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During neurogenesis, mitotic progenitor cells lining the ventricles of the embryonic mouse brain undergo their final rounds of cell division, giving rise to a wide spectrum of postmitotic neurons and glia 1 , 2 . The link between developmental lineage and cell-type diversity remains an open question. Here we used massively parallel tagging of progenitors to track clonal relationships and transcriptomic signatures during mouse forebrain development. We quantified clonal divergence and convergence across all major cell classes postnatally, and found diverse types of GABAergic neuron that share a common lineage. Divergence of GABAergic clones occurred during embryogenesis upon cell-cycle exit, suggesting that differentiation into subtypes is initiated as a lineage-dependent process at the progenitor cell level. Single-cell RNA sequencing with parallel tagging of progenitor cells is used to track clonal relationships and transcriptomic signatures during development of the mouse forebrain.

The mammalian telencephalon contains distinct GABAergic projection neuron and interneuron types, originating in the germinal zone of the embryonic basal ganglia. How genetic information in the germinal zone determines cell types is unclear. Here we use a combination of in vivo CRISPR perturbation, lineage tracing and ChIP–sequencing analyses and show that the transcription factor MEIS2 favors the development of projection neurons by binding enhancer regions in projection-neuron-specific genes during mouse embryonic development. MEIS2 requires the presence of the homeodomain transcription factor DLX5 to direct its functional activity toward the appropriate binding sites. In interneuron precursors, the transcription factor LHX6 represses the MEIS2–DLX5-dependent activation of projection-neuron-specific enhancers. Mutations of Meis2 result in decreased activation of regulatory enhancers, affecting GABAergic differentiation. We propose a differential binding model where the binding of transcription factors at cis -regulatory elements determines differential gene expression programs regulating cell fate specification in the mouse ganglionic eminence. How genetic information in the germinal zone determines neuronal cell types is unclear. Here the authors show that MEIS2 plays an important role in determining GABAergic neuron diversity during development.

Exposure to excess glucocorticoid (GC) during early development is implicated in adult dysfunctions. Reduced adult hippocampal neurogenesis is a well-known consequence of exposure to early life stress or elevated GC, however the effects on neurogenesis during development and effects on other brain regions are not well understood. Using an optogenetic zebrafish model, here we analyse the effects of GC exposure on neurogenesis during development in the whole brain. We identify that the hypothalamus is a highly GC-sensitive region where elevated GC causes precocious development. This is followed by failed maturation and early decline accompanied by impaired feeding, growth, and survival. In GC-exposed animals, the developmental trajectory of hypothalamic progenitor cells is strikingly altered, potentially mediated by direct regulation of transcription factors such as rx3 by GC. Our data provide cellular and molecular level insight into GC-induced alteration of the hypothalamic developmental trajectory, a process crucial for health across the life-course. A study in zebrafish indicates that elevated cortisol levels during early life can alter the developmental trajectory of the hypothalamus, inducing short-term precocious development, but leading to failed maturation in the long-term.

A previous study has shown that synthetic antimicrobial peptides (AMPs) derived from Anabas testudineus (ATMP1) could in-vitro inhibit the progression of breast cancer cell lines. In this study, we are interested in studying altered versions of previous synthetic AMPs to gain some insight into the peptides functions. The AMPs were altered and subjected to bioinformatics prediction using four databases (ADP3, CAMP-R3, AMPfun, and ANTICP) to select the highest anticancer activity. The bioinformatics in silico analysis led to the selection of two AMPs, which are ATMP5 (THPPTTTTTTTTTTTYTAAPATTT) and ATMP6 (THPPTTTTTTTTTTTTTAAPARTT). The in silico analysis predicted that ATMP5 and ATMP6 have anticancer activity and lead to cell death. The ATMP5 and ATMP6 were submitted to deep learning databases (ToxIBTL and ToxinPred2) to predict the toxicity of the peptides and to (AllerTOP & AllergenFP) check the allergenicity. The results of databases indicated that AMPs are non-toxic to normal human cells and allergic to human immunoglobulin. The bioinformatics findings led to select the highest active peptide ATMP5, which was synthesised and applied for in-vitro experiments using cytotoxicity assay MTT Assay, apoptosis detection using the Annexin V FTIC-A assay, and gene expression using Apoptosis PCR Array to evaluate the AMP’s anticancer activity. The antimicrobial activity is approved by the disc diffusion method. The in-vitro experiments analysis showed that ATMP5 had the activity to inhibit the growth of the breast cancer cell line (MDA-MB-231) after 48 h and managed to arrest the cell cycle of the MDA-MB-231, apoptosis induction, and overexpression of the p53 by interaction with the related apoptotic genes. This research opened up new opportunities for developing potential and selective anticancer agents relying on antimicrobial peptide properties.

A successful self-participation experience empowers patients to adapt to living with hemodialysis. However, few studies regarding the subjective experiences of such patient participation have been conducted. This study’s purpose was to describe hemodialysis patients’ perspectives on integrating hemodialysis into a new life regarding self-participation experience. A qualitative study using the grounded theory method was applied. Thirty-two well-adaptive hemodialysis Taiwanese patients attended in-depth interviews. “Integrating hemodialysis into a new life journey” was identified as the core category guiding the entire self-participation experience of hemodialysis patients. The three antecedent themes were “Sense of worthlessness”, “Life is still worth living”, and “Friendly and joyful atmosphere of the hemodialysis room”. Once the patients went through the three antecedent themes, they gradually began making efforts to participate more fully in their hemodialysis. Within this participation experience, the hemodialysis patients exhibited these four interactive themes: “Overcoming one’s predicament”, “Integrating self-care skills into my life”, “Resuming previous roles and tasks”, and “Adapting to independent living”. Finally, most adaptive patients master the hemodialysis life. Encouraging patients to discover that their life is worth living and providing a friendly and joyful atmosphere in hemodialysis units are the keys to facilitating patients’ self-participation more fully.

Sickle trait, the heterozygous state of normal hemoglobin A (HbA) and sickle hemoglobin S (HbS), confers protection against malaria in Africa. AS children infected with Plasmodium falciparum are less likely than AA children to suffer the symptoms or severe manifestations of malaria, and they often carry lower parasite densities than AA children. The mechanisms by which sickle trait might confer such malaria protection remain unclear. We have compared the cytoadherence properties of parasitized AS and AA erythrocytes, because it is by these properties that parasitized erythrocytes can sequester in postcapillary microvessels of critical tissues such as the brain and cause the life-threatening complications of malaria. Our results show that the binding of parasitized AS erythrocytes to microvascular endothelial cells and blood monocytes is significantly reduced relative to the binding of parasitized AA erythrocytes. Reduced binding correlates with the altered display of P. falciparum erythrocyte membrane protein-1 (PfEMP-1), the parasite's major cytoadherence ligand and virulence factor on the erythrocyte surface. These findings identify a mechanism of protection for HbS that has features in common with that of hemoglobin C (HbC). Coinherited hemoglobin polymorphisms and naturally acquired antibodies to PfEMP-1 may influence the degree of malaria protection in AS children by further weakening cytoadherence interactions.

The emergence of Virulent Plasmodium falciparum in Africa within the past 6000 years as a result of a cascade of changes in human behavior and mosquito transmission has recently been hypothesized. Here, we provide genetic evidence for a sudden increase in the African malaria parasite population about 10,000 years ago, followed by migration to other regions on the basis of variation in 100 worldwide mitochondrial DNA sequences. However, both the world and some regional populations appear to be older (50,000 to 100,000 years old), suggesting an earlier wave of migration out of Africa, perhaps during the Pleistocene migration of human beings.

Background. Cytoadherence and sequestration of erythrocytes containing mature stages of Plasmodium falciparum are central to the pathogenesis of severe malaria. The oral anthelminthic drug levamisole inhibits cytoadherence in vitro and reduces sequestration of late-stage parasites in uncomplicated falciparum malaria treated with quinine. Methods. Fifty-six adult patients with severe malaria and high parasitemia admitted to a referral hospital in Bangladesh were randomized to receive a single dose of levamisole hydrochloride (150 mg) or no adjuvant to antimalarial treatment with intravenous artesunate. Results. Circulating late-stage parasites measured as the median area under the parasite clearance curves were 2150 (interquartile range [IQR], 0-28 025) parasites/µL × hour in patients treated with levamisole and 5489 (IQR, 192-25 848) parasites/µL × hour in controls (P = .25). The \"sequestration ratios\" at 6 and 12 hours for all parasite stages and changes in microvascular blood flow did not differ between treatment groups (all P > .40). The median time to normalization of plasma lactate (<2 mmol/L) was 24 (IQR, 12-30) hours with levamisole vs 28 (IQR, 12-36) hours without levamisole (P = .15). Conclusions. There was no benefit of a single-dose of levamisole hydrochloride as adjuvant to intravenous artesunate in the treatment of adults with severe falciparum malaria. Rapid parasite killing by intravenous artesunate might obscure the effects of levamisole.

IntroductionThere are 161 million people living with vision impairment, due to uncorrected refractive errors. A further 510 million people are living with near-vision impairment. There is a need for clearly defined indicators that capture the quality of refractive error service outputs and outcomes and provide insights to shape, change and stimulate action. This study aims to evaluate the quality of refractive error care (Q.REC) in Cambodia, Malaysia and Pakistan, by using unannounced standardised patients (USPs) to identify the proportion of prescribed and dispensed spectacles appropriate for people’s refractive error needs and pinpoint/detail opportunities for quality improvement.Method and analysisA cross-sectional Q.REC study will be conducted in randomly selected optical services in Cambodia (180 services, 900 USP visits), the Klang Valley in Malaysia (66 services, 198 USP visits) and in Jhang, Sahiwal and Khanewal districts of Punjab region/state in Pakistan (64 services, 256 USP visits). USPs will receive baseline refractions by three skilled study optometrists/refractionists trained in the Q.REC protocol. USPs will then visit individual optical services, undergo a refraction, purchase spectacles or lenses (if recommended) and record observations about which elements of a refraction and dispensing were conducted. The study optometrist/refractionist will assess each pair of dispensed spectacles by examining the USP’s aided visual acuity and visual comfort at distance and/or near and compare the lens prescription to the averaged baseline refraction.Ethics and disseminationThis study has been approved by the University of New South Wales Human Research Ethics Committee (HC210102), the National Ethics Committee for Health Research in Cambodia (043 NECHR), National Medical Research Registry and the Medical Research and Ethics Committee (NMRR-21-689-59279) in Malaysia and the College of Ophthalmology & Allied Vision Sciences Ethical Review Board (COAVS 545/2021) in Pakistan. Written informed consent will be obtained from USPs. Service owners will have the opportunity to opt-out verbally or in writing. Results will be disseminated locally through workshops including the relevant local ministry of health personnel and stakeholders, published in peer-reviewed publications and presented at national and international conferences.

The adhesion of Plasmodium falciparum-infected erythrocytes (IRBC) to receptors on different host cells plays a divergent yet critical role in determining the progression and outcome of the infection. Based on our ex vivo studies with clinical parasite isolates from adult Thai patients, we have previously proposed a paradigm for IRBC cytoadherence under physiological shear stress that consists of a recruitment cascade mediated largely by P-selectin, ICAM-1 and CD36 on primary human dermal microvascular endothelium (HDMEC). In addition, we detected post-adhesion signaling events involving Src family kinases and the adaptor protein p130CAS in endothelial cells that lead to CD36 clustering and cytoskeletal rearrangement which enhance the magnitude of the adhesive strength, allowing adherent IRBC to withstand shear stress of up to 20 dynes/cm². In this study, we addressed whether CD36 supports IRBC adhesion as part of an assembly of membrane receptors. Using a combination of flow chamber assay, atomic force and confocal microscopy, we showed for the first time by loss- and gain-of function assays that in the resting state, the integrin α₅β₁ does not support adhesive interactions between IRBC and HDMEC. Upon IRBC adhesion to CD36, the integrin is recruited either passively as part of a molecular complex with CD36, or actively to the site of IRBC attachment through phosphorylation of Src family kinases, a process that is Ca²⁺-dependent. Clustering of β1 integrin is associated with an increase in IRBC recruitment as well as in adhesive strength after attachment (∼40% in both cases). The adhesion of IRBC to a multimolecular complex on the surface of endothelial cells could be of critical importance in enabling adherent IRBC to withstand the high shear stress in the microcirculations. Targeting integrins may provide a novel approach to decrease IRBC cytoadherence to microvascular endothelium.