Miracle-dz/UniFAR-FTUs huggingface dataset:
Introduction to the Frontiers Research Topic: Optimization of Exercise Countermeasures for Human Space Flight – Lessons From Terrestrial Physiology and Operational Considerations

Exercise in space has evolved from rudimental testing into the multi-modal countermeasure (CM) program used on the International Space Station (ISS). However, with the constraints of future exploration missions, replicating this program will be a significant challenge. Recent ISS data suggest that crew now experience only relatively moderate levels of microgravity (μG)-induced adaptation, although significant variation remains, with some crew displaying marked changes despite significant time/effort investment. This suggests that the efficacy of exercise CMs is yet to be optimized for all individuals. With the current suite of exercise devices operational for almost a decade, and with exploration approaching, it is timely to re-visit the terrestrial literature to identify new knowledge relevant to the management of μG adaptation. As such, the aim of the Frontiers Research Topic Optimization of Exercise Countermeasures for Human Space Flight – Lessons from Terrestrial Physiology and Operational Considerations, is to synthesize current terrestrial exercise physiology knowledge and consider how this might be employed to optimize the use of exercise CM. The purpose of this Perspective, which serves as a preface to the Research Topic is threefold: to briefly review the use and apparent efficacy of exercise in space, to consider the impact of the transition from ISS to exploration mission vehicles and habitats, and to identify areas of terrestrial exercise physiology where current knowledge might contribute to the optimization of CM exercise for exploration. These areas include individual variation, high intensity interval training, strength development/maintenance, concurrent training, plyometric/impact exercise, and strategies to enhance exercise efficacy.
Sensor Enhanced Health Information Systems: Issues and Challenges

Owing to the fact that the world population is aging and considering the high cost of healthcare services, researchers are exploiting the use of sensors to support mobile monitoring of healthcare systems remotely. However, this area is faced with numerous challenges. In this research, the challenges facing the integration of sensors in Health Information Systems (HIS) were reviewed. One of the major challenges faced by such systems is interoperability. In this article, a survey of existing mobile monitoring system is presented and the challenges facing this area are categorized. A significant contribution by some research has indicated the need for further study to thoroughly investigate Interoperability as a Property (IaaP) paradigm for HIS. Recommendation by some researchers requires that a prototype be developed in order to evaluate the performance of IaaP paradigm.
Essential Roles of the Chromatin Remodeling Factor Brg1 in Spermatogenesis in Mice1

ABSTRACT Mammalian spermatogenesis is a complex process that involves spatiotemporal regulation of gene expression and meiotic recombination, both of which require the modulation of chromatin structure. Proteins important for chromatin regulation during spermatogenesis remain poorly understood. Here we addressed the role of BRG1, the catalytic subunit of the mammalian Swi/Snf-like BAF chromatin-remodeling complex, during spermatogenesis in mice. BRG1 expression is dynamically regulated in the male germline, being weakly detectable in spermatogonia, highly expressed in pachytene spermatocytes, and turned off in maturing round spermatids. This expression pattern overlaps that of Brm, the Brg1 homolog. While Brm knockout males are known to be fertile, germline-specific Brg1 deletion completely arrests spermatogenesis at the midpachytene stage, which is associated with spermatocyte apoptosis and apparently also with impaired homologous recombination and meiotic sex chromosome inactivation. However, Brg1 is dispensable for gammaH2AX formation during meiotic recombination, contrary to its reported role in DNA repair in somatic cells. Our study reveals the essential role of Brg1 in meiosis and underscores the differences in the mechanisms of DNA repair between germ cells and somatic cells.
The predictive validity of the BioMedical Admissions Test for pre‐clinical examination performance

Context Some medical courses in the UK have many more applicants than places and almost all applicants have the highest possible previous and predicted examination grades. The BioMedical Admissions Test (BMAT) was designed to assist in the student selection process specifically for a number of ‘traditional’ medical courses with clear pre‐clinical and clinical phases and a strong focus on science teaching in the early years. It is intended to supplement the information provided by examination results, interviews and personal statements. This paper reports on the predictive validity of the BMAT and its predecessor, the Medical and Veterinary Admissions Test.
Optimizing Precision Medicine for Public Health

