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Grapes powdery mildew and downy mildew caused by Erysiphe necator and Plasmopara viticola respectively are the most devastating diseases worldwide resulting in significant loss of yield and quality. Epidemics of grapevine mildews are caused by airborne inocula such as conidia and sporangia. Rapid detection of airborne inocula will help to face up timely management strategies under field conditions. The aim of the current study was to design a suction spore trap to trap the airborne mildew inocula and their early detection by molecular methods of PCR and LAMP assay. A total of twelve airborne inocula samples were collected the weekly intervals from 3 to 14 standard weeks of 2021 during the cropping season. The presence of airborne inocula of E. necator was detected on standard weeks 3,6,10 and 13 through PCR assay which yielded an amplicon of 470 bp. Similarly, airborne inocula of P.viticola were detected on standard week 6 only through PCR which yielded an amplicon of 520 bp. A rapid, highly specific , sensitive Loop mediated isothermal amplification (LAMP) assay was performed to detect the E. necator and P. viticola using six sets of LAMP primers constructed by targeting rDNA region of ITS and the 5S rRNA and CesA4 a gene, respectively. LAMP assay efficiently detected the presence of airborne inocula of E.necator in most of the samples collected from standard week 3 – 14 except 7, 8, and 9. However, the presence of airborne inocula of P.viticola from standard week 3 – 14 was confirmed by LAMP assay. The LAMP assay is absolutely the best in identifying airborne inocula of grapevine mildews compared to PCR and phenotypic microscopic observation.

Background: Nipah virus (NiV) is a zoonotic paramyxovirus that can cause severe respiratory illness and encephalitis in humans, with no effective targets and treatment. Objective: To investigate potential targets involved in the progression of NiV infection by bioinformatics studies. Methods: To identify the key gene involved in NiV infection, a microarray dataset (GSE32902) was downloaded from the National Centre of Biotechnology Information (NCBI). The differentially expressed genes were unraveled by using Geo2Enrichr, and the functional enrichment analysis was facilitated by using Database for Annotation, Visualization, and Integrated Discovery (DAVID). Search Tool for the Retrieval of Interacting Genes (STRING) was used to construct the Protein-protein interaction (PPI) network and visualized by using Cytoscape. Results: A total of 500 genes (262 up-regulated and 238 down-regulated) were identified among NiV infected cells. Nineteen upregulated genes were found with a node degree of more than 10, Among which MX1, ISG15, and IFIT1 were found to have the highest node degree (degree=20), followed by RSAD2 and IRF7 with node degree 18 and MX2 and IFIT3 with node degree 17. Conclusion: The above results explicitly demonstrate that the expressed genes attribute to a defensive response against the virus. Henceforth finding agonists for these genes would help in the effective management of Niv infection.

The prevalence of obesity and dyslipidaemia was observed to be increased among the tribal populations, due to globalization. In the present study, data on demographic, somatometric and blood samples were collected from 613 participants of both sex, age 18–60 years, further lipid profiling and genotyping was executed. Multifactor dimensionality reduction (MDR) software was used for gene–gene interactions analysis. Significantly differences were observed with respect to the general characteristic and selected gene polymorphisms in both the tribes. Among the Liangmai tribe, MC4R gene was found to pose significant decreased risk for waist–height ratio (WHtR) (OR = 0.56; 95% confidence interval (CI)= 0.32–0.99; p value = .04) and HDL (OR = 0.58; 95% CI = 0.36–0.92; p value = .02). Similar trends of significant decreased risk (OR = 0.39; 95% CI = 0.20–0.76; p value=.006) for BMI were observed among the Mizo tribe. The gene–gene interaction revealed the combined model of FTO+MC4R genes shows an increased risk for BMI in both the tribes. The independent significant increased risk posed by FTO gene was moderated by interaction with MC4R gene. The observed differences can possibly attribute to both their respective ancestries resulting in different gene pools and the physical environment. The results of the study highlight the importance of gene–gene and gene–environment interactions in adverse phenotype groups.KEY MESSAGEAmong the tribal population, the prevalence of obesity and dyslipidaemia has been increased.Differential distribution and associations of selected markers hint towards differential genetic architecture in these populations.MC4R rs17782313 polymorphism was found to show a significantly decreased risk for WHtR and low HDL among the Liangmai tribe and BMI among the Mizo tribe.Significant increased risk posed by FTO rs9939609 gene polymorphism was moderated by the interaction with MC4R rs17782313. Among the tribal population, the prevalence of obesity and dyslipidaemia has been increased. Differential distribution and associations of selected markers hint towards differential genetic architecture in these populations. MC4R rs17782313 polymorphism was found to show a significantly decreased risk for WHtR and low HDL among the Liangmai tribe and BMI among the Mizo tribe. Significant increased risk posed by FTO rs9939609 gene polymorphism was moderated by the interaction with MC4R rs17782313.

Sulphide is one of the known environmental stressors, which potentially binds to cytochrome C oxidase (COX), a key enzyme in the electron transport chain, thereby blocking oxygen transport and ATP production. To ascertain the toxic effects of sulphide on Pacific white shrimp, Penaeus vannamei, two distinct exposure experiments were carried out with varying concentration of sulphide (0–1 mg/L), dissolved oxygen (normoxia and hypoxia) and pH values (8.2, 6 and 5). The activity of enzymes viz COX, superoxide dismutase (SOD), phenoloxidase and lactate accumulation was investigated. Outer membrane integrity and COX monomer separation were also done with the isolated crude mitochondrial preparations. Results indicated a significant reduction (p ≤ .05) in COX enzyme activity in sulphide exposed treatments when compared to control. The reduction was more intense when pH levels were reduced under hypoxia condition. Lactate accumulation as a result of anaerobic metabolism was found to be higher in hypoxic treatments. No significant difference (p ≥ .05) was observed in superoxide dismutase activity between the treatments, whereas phenoloxidase activity significantly decreased at higher concentration sulphide. Separation of mitochondrial proteins resulted in the identification of ~205 kDa of COX monomer, and significant damage was found in outer membrane integrity under hypoxia and pH treatments. From this study, it is evident that at a given concentration, sulphide is toxic to P. vannamei, and in association with hypoxia and low pH, they further intensify sulphide toxicity. Our results indicated that sulphide toxicity should not be considered as a single factor, rather it should be a considered as combination of factors.

Hepatocellular carcinoma (HCC) is the fifth most common neoplasm in the world. Chronic inflammation of liver and associated wound healing processes collectively contribute to the development of cirrhosis which further progresses to dysplastic nodule and then to HCC. Etiological mediators and ongoing manipulations at cellular level in HCC are well established; however, key protein interactions and genetic alterations involved in stepwise hepatocarcinogenic pathways are seldom explored. This study aims to unravel novel targets of HCC and repurpose the FDA-approved drugs against the same. Genetic data pertinent to different stages of HCC were retrieved from GSE6764 dataset and analyzed via GEO2R. Subsequently, protein–protein interaction network analysis of differentially expressed genes was performed to identify the hub genes with significant interaction. Hub genes displaying higher interactions were considered as potential HCC targets and were validated thorough UALCAN and GEPIA databases. These targets were screened against FDA-approved drugs through molecular docking and dynamics simulation studies to capture the drugs with potential activity against HCC. Finally, cytotoxicity of the shortlisted drug was confirmed in vitro by MTT assay. CDC20 was identified as potential druggable target. Docking, binding energy calculations, and dynamic studies revealed significant interaction exhibited by Labetalol with CDC20. Further, in MTT assay, Labetalol demonstrated an IC50 of 200.29 µg/ml in inhibiting the cell growth of HepG2 cell line. In conclusion, this study discloses a series of key genetic underpinnings of HCC and recommends the pertinence of labetalol as a potential repurposable drug against HCC.

AIMType 2 diabetes is a serious public health concern in India, even the indigenous tribal populations are not felt unaffected. The present study aims to understand the association of major risk factors i.e obesity, hypertension, dyslipidemia, ACE I/D polymorphism with impaired (IFG) and type 2 diabetes (T2D) among two different Mendelian populations of North East India. METHODDemographic, somatometric and physiological variables along with fasting blood samples were collected from 609 individuals. ACE I/D polymorphism was screened. RESULTACE I/D polymorphism was found to follow HWE among Liangmai tribe but not among Mizo tribe. Distribution of DD genotype/D allele was found to be significantly higher for T2D among Mizo (OR 2.10; 95% CI 1.10-4.39, OR 2.10;1.16-4.09 respectively ).Significant association between DD genotype/D allele of ACE I/D polymorphism and TC in both IFG (OR 2.22; 95% CI 1.14-4.32) and T2D (OR 2.53;95%CI 1.51-4.23) were observed . LDL was also found to posed significant risk for IFG (OR 2.10;95% CI 1.10-3.91) and T2D (OR 1.04; 95%CI 1.02-1.06). CONCLUSIONThe present study is an example of gene-environment interaction where DD genotype or D allele and dyslipidemia (high TC and high LDL) are posing risk for IFG and T2D both independently and in combination only among Mizo tribe with relatively less physical activity attributed to their residence in less hilly terrain, but Liangmai tribe which resides in high hilly terrain shows no such association.

Artículo con numerosos autores, sólo se mencionan el primero, los de la UAM y grupo colectivo, A double burden of malnutrition occurs when individuals, household members or communities experience both undernutrition and overweight. Here, we show geospatial estimates of overweight and wasting prevalence among children under 5 years of age in 105 low- and middle-income countries (LMICs) from 2000 to 2017 and aggregate these to policy-relevant administrative units. Wasting decreased overall across LMICs between 2000 and 2017, from 8.4% (62.3 (55.1–70.8) million) to 6.4% (58.3 (47.6–70.7) million), but is predicted to remain above the World Health Organization’s Global Nutrition Target of, This work was primarily supported by grant OPP1132415 from the Bill & Melinda Gates Foundation awarded to S.I.H.

Intrinsic and extrinsic inhibition of axonal and neuronal regeneration obstruct spinal cord (SC) repair in mammals. In contrast, adult zebrafish achieve functional recovery after SC damage. While studies of innate SC regeneration have focused on axon regrowth as a primary repair mechanism, how local neurogenesis impacts functional recovery is unknown. We uncovered dynamic expression of myostatin b (mstnb) in a niche of dorsal ependymal progenitors after complete SC transection in zebrafish. Genetic loss-of-function in mstnb impaired functional recovery, although glial and axonal bridging across the lesion were unaffected. Using a series of transgenic reporter lines, we quantified the numbers of stem, progenitor, and neuronal cells in the absence of mstnb. We found neural stem cell proliferation was reduced, while newborn neurons were increased in mstnb null tissues, suggesting mstnb is a negative regulator of neurogenesis. Molecularly, neuron differentiation genes were upregulated, while the neural stem cell maintenance gene fgf1b was downregulated in mstnb mutants. Finally, we show that human FGF1 treatment rescued neuronal gene expression in mstnb mutants. These studies uncover unanticipated neurogenic functions for mstnb in adult zebrafish, and establish the importance of local neurogenesis for functional SC repair.

Vertebrate Delta/Notch signaling involves multiple ligands, receptors and transcription factors. Delta endocytosis – a critical event for Notch activation – is however essentially controlled by the E3 Ubiquitin ligase Mindbomb1 (Mib1). Due to its position at a molecular bottleneck of the pathway, Mib1 inactivation is often used to inhibit Notch signaling. However, recent findings indicate that the importance of Mib1 extends beyond the Notch pathway. We report an essential role of Mib1 in Planar Cell Polarity (PCP).mib1 null mutants or morphants display impaired gastrulation stage Convergence Extension (CE) movements. Comparison of different mib1 mutants and functional rescue experiments indicate that Mib1 controls CE independently of Notch. In contrast, Mib1-dependent CE defects can be rescued using the PCP downstream mediator RhoA. Mib1 regulates CE through the RING Finger domains that have been implicated in substrate ubiquitination, suggesting that Mib1 may control PCP protein trafficking. Accordingly, we show that Mib1 controls the endocytosis of the PCP component Ryk and that Ryk internalization is required for CE.Numerous morphogenetic processes involve both Notch and PCP signaling. We show that Mib1, a known Notch signaling regulator, is also an essential PCP pathway component. Care should therefore be taken when interpreting Mib1 loss of function phenotypes.

The morphogenesis of the nervous system requires coordinating the specification and differentiation of neural precursor cells, the establishment of neuroepithelial tissue architecture and the execution of specific cellular movements. How these aspects of neural development are linked is incompletely understood. Here we inactivate a major regulator of embryonic neurogenesis - the Delta/Notch pathway - and analyze the effect on zebrafish central nervous system morphogenesis. While some parts of the nervous system can establish neuroepithelial tissue architecture independently of Notch, Notch signaling is essential for spinal cord morphogenesis. In this tissue, Notch signaling is required to repress neuronal differentiation and allow thereby the emergence of neuroepithelial apico-basal polarity. Notch-mediated suppression of neurogenesis is also essential for the execution of specific morphogenetic movements of zebrafish spinal cord precursor cells. In the wild-type neural tube, cells divide at the organ midline to contribute one daughter cell to each organ half. Notch signaling deficient animals fail to display this behavior and therefore form a misproportioned spinal cord. Taken together, our findings show that Notch-mediated suppression of neurogenesis is required to allow the execution of morphogenetic programs that shape the zebrafish spinal cord.

Aim The purpose of the present study is to evaluate and understand the association of global and MTHFR gene specific methylation in preeclampsia and recurrent miscarriages in light of MTHFR C677T polymorphism. Methods The subjects comprised of recurrent miscarriage cases, their gestation matched controls, preeclampