretical understanding of marginalized groups in business

In Vivo (31) P magnetic resonance spectroscopic imaging (MRSI) for metabolic profiling of human breast cancer xenografts

Contains fulltext : 153127.pdf (publisher's version ) (Closed access)To study cancer associated with abnormal metabolism of phospholipids, of which several have been proposed as biomarkers for malignancy or to monitor response to anticancer therapy. We explored 3D (31) P magnetic resonance spectroscopic imaging (MRSI) at high magnetic field for in vivo assessment of individual phospholipids in two patient-derived breast cancer xenografts representing good and poor prognosis (luminal- and basal-like tumors).Metabolic profiles from luminal-like and basal-like xenograft tumors were obtained in vivo using 3D (31) P MRSI at 11.7T and from tissue extracts in vitro at 14.1T. Gene expression analysis was performed in order to support metabolic differences between the two xenografts.In vivo (31) P MR spectra were obtained in which the prominent resonances from phospholipid metabolites were detected at a high signal-to-noise ratio (SNR >7.5). Metabolic profiles obtained in vivo were in agreement with those obtained in vitro and could be used to discriminate between the two xenograft models, based on the levels of phosphocholine, phosphoethanolamine, glycerophosphocholine, and glycerophosphoethanolamine. The differences in phospholipid metabolite concentration could partly be explained by gene expression profiles.Noninvasive metabolic profiling by 3D (31) P MRSI can discriminate between subtypes of breast cancer based on different concentrations of choline- and ethanolamine-containing phospholipids.J. Magn. Reson. Imaging 2014. © 2014 Wiley Periodicals, Inc

The Ultraviolet Spectrograph on NASA’s Juno Mission

The ultraviolet spectrograph instrument on the Juno mission (Juno-UVS) is a long-slit imaging spectrograph designed to observe and characterize Jupiter’s far-ultraviolet (FUV) auroral emissions. These observations will be coordinated and correlated with those from Juno’s other remote sensing instruments and used to place in situ measurements made by Juno’s particles and fields instruments into a global context, relating the local data with events occurring in more distant regions of Jupiter’s magnetosphere. Juno-UVS is based on a series of imaging FUV spectrographs currently in flight—the two Alice instruments on the Rosetta and New Horizons missions, and the Lyman Alpha Mapping Project on the Lunar Reconnaissance Orbiter mission. However, Juno-UVS has several important modifications, including (1) a scan mirror (for targeting specific auroral features), (2) extensive shielding (for mitigation of electronics and data quality degradation by energetic particles), and (3) a cross delay line microchannel plate detector (for both faster photon counting and improved spatial resolution). This paper describes the science objectives, design, and initial performance of the Juno-UVS