Advances in precision medicine have presented challenges to traditional public health decision-making paradigms. Historical methods of allocating healthcare funds based on safety, efficacy, and efficiency, are challenged in a healthcare delivery model that focuses on individualized variations in pathology that form the core of precision medicine. Public health policy and decision-making must adapt to this new frontier of healthcare delivery to ensure that the broad public health goals of reducing healthcare disparities and improving the health of populations are achieved, through effective and equitable allocation of healthcare funds. This paper discusses contemporary applications of precision medicine, and the potential impacts of these on public health policy and decision-making, with particular focus on patients living with rare diseases and rare cancers. The authors then reconcile these, presenting precision public health as the bridge between these seemingly competing fields.
Organophosphate Hydrolase Is a Lipoprotein and Interacts with Pi-specific Transport System to Facilitate Growth of Brevundimonas diminuta Using OP Insecticide as Source of Phosphate*

Organophosphate hydrolase (OPH), encoded by the organophosphate degradation (opd) island, hydrolyzes the triester bond found in a variety of organophosphate insecticides and nerve agents. OPH is targeted to the inner membrane of Brevundimonas diminuta in a pre-folded conformation by the twin arginine transport (Tat) pathway. The OPH signal peptide contains an invariant cysteine residue at the junction of the signal peptidase (Spase) cleavage site along with a well conserved lipobox motif. Treatment of cells producing native OPH with the signal peptidase II inhibitor globomycin resulted in accumulation of most of the pre-OPH in the cytoplasm with negligible processed OPH detected in the membrane. Substitution of the conserved lipobox cysteine to serine resulted in release of OPH into the periplasm, confirming that OPH is a lipoprotein. Analysis of purified OPH revealed that it was modified with the fatty acids palmitate and stearate. Membrane-bound OPH was shown to interact with the outer membrane efflux protein TolC and with PstS, the periplasmic component of the ABC transporter complex (PstSACB) involved in phosphate transport. Interaction of OPH with PstS appears to facilitate transport of Pi generated from organophosphates due to the combined action of OPH and periplasmically located phosphatases. Consistent with this model, opd null mutants of B. diminuta failed to grow using the organophosphate insecticide methyl parathion as sole source of phosphate.
Localization and Regulation of Murine Esco2 During Male and Female Meiosis1

ABSTRACT Meiosis is essential for generation of healthy gametes in both sexes and involves recombination and segregation of homologous chromosomes to produce haploid gametes. The initiation of meiosis in both sexes relies upon retinoic acid (RA) (Griswold MD, Hogarth CA, Bowles J, Koopman P. Initiating Meiosis: The Case for Retinoic Acid. Biol Reprod 2012; 86(35):1–7). Previous studies have demonstrated that the stimulated by retinoic acid gene 8 (Stra8) was required for meiotic progression in both the mouse ovary and postnatal testis. To identify additional candidates that may play a role during meiosis, we used microarray databases to generate lists of transcripts with expression profiles similar to that of Stra8 in the embryonic ovary and postnatal testis. One such gene, establishment of cohesion 1 homolog 2 (Saccharomyces cerevisiae) (Esco2), has been described as a regulator of sister chromatid cohesion during mitosis. This study describes the first in-depth analysis of ESCO2 localization and regulation during meiosis in both males and females. ESCO2 colocalized with the gamma H2A histone family member X (H2AFX) in pachytene spermatocytes, indicating that ESCO2 is a component of the XY body. In pachytene cells of the embryonic ovary, ESCO2 colocalized with H2AFX, which is consistent with the presence of ESCO2 in areas of double-stranded breaks. In addition, the expression of Esco2 was found to be regulated by RA in the postnatal testis. These data indicate that ESCO2 may play a vital role in meiosis in both males and females.
Acute Slices of Mice Testis Seminiferous Tubules Unveil Spontaneous and Synchronous Ca2+ Oscillations in Germ Cell Clusters1

