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The human microbiota heavily influences most vital aspects of human physiology including organ transplantation outcomes and transplant rejection risk. A variety of organ transplantation scenarios such as lung and heart transplantation as well as hematopoietic stem cell transplantation is heavily influenced by the human microbiotas. The human microbiota refers to a rich, diverse, and complex ecosystem of bacteria, fungi, archaea, helminths, protozoans, parasites, and viruses. Research accumulating over the past decade has established the existence of complex cross-species, cross-kingdom interactions between the residents of the various human microbiotas and the human body. Since the gut microbiota is the densest, most popular, and most studied human microbiota, the impact of other human microbiotas such as the oral, lung, urinary, and genital microbiotas is often overshadowed. However, these microbiotas also provide critical and unique insights pertaining to transplantation success, rejection risk, and overall host health, across multiple different transplantation scenarios. Organ transplantation as well as the pre-, peri-, and post-transplant pharmacological regimens patients undergo is known to adversely impact the microbiotas, thereby increasing the risk of adverse patient outcomes. Over the past decade, holistic approaches to post-transplant patient care such as the administration of clinical and dietary interventions aiming at restoring deranged microbiota community structures have been gaining momentum. Examples of these include prebiotic and probiotic administration, fecal microbial transplantation, and bacteriophage-mediated multidrug-resistant bacterial decolonization. This review will discuss these perspectives and explore the role of different human microbiotas in the context of various transplantation scenarios.

Epigenetic processes have become increasingly relevant in understanding disease-modifying mechanisms. 5-Methylcytosine methylations of DNA (5mC) and RNA (m 5 C) have functional transcriptional and RNA translational consequences and are tightly regulated by writer, reader and eraser effector proteins. To investigate the involvement of 5mC/5hmC and m 5 C effector proteins contributing to the development of dementia neuropathology, RNA sequencing data of 31 effector proteins across four brain regions was examined in 56 aged non-affected and 51 Alzheimer’s disease (AD) individuals obtained from the Aging, Dementia and Traumatic Brain Injury Study. Gene expression profiles were compared between AD and controls, between neuropathological Braak and CERAD scores and in individuals with a history of traumatic brain injury (TBI). We found an increase in the DNA methylation writers DNMT1 , DNMT3A and DNMT3B messenger RNA (mRNA) and a decrease in the reader UHRF1 mRNA in AD samples across three brain regions whilst the DNA erasers GADD45B and AICDA showed changes in mRNA abundance within neuropathological load groupings. RNA methylation writers NSUN6 and NSUN7 showed significant expression differences with AD and, along with the reader ALYREF , differences in expression for neuropathologic ranking. A history of TBI was associated with a significant increase in the DNA readers ZBTB4 and MeCP2 ( p  < 0.05) and a decrease in NSUN6 ( p  < 0.001) mRNA. These findings implicate regulation of protein pathways disrupted in AD and TBI via multiple pre- and post-transcriptional mechanisms including potentially acting upon transfer RNAs, enhancer RNAs as well as nuclear-cytoplasmic shuttling and cytoplasmic translational control. The targeting of such processes provides new therapeutic avenues for neurodegenerative brain conditions. Graphical abstract

BackgroundGovernmental investment in mental health is of vital importance for the implementation and maintenance of educational, preventive, and therapeutic services related to mental illness, particularly in low- and middle-income countries (LMICs). However, mental health expenditures represent only a small portion of total health spending in many countries. Little is known about the economic, social, or health-related factors that may influence variations in governmental spending in this sector.MethodsData on government expenditure on mental health as a percentage of total healthcare expenditure, collected by the WHO from 78 countries and regions in the period 2013-2014, was available for study. These data were analyzed in relation to key economic, social, and health-related indicators. The selection of these indicators was based on prior national and regional research and expert opinion as reported in the existing literature.ResultsGovernment spending on mental health was below 1% of health expenditure in 24.4% of the countries studied. A number of economic, social, and health-related indicators were significantly associated with variations in spending on mental health. Based on the partial correlation, sub-group, and multivariate linear regression analyses, the variables most significantly associated with low government spending on mental health were the burden of communicable diseases (β = −.47, p = .001) and cultural collectivism (β = −.37, p = .008).ConclusionsThese results suggest that low government investment in mental health may be associated not only with economic or political factors but also with variations in disease burden and in cultural attitudes across countries. Though no direct assumption regarding causation can be made, such findings may be of value when advocating for greater public investment in mental health, particularly in non-Western cultures with a high competing burden of infectious diseases.

