Yolk-sac–derived macrophages regulate fetal testis vascularization and morphogenesis

Organogenesis of the testis is initiated when expression of Sry in pre-Sertoli cells directs the gonad toward a male-specific fate. The cells in the early bipotential gonad undergo de novo organization to form testis cords that enclose germ cells inside tubules lined by epithelial Sertoli cells. Although Sertoli cells are a driving force in the de novo formation of testis cords, recent studies in mouse showed that reorganization of the vasculature and of interstitial cells also play critical roles in testis cord morphogenesis. However, the mechanism driving reorganization of the vasculature during fetal organogenesis remained unclear. Here we demonstrate that fetal macrophages are associated with nascent gonadal and mesonephric vasculature during the initial phases of testis morphogenesis. Macrophages mediate vascular reorganization and prune errant germ cells and somatic cells after testis architecture is established. We show that gonadal macrophages are derived from primitive yolk-sac hematopoietic progenitors and exhibit hallmarks of M2 activation status, suggestive of angiogenic and tissue remodeling functions. Depletion of macrophages resulted in impaired vascular reorganization and abnormal cord formation. These findings reveal a previously unappreciated role for macrophages in testis morphogenesis and suggest that macrophages are an intermediary between neovascularization and organ architecture during fetal organogenesis.Mammalian testis morphogenesis is a highly orchestrated process involving pre-Sertoli cells, germ cells, interstitial/mesenchymal cells, and vascular endothelial cells (1), providing an ideal model system to study cellular interactions during fetal organ patterning. In the mouse, cells in the XY (male) gonad undergo extensive cellular rearrangements between embryonic day (E) 11.5 and E12.5 that lead to the formation of testis cords, the precursors of seminiferous tubules in the adult organ (2). Pre-Sertoli cells express sex-determining genes, such as sex determining region of chromosome Y (Sry) and sex determining region Y (SRY)-box 9 (Sox9) (3, 4), and traditionally have been considered the main driving force in generating testicular architecture. However, recent evidence from our laboratory and others suggests that endothelial and other interstitial mesenchymal cells also play critical roles in testis morphogenesis (5–8).Mononuclear phagocytes (MPs) represent a diverse subset of the myeloid immune cell lineage which includes macrophages and dendritic cells. MPs play diverse roles in developmental and disease contexts (9, 10), likely acting through their control of vessel anastomosis, clearing of apoptotic cells and other cellular debris, secretion of cytokines and growth factors, and modulation of extracellular matrix (9, 11). MPs are nearly ubiquitous in adult organs throughout the body and are involved in the morphogenesis of multiple tissues, such as bone, mammary gland ducts, pancreatic islets, and eye vasculature (12–15). However, almost all these processes are postnatal tissue-remodeling events.The origin and function of MPs during fetal organogenesis is poorly understood. Traditional models assumed that hematopoietic stem cells (HSCs) differentiate into monocytes, which circulate through peripheral blood and subsequently are recruited to target tissues via local secretion of cytokines, leading to their differentiation into monocyte-derived lineages, e.g., granulocytes, dendritic cells, or macrophages (reviewed in ref. 10). Definitive hematopoiesis (and the appearance of HSCs) occurs initially in the yolk sac, placenta, and aorta-gonad-mesonephros region (AGM) at different time points between E8.5 and E10.5. HSCs populate the fetal liver shortly thereafter (E11.5–E13.5), before the establishment of the bone marrow. However, “primitive” hematopoiesis, originating from unique yolk-sac–derived progenitor cells, takes place at around E7.5, before definitive hematopoiesis, and gives rise to hematopoietic cell types, including erythrocytes and macrophages, that migrate through the yolk-sac vasculature to colonize the fetus (16). Yolk-sac–derived primitive macrophages can contribute to adult hematopoiesis and adult cell types (17–19). In particular, lineage-tracing analyses showed that adult microglia (brain-specific macrophages) are derived exclusively from primitive yolk-sac precursors (17). Yolk-sac–derived macrophages are distinct from HSC-derived macrophages: Yolk-sac–derived macrophages are F4/80-bright, CD11b-dim, and myeloblastosis oncogene (Myb)- and FMS-like tyrosine kinase 3 (Flt3)-independent, whereas HSC-derived macrophages are F4/80-dim, CD11b-bright, and Myb- and Flt3-dependent (19). It is likely that the distinct origins of these cells impart unique identities and functions.In the postnatal and adult testis, macrophages make up a large portion of the interstitial compartment (20) and are important for Leydig cell development and steroidogenic function (21, 22). However, macrophages have not been detected or functionally characterized during fetal testis morphogenesis. We show that yolk-sac–derived macrophages are the only major myeloid cell type in the fetal gonad during morphogenesis of the testis. These macrophages interacted with multiple cell types but were prominent near developing vasculature. Specific depletion of macrophages resulted in significant vascular and architectural abnormalities in the fetal testis. These studies uncover a previously unidentified role for gonadal–mesonephric macrophages in testis morphogenesis, consistent with a broader role for macrophages in fetal development and organogenesis.     