ABSTRACT Spermatogenic cell differentiation involves changes in the concentration of cytoplasmic Ca2+ ([Ca2+]i); however, very few studies exist on [Ca2+]i dynamics in these cells. Other tissues display Ca2+ oscillations involving multicellular functional arrangements. These phenomena have been studied in acute slice preparations that preserve tissue architecture and intercellular communications. Here we report the implementation of intracellular Ca2+ imaging in a sliced seminiferous tubule (SST) preparation to visualize [Ca2+]i changes of living germ cells in situ within the SST preparation. Ca2+ imaging revealed that a subpopulation of male germ cells display spontaneous [Ca2+]i fluctuations resulting from Ca2+ entry possibly throughout CaV3 channels. These [Ca2+]i fluctuation patterns are also present in single acutely dissociated germ cells, but they differ from those recorded from germ cells in the SST preparation. Often, spontaneous Ca2+ fluctuations of spermatogenic cells in the SST occur synchronously, so that clusters of cells can display Ca2+ oscillations for at least 10 min. Synchronous Ca2+ oscillations could be mediated by intercellular communication via gap junctions, although intercellular bridges could also be involved. We also observed an increase in [Ca2+]i after testosterone application, suggesting the presence of functional Sertoli cells in the SST. In summary, we believe that the SST preparation is suitable to explore the physiology of spermatogenic cells in their natural environment, within the seminiferous tubules, in particular Ca2+ signaling phenomena, functional cell-cell communication, and multicellular functional arrangements.
The Role of Hypoxia and Hypoxia-Inducible Factor-1Alpha in Preeclampsia Pathogenesis

ABSTRACT Preeclampsia affects 5%–8% of pregnancies and is the leading worldwide cause of maternal and fetal morbidity and mortality. Preeclampsia is associated with shallow trophoblast invasion and inadequate spiral artery remodeling, which are widely believed to lead to placental hypoxia, the putative culprit initiating the cascade of events that ultimately results in the maternal manifestations of the disease. Despite extensive research, however, the pathophysiology of this disease remains poorly understood, no effective prevention exists, and treatment is limited to symptomatic therapy. Recent research has introduced exciting new theories regarding the pathogenesis of preeclampsia. Clinical and experimental evidence implicating the circulating antiangiogenic molecules soluble Fms-like tyrosine kinase-1 (sFLT-1) and soluble endoglin (sENG), as well as endothelin-1 and the angiotensin II receptor type I autoimmune antibody (AT-1AA), have been especially promising. This review collates evidence for a role of hypoxia and hypoxia-inducible factor-1alpha (HIF1A; referred to as HIF-1α throughout) in the pathogenesis of preeclampsia and discusses possible molecular links between hypoxia and the newly reported potential mediators of the disease's manifestations.
Plasminogen Activator Inhibitor 1 RNA-Binding Protein Interacts with Progesterone Receptor Membrane Component 1 to Regulate Progesterone's Ability to Maintain the Viability of Spontaneously Immortalized Granulosa Cells and Rat Granulosa Cells1

ABSTRACT Progesterone receptor membrane component 1 (PGRMC1) mediates the antiapoptotic action of progesterone (P4). PGRMC1 interacts with plasminogen activator inhibitor 1 RNA-binding protein (PAIRBP1), but the functional significance of this interaction is unknown. To examine the function of PGRMC1-PAIRBP1 interaction, PAIRBP1 was depleted from spontaneously immortalized granulosa cells (SIGCs) and the effects on the expression and localization of PGRMC1 as well as P4's ability to bind to SIGCs and prevent apoptosis was assessed. Depleting PAIRBP1 enhanced cellular 3H-P4 binding and did not alter the expression or cellular localization of PGRMC1 but attenuated P4's antiapoptotic action. Transfection of a PGRMC1-green fluorescent protein (GFP) peptide mimic, which binds PAIRBP1 as demonstrated by in situ proximity assay, doubled the rate at which SIGCs undergo apoptosis compared to cells transfected with either the empty GFP expression vector or Pairbp1 small interfering RNA. Moreover, P4 did not prevent these cells from undergoing apoptosis. Similar studies conducted with granulosa cells isolated from immature rats also showed that PGRMC1 interacts with PAIRBP1 and that transfection of PGRMC1-GFP peptide mimic accelerates the rate of granulosa cell apoptosis by 4-fold even in the presence of serum and P4. These studies support the concept that the interaction between PAIRBP1-PGRMC1 is an essential component of the mechanism through which P4 inhibits apoptosis. Surprisingly, PGRMC1-PAIRBP1 interaction is not required for P4 binding or the cellular localization of PGRMC1 but rather appears to couple PGRMC1 to downstream components of the P4-PGRMC1 signal transduction pathway.
Letter: Meta-analysis can be statistically misleading