Background Massively parallel cDNA sequencing (RNA-seq) experiments are gradually superseding microarrays in quantitative gene expression profiling. However, many biologists are uncertain about the choice of differentially expressed gene (DEG) analysis methods and the validity of cost-saving sample pooling strategies for their RNA-seq experiments. Hence, we performed experimental validation of DEGs identified by Cuffdiff2, edgeR, DESeq2 and Two-stage Poisson Model (TSPM) in a RNA-seq experiment involving mice amygdalae micro-punches, using high-throughput qPCR on independent biological replicate samples. Moreover, we sequenced RNA-pools and compared their results with sequencing corresponding individual RNA samples. Results False-positivity rate of Cuffdiff2 and false-negativity rates of DESeq2 and TSPM were high. Among the four investigated DEG analysis methods, sensitivity and specificity of edgeR was relatively high. We documented the pooling bias and that the DEGs identified in pooled samples suffered low positive predictive values. Conclusions Our results highlighted the need for combined use of more sensitive DEG analysis methods and high-throughput validation of identified DEGs in future RNA-seq experiments. They indicated limited utility of sample pooling strategies for RNA-seq in similar setups and supported increasing the number of biological replicate samples.

Background Gender inequality weakens maternal health and harms children through many direct and indirect pathways. Allied biological disadvantage and psychosocial adversities challenge the survival of children of both genders. United Nations Development Programme (UNDP) has recently developed a Gender Inequality Index to measure the multidimensional nature of gender inequality. The global impact of Gender Inequality Index on the child mortality rates remains uncertain. Methods We employed an ecological study to investigate the association between child mortality rates and Gender Inequality Indices of 138 countries for which UNDP has published the Gender Inequality Index. Data on child mortality rates and on potential confounders, such as, per capita gross domestic product and immunization coverage, were obtained from the official World Health Organization and World Bank sources. We employed multivariate non-parametric robust regression models to study the relationship between these variables. Results Women in low and middle income countries (LMICs) suffer significantly more gender inequality (p < 0.001). Gender Inequality Index (GII) was positively associated with neonatal (β = 53.85; 95% CI 41.61-64.09), infant (β = 70.28; 95% CI 51.93-88.64) and under five mortality rates (β = 68.14; 95% CI 49.71-86.58), after adjusting for the effects of potential confounders (p < 0.001). Conclusions We have documented statistically significant positive associations between GII and child mortality rates. Our results suggest that the initiatives to curtail child mortality rates should extend beyond medical interventions and should prioritize women’s rights and autonomy. We discuss major pathways connecting gender inequality and child mortality. We present the socio-economic problems, which sustain higher gender inequality and child mortality in LMICs. We further discuss the potential solutions pertinent to LMICs. Dissipating gender barriers and focusing on social well-being of women may augment the survival of children of both genders.

This study focuses on a structural element bio-mimicked from the human cranium (HC) into a shell element. As the HC is effective in resisting intracranial pressure developed by the brain, a water tank was considered to use a bio-mimicked shape of a shell as a roof. An optimized numerical model was validated experimentally and compared with a conventional specimen. The structural behavior of the bio-mimicked specimen is similar and performs more efficiently than the conventional specimen in capacity ratio, crack formation, and load-carrying capacity. Methodology followed: A Computed Tomography (CT) scan of the HC was obtained in Digital Imaging and Communications in Medicine (DICOM) format for finite element analysis (FEA). From the geometric parameters of the HC, the radius of the curvature-to-thickness ratio was derived for the shell. The span and thickness of the shell under two criteria were considered. The spherical and circular shell behaviors were found to be similar to those of the HC, whereas the elliptical shell behavior was not. We studied the shape effect of the HC with the conventional slab and found that the HC shape has an impact on the behavior and is the most efficient. A bio-mimicked mono column was considered as a supporting column for the water tank and analyzed. Overall, adopting this bio-mimicking of the HC into the shell roof connects nature with sustainable architecture.

