Management of blood transfusion services in low‐resource countries

Background and Objectives Enabling universal access to safe blood components should be a key component of every country's national healthcare strategy. This study aimed to assess the current status of infrastructure and resources of blood transfusion services (BTS) in low- and middle-income countries. Materials and Methods A cross-sectional survey was designed to gather information on blood donations, components, redistribution, testing resources and quality management systems (QMSs). The survey was distributed to the International Society of Blood Transfusion members between October 2021 and November 2021. Results A total of 54 respondents from 20 countries responded to the survey. This included hospital-based BTS/blood centres (46%), national blood centres (11%)and national and regional blood services (11%). Voluntary non-remunerated, replacement and paid donors accounted for 94.2%, 84.6% and 21.1% of donations, respectively. Apheresis donation was available in 59.6% of institutions. National/regional criteria for redistribution of blood components were reported by 75.9% of respondents. Blood components incurred payment charges in 81.5% of respondents' institutions, and payments were borne by patients in 50% of them. Testing methods, such as manual (83%), semi-automated (68%) or fully automated (36.2%), were used either alone or in combination. QMSs were reported in 17 institutions, while accreditation and haemovigilance were reported in 12 and 8 countries, respectively. Conclusion QMS was implemented in most of the countries despite the common use of paid donations and the lack of advanced testing. Efforts to overcome persistent challenges and wider implementation of patient blood management programmes are required

The inwardly rectifying K+ channel KIR7.1 controls uterine excitability throughout pregnancy

Abnormal uterine activity in pregnancy causes a range of important clinical disorders, including preterm birth, dysfunctional labour and post-partum haemorrhage. Uterine contractile patterns are controlled by the generation of complex electrical signals at the myometrial smooth muscle plasma membrane. To identify novel targets to treat conditions associated with uterine dysfunction, we undertook a genome-wide screen of potassium channels that are enriched in myometrial smooth muscle. Computational modelling identified Kir7.1 as potentially important in regulating uterine excitability during pregnancy. We demonstrate Kir7.1 current hyper-polarizes uterine myocytes and promotes quiescence during gestation. Labour is associated with a decline, but not loss, of Kir7.1 expression. Knockdown of Kir7.1 by lentiviral expression of miRNA was sufficient to increase uterine contractile force and duration significantly. Conversely, overexpression of Kir7.1 inhibited uterine contractility. Finally, we demonstrate that the Kir7.1 inhibitor VU590 as well as novel derivative compounds induces profound, long-lasting contractions in mouse and human myometrium; the activity of these inhibitors exceeds that of other uterotonic drugs. We conclude Kir7.1 regulates the transition from quiescence to contractions in the pregnant uterus and may be a target for therapies to control uterine contractility

Combinatorial Binding in Human and Mouse Embryonic Stem Cells Identifies Conserved Enhancers Active in Early Embryonic Development

Transcription factors are proteins that regulate gene expression by binding to cis-regulatory sequences such as promoters and enhancers. In embryonic stem (ES) cells, binding of the transcription factors OCT4, SOX2 and NANOG is essential to maintain the capacity of the cells to differentiate into any cell type of the developing embryo. It is known that transcription factors interact to regulate gene expression. In this study we show that combinatorial binding is strongly associated with co-localization of the transcriptional co-activator Mediator, H3K27ac and increased expression of nearby genes in embryonic stem cells. We observe that the same loci bound by Oct4, Nanog and Sox2 in ES cells frequently drive expression in early embryonic development. Comparison of mouse and human ES cells shows that less than 5% of individual binding events for OCT4, SOX2 and NANOG are shared between species. In contrast, about 15% of combinatorial binding events and even between 53% and 63% of combinatorial binding events at enhancers active in early development are conserved. Our analysis suggests that the combination of OCT4, SOX2 and NANOG binding is critical for transcription in ES cells and likely plays an important role for embryogenesis by binding at conserved early developmental enhancers. Our data suggests that the fast evolutionary rewiring of regulatory networks mainly affects individual binding events, whereas “gene regulatory hotspots” which are bound by multiple factors and active in multiple tissues throughout early development are under stronger evolutionary constraints

Global analysis of in vivo Foxa2-binding sites in mouse adult liver using massively parallel sequencing

Foxa2 (HNF3β) is a one of three, closely related transcription factors that are critical to the development and function of the mouse liver. We have used chromatin immunoprecipitation and massively parallel Illumina 1G sequencing (ChIP–Seq) to create a genome-wide profile of in vivo Foxa2-binding sites in the adult liver. More than 65% of the ∼11.5 k genomic sites associated with Foxa2 binding, mapped to extended gene regions of annotated genes, while more than 30% of intragenic sites were located within first introns. 20.5% of all sites were further than 50 kb from any annotated gene, suggesting an association with novel gene regions. QPCR analysis demonstrated a strong positive correlation between peak height and fold enrichment for Foxa2-binding sites. We measured the relationship between Foxa2 and liver gene expression by overlapping Foxa2-binding sites with a SAGE transcriptome profile, and found that 43.5% of genes expressed in the liver were also associated with Foxa2 binding. We also identified potential Foxa2-interacting transcription factors whose motifs were enriched near Foxa2-binding sites. Our comprehensive results for in vivo Foxa2-binding sites in the mouse liver will contribute to resolving transcriptional regulatory networks that are important for adult liver function

HESML: A scalable ontology-based semantic similarity measures library with a set of reproducible experiments and a replication dataset

This work is a detailed companion reproducibility paper of the methods and experiments proposed by Lastra-Díaz and García-Serrano in (2015, 2016) [56–58], which introduces the following contributions: (1) a new and efficient representation model for taxonomies, called PosetHERep, which is an adaptation of the half-edge data structure commonly used to represent discrete manifolds and planar graphs; (2) a new Java software library called the Half-Edge Semantic Measures Library (HESML) based on PosetHERep, which implements most ontology-based semantic similarity measures and Information Content (IC) models reported in the literature; (3) a set of reproducible experiments on word similarity based on HESML and ReproZip with the aim of exactly reproducing the experimental surveys in the three aforementioned works; (4) a replication framework and dataset, called WNSimRep v1, whose aim is to assist the exact replication of most methods reported in the literature; and finally, (5) a set of scalability and performance benchmarks for semantic measures libraries. PosetHERep and HESML are motivated by several drawbacks in the current semantic measures libraries, especially the performance and scalability, as well as the evaluation of new methods and the replication of most previous methods. The reproducible experiments introduced herein are encouraged by the lack of a set of large, self-contained and easily reproducible experiments with the aim of replicating and confirming previously reported results. Likewise, the WNSimRep v1 dataset is motivated by the discovery of several contradictory results and difficulties in reproducing previously reported methods and experiments. PosetHERep proposes a memory-efficient representation for taxonomies which linearly scales with the size of the taxonomy and provides an efficient implementation of most taxonomy-based algorithms used by the semantic measures and IC models, whilst HESML provides an open framework to aid research into the area by providing a simpler and more efficient software architecture than the current software libraries. Finally, we prove the outperformance of HESML on the state-of-the-art libraries, as well as the possibility of significantly improving their performance and scalability without caching using PosetHERep

DNA glycosylases: in DNA repair and beyond

The base excision repair machinery protects DNA in cells from the damaging effects of oxidation, alkylation, and deamination; it is specialized to fix single-base damage in the form of small chemical modifications. Base modifications can be mutagenic and/or cytotoxic, depending on how they interfere with the template function of the DNA during replication and transcription. DNA glycosylases play a key role in the elimination of such DNA lesions; they recognize and excise damaged bases, thereby initiating a repair process that restores the regular DNA structure with high accuracy. All glycosylases share a common mode of action for damage recognition; they flip bases out of the DNA helix into a selective active site pocket, the architecture of which permits a sensitive detection of even minor base irregularities. Within the past few years, it has become clear that nature has exploited this ability to read the chemical structure of DNA bases for purposes other than canonical DNA repair. DNA glycosylases have been brought into context with molecular processes relating to innate and adaptive immunity as well as to the control of DNA methylation and epigenetic stability. Here, we summarize the key structural and mechanistic features of DNA glycosylases with a special focus on the mammalian enzymes, and then review the evidence for the newly emerging biological functions beyond the protection of genome integrity

SOX2 Co-Occupies Distal Enhancer Elements with Distinct POU Factors in ESCs and NPCs to Specify Cell State

SOX2 is a master regulator of both pluripotent embryonic stem cells (ESCs) and multipotent neural progenitor cells (NPCs); however, we currently lack a detailed understanding of how SOX2 controls these distinct stem cell populations. Here we show by genome-wide analysis that, while SOX2 bound to a distinct set of gene promoters in ESCs and NPCs, the majority of regions coincided with unique distal enhancer elements, important cis-acting regulators of tissue-specific gene expression programs. Notably, SOX2 bound the same consensus DNA motif in both cell types, suggesting that additional factors contribute to target specificity. We found that, similar to its association with OCT4 (Pou5f1) in ESCs, the related POU family member BRN2 (Pou3f2) co-occupied a large set of putative distal enhancers with SOX2 in NPCs. Forced expression of BRN2 in ESCs led to functional recruitment of SOX2 to a subset of NPC-specific targets and to precocious differentiation toward a neural-like state. Further analysis of the bound sequences revealed differences in the distances of SOX and POU peaks in the two cell types and identified motifs for additional transcription factors. Together, these data suggest that SOX2 controls a larger network of genes than previously anticipated through binding of distal enhancers and that transitions in POU partner factors may control tissue-specific transcriptional programs. Our findings have important implications for understanding lineage specification and somatic cell reprogramming, where SOX2, OCT4, and BRN2 have been shown to be key factors