The double blind randomised controlled trial (RCT) is the basis of good evidence-based medicine because it eliminates problems of bias and confounding. However, systematic reviews show different RCTs arriving at diametrically opposite conclusions. The reason for this is that the samples for the RCTs are drawn from different populations and it reflects the truth in those various populations. …
Atherogenesis and Vascular Disease in SLE

SLE is the classical model of a chronic multi-systemic immune-mediated inflammatory disease. It affects mainly young women, a subgroup of the general population usually free of cardiovascular risk. Although survival rates have improved dramatically, mainly due to early diagnosis, improved treatment, and better management of complications, death rates for patients with SLE remain 3 to 5 times higher than in the general population (Haque & Bruce, 2009). Nevertheless, whilst the 5-year survival of SLE was below 50% in the 1950s, it is nowadays above 90% (Nikpour et al., 2005). Atherosclerosis in SLE is a highly complex process with autoimmunity, local and systemic inflammation, and endothelial dysfunction playing critical roles in its initiation and propagation. In the particular case of SLE, the extremely intricate immune system deregulation involving all types of immune cells up to an increased autoantibody production seems to play a major role for the accelerated atheroma formation found in these patients. Cardiovascular events are now the major cause of morbidity and mortality in SLE. The acceptance of the importance of vascular risk in this context came from the description of a bimodal mortality pattern (Urowitz et al., 1976), with the early peak (within 1 year of diagnosis) as a consequence of active lupus and its complications, and the later peak (more than 5 years after diagnosis) mainly attributable to atherosclerosis. SLE is now considered to be a coronary heart disease-risk equivalent, mainly due to accelerated atherosclerosis (Aranow & Ginzler, 2000; Bjornadal et al., 2004; Manzi et al., 1997; Esdaile et al., 2001; Fischer et al. 2004; Roman et al., 2003; Ward, 1999). This can be especially relevant in young women, where up to a 50-fold increase in cardiovascular risk over age and gender-matched controls has been reported (Manzi et al., 1997). In fact, the majority of those women were aged less than 55 years at the time of their first cardiac event. Framingham risk factors do not explain entirely the atherosclerotic burden found in patients with SLE. Furthermore, traditional cardiovascular risk factors seem to be less important predictors of cardiovascular events than the activity of lupus (Esdaile et al., 2001). (see table 1). The direct relation between conventional and SLE-related risk factors and the actual incidence of events has not been easy to establish for different reasons: most patients with
Brain Infarction and the Clinical Expression of Alzheimer Disease-Reply

In Reply. —The analyses of Drs Mirra and Gearing indicate that brain infarcts are not associated with NFTs in the neocortex. Our analyses also indicated that brain infarcts were not associated with the number of NFTs, senile plaques, or neuritic plaques in the neocortex, suggesting that AD lesions and brain infarcts were likely to have occured independently of each other. While AD and brain infarction may represent separate disease processes, their combination may nonetheless increase the likelihood that dementia will occur. Among the participants in our study who met our neuropathologic criteria for AD (ie, abundant senile plaques and some NFTs in the neocortex), those with 1 or 2 lacunar infarcts in the basal ganglia, thalamus, or deep white matter had an especially high prevalence of dementia, compared with those without brain infarcts. The prevalence of dementia was 93% for those with such subcortical lacunar infarcts and 57% in those without infarcts.
MicroRNA-127 Promotes Mesendoderm Differentiation of Mouse Embryonic Stem Cells by Targeting Left-Right Determination Factor 2*

Specification of the three germ layers is a fundamental process and is essential for the establishment of organ rudiments. Multiple genetic and epigenetic factors regulate this dynamic process; however, the function of specific microRNAs in germ layer differentiation remains unknown. In this study, we established that microRNA-127 (miR-127) is related to germ layer specification via microRNA array analysis of isolated three germ layers of E7.5 mouse embryos and was verified through differentiation of mouse embryonic stem cells. miR-127 is highly expressed in endoderm and primitive streak. Overexpression of miR-127 increases and inhibition of miR-127 decreases the expression of mesendoderm markers. We further show that miR-127 promotes mesendoderm differentiation through the nodal pathway, a determinative signaling pathway in early embryogenesis. Using luciferase reporter assay, left-right determination factor 2 (Lefty2), an antagonist of nodal, is identified to be a novel target of miR-127. Furthermore, the role of miR-127 in mesendoderm differentiation is attenuated by Lefty2 overexpression. Altogether, our results indicate that miR-127 accelerates mesendoderm differentiation of mouse embryonic stem cells through nodal signaling by targeting Lefty2.
Transcriptional Wiring for Establishing Cell Lineage Specification at the Blastocyst Stage in Cattle1

ABSTRACT Mice and cattle use distinct pathways for the first cell segregation into inner cell mass (ICM) and trophectoderm (TE) lineages at the blastocyst stage. However, limited knowledge is available regarding the reliable transcriptional networks that orchestrate the complex developmental processes at this stage in nonrodent species. In order to elucidate the site-dominant transcriptomic properties of bovine blastocysts, we separated cell samples into the ICM and TE using both mechanical and chemical methods and performed in silico prescreening for candidate genes that were site-dominantly expressed in bovine blastocysts. We further performed quantitative real-time PCR and in situ hybridization using the site-specific cell samples. As a result, we identified seven ICM-dominant genes and five TE-dominant genes not found in earlier studies. Our findings provide novel insights into the mechanism of cell-fate specification in the pre-implantation bovine embryo.
Medical education, social accountability and patient outcomes

The ultimate goal of those who practice medicine is to improve the physical, mental and social well-being of fellow human beings. In this regard, medicine is a public service profession; thus, social accountability is an integral feature of medical education and practice, as indicated in the article by Woollard and Boelen in this issue. In addition, as Dauphinee claims, also in this issue, the effectiveness of medical education is ultimately reflected in patient outcomes. In this commentary, we would like to expand the discussion on the notions of social accountability and patient outcomes in the context of a model of doctor performance.
The Plasma Membrane Protein Nce102 Implicated in Eisosome Formation Rescues a Heme Defect in Mitochondria*

The cellular transport of the cofactor heme and its biosynthetic intermediates such as protoporphyrin IX is a complex and highly coordinated process. To investigate the molecular details of this trafficking pathway, we created a synthetic lesion in the heme biosynthetic pathway by deleting the gene HEM15 encoding the enzyme ferrochelatase in S. cerevisiae and performed a genetic suppressor screen. Cells lacking Hem15 are respiratory-defective because of an inefficient heme delivery to the mitochondria. Thus, the biogenesis of mitochondrial cytochromes is negatively affected. The suppressor screen resulted in the isolation of respiratory-competent colonies containing two distinct missense mutations in Nce102, a protein that localizes to plasma membrane invaginations designated as eisosomes. The presence of the Nce102 mutant alleles enabled formation of the mitochondrial respiratory complexes and respiratory growth in hem15Δ cells cultured in supplemental hemin. Respiratory function in hem15Δ cells can also be restored by the presence of a heterologous plasma membrane heme permease (HRG-4), but the mode of suppression mediated by the Nce102 mutant is more efficient. Attenuation of the endocytic pathway through deletion of the gene END3 impaired the Nce102-mediated rescue, suggesting that the Nce102 mutants lead to suppression through the yeast endocytic pathway.