More than a decade ago, a pioneering study reported generation of induced Pluripotent Stem Cells (iPSCs) by ectopic expression of a cocktail of reprogramming factors in fibroblasts. This study has revolutionized stem cell research and has garnered immense interest from the scientific community globally. iPSCs hold tremendous potential for understanding human developmental biology, disease modeling, drug screening and discovery, and personalized cell-based therapeutic applications. The seminal study identified Oct4, Sox2, Klf4 and c-Myc as a potent combination of genes to induce reprogramming. Subsequently, various reprogramming factors were identified by numerous groups. Most of these studies have used integrating viral vectors to overexpress reprogramming factors in somatic cells to derive iPSCs. However, these techniques restrict the clinical applicability of these cells as they may alter the genome due to random viral integration resulting in insertional mutagenesis and tumorigenicity. To circumvent this issue, alternative integration-free reprogramming approaches are continuously developed that eliminate the risk of genomic modifications and improve the prospects of iPSCs from lab to clinic. These methods establish that integration of transgenes into the genome is not essential to induce pluripotency in somatic cells. This review provides a comprehensive overview of the most promising DNA-free reprogramming techniques that have the potential to derive integration-free iPSCs without genomic manipulation, such as sendai virus, recombinant proteins, microRNAs, synthetic messenger RNA and small molecules. The understanding of these approaches shall pave a way for the generation of clinical-grade iPSCs. Subsequently, these iPSCs can be differentiated into desired cell type(s) for various biomedical applications.

Transcription factor MESP1 is a crucial factor regulating cardiac, hematopoietic, and skeletal myogenic development. Besides, it also contributes to the generation of functional cardiomyocytes. Here, we report the soluble expression and purification of the full-length human MESP1 protein from the heterologous system, which can be delivered into the target mammalian cells. To generate this biological macromolecule, we cloned its codon-optimized gene sequence fused to a nuclear localization sequence, a cell-penetrating peptide, and a His-tag into the protein expression vector and expressed in the bacterial system (E. coli strain BL21(DE3)). Subsequently, we have screened and identified the optimal expression parameters to obtain this recombinant fusion protein in soluble form from E. coli and examined its expression concerning the placement of fusion tags at either terminal. Further, we have purified this recombinant fusion protein to homogeneity under native conditions. Notably, this purified fusion protein has maintained its secondary structure after purification, primarily comprising α-helices and random coils. This molecular tool can potentially replace its genetic and viral forms in the cardiac reprogramming of fibroblasts to induce a cardiac transcriptional profile in an integration-free manner and elucidating its role in various biological processes and diseases.Key points• Screening of the suitable gene construct was performed and identified.• Screening of optimal expression conditions was performed and identified.• Native purification of recombinant human MESP1 protein from E. coli was performed.• Recombinant MESP1 protein has retained its secondary structure after purification.

Cerebrospinal fluid analyses and neuroimaging can identify the underlying pathophysiology at the earliest stage of some neurodegenerative disorders, but do not have the scalability needed for population screening. Therefore, a blood-based marker for such pathophysiology would have greater utility in a primary care setting and in eligibility screening for clinical trials. Rapid advances in ultra-sensitive assays have enabled the levels of pathological proteins to be measured in blood samples, but research has been predominantly focused on Alzheimer disease (AD). Nonetheless, proteins that were identified as potential blood-based biomarkers for AD, for example, amyloid-β, tau, phosphorylated tau and neurofilament light chain, are likely to be relevant to other neurodegenerative disorders that involve similar pathological processes and could also be useful for the differential diagnosis of clinical symptoms. This Review outlines the neuropathological, clinical, molecular imaging and cerebrospinal fluid features of the most common neurodegenerative disorders outside the AD continuum and gives an overview of the current status of blood-based biomarkers for these disorders.Most research into blood-based biomarkers for neurodegenerative disorders has so far focused on Alzheimer disease. In this Review, Aarsland and colleagues give an overview of the current status of blood-based biomarkers for the non-Alzheimer disease neurodegenerative disorders.