Triphala inhibits alpha-synuclein fibrillization and their interaction study by NMR provides insights into the self-association of the protein

The process of assembly and accumulation of the intrinsically disordered protein (IDP), alpha-synuclein (αSyn) into amyloid fibrils is a pathogenic process leading to several neurodegenerative disorders such as Parkinson''s disease, multiple system atrophy and others. Although several molecules are known to inhibit αSyn fibrillization, the mechanism of inhibition is just beginning to emerge. Here, we report the inhibition of fibrillization of αSyn by Triphala, a herbal preparation in the traditional Indian medical system of Ayurveda. Triphala was found to be a rich source of polyphenols which are known to act as amyloid inhibitors. ThT fluorescence and TEM studies showed that Triphala inhibited the fibrillization of αSyn. However, it was observed that Triphala does not disaggregate preformed αSyn fibrils. Further, native-PAGE showed that Triphala reduces the propensity of αSyn to oligomerize during the lag phase of fibrillization. Our NMR results showed that certain stretches of residues in the N-terminal and NAC regions of αSyn play an anchor role in the self-association process of the protein, thereby providing mechanistic insights into the early events during αSyn fibrillization.

Triphala inhibits αSyn self-association by interacting with anchoring regions which are responsible for αSyn oligomerization.     

A diabetes perception study among rural and urban individuals of West Bengal,India: are we ready for the pandemic?

International Journal of Diabetes in Developing Countries - Type 2 diabetes is a pandemic in India, yet studies regarding knowledge, attitude, and practices in diabetes in various Indian...     

Development of epitope-based peptide vaccine against novel coronavirus 2019 (SARS-COV-2): Immunoinformatics approach

Recently, a novel coronavirus (SARS-COV-2) emerged which is responsible for the recent outbreak in Wuhan, China. Genetically, it is closely related to SARS-CoV and MERS-CoV. The situation is getting worse and worse, therefore, there is an urgent need for designing a suitable peptide vaccine component against the SARS-COV-2. Here, we characterized spike glycoprotein to obtain immunogenic epitopes. Next, we chose 13 Major Histocompatibility Complex-(MHC) I and 3 MHC-II epitopes, having antigenic properties. These epitopes are usually linked to specific linkers to build vaccine components and molecularly dock on toll-like receptor-5 to get binding affinity. Therefore, to provide a fast immunogenic profile of these epitopes, we performed immunoinformatics analysis so that the rapid development of the vaccine might bring this disastrous situation to the end earlier.     

Pharmacological Studies on the Effect of the Treatment of Swiss A Mice with Diospyrin,a Tumour-inhibitory Plant Product,and its Synthetic Derivatives

Diospyrin, a bisnaphthoquinonoid plant product and its derivatives have shown significant inhibitory activities against murine tumours in vivo . Studies on the haematological status, serum protein and creatinine levels, activities of several serum glycolytic enzymes, and histopathology of the mice inoculated with Ehrlich ascites carcinoma were carried out after treatment with diospyrin and four synthetic derivatives. The prognostic significance of the pharmacological parameters acting as markers of the diseased state was evident from these findings. Normal mice were also studied before and after treatment with these compounds which did not cause noticeable adverse effects on the vital parameters, thereby indicating the possibility of the utilization of diospyrin and derivatives as appropriate therapeutic agents.     

Shilajit attenuates streptozotocin induced diabetes mellitus and decrease in pancreatic islet superoxide dismutase activity in rats

Diabetes mellitus was induced in male Wistar rats by the administration of streptozotocin (STZ, 45 mg/kg, s.c. on 2 consecutive days). Hyperglycaemia and superoxide dismutase activity of pancreatic islet cells was assessed on days 7, 14, 21 and 28, following STZ administration. In two other groups, shilajit (50 and 100 mg/kg, p.o.) was administered concurrently for 28 days. STZ induced significant hyperglycaemia by day 14, which increased progressively on days 21 and 28. STZ also induced a decrease in pancreatic islet cell superoxide dismutase, which was apparent by day 7 and increased progressively, thereafter on days 14, 21 and 28. Shilajit (50 and 100 mg/kg, p.o.) had no discernible per se effect on blood glucose levels in normal rats but attenuated the hyperglycaemic response of STZ from day 14 onwards, though only the effect of the higher dose was statistically significant. Similarly, both the doses of shilajit reduced the STZ-induced decrease in superoxide dismutase activity from day 14 onwards, the effect of the lower dose being statistically insignificant. The findings confirm earlier observations that STZ-induced hyperglycaemia may be the consequence of a decrease in pancreatic islet superoxide dismutase activity, leading to accumulation of free radicals and damage of the β-cells. Shilajit attenuates both these effects of STZ possibly by its action as a free radical scavenger. The findings support the postulate that shilajit can prevent maturity onset diabetes mellitus.     

Cross-sectional echocardiographic recognition of submitral left ventricular aneurysm

Three cases of annular submitral left ventricular aneurysm precisely diagnosed by cross-sectional echocardiography are reported from the Indian subcontinent. The cineangiographic findings are available in all and morphologic findings in two cases. The apical four-chamber view demonstrated a characteristically large aneurysm arising below the mural leaflet of the mitral valve extending anterolaterally and posteriorly and communicating with the left ventricular cavity in all the cases. Contrast echocardiography performed during cardiac catheterisation promises to be a good technique for the qualitative assessment of the associated mitral regurgitation. Cross-sectional echocardiography is invaluable in diagnosis and assessment of results of surgery in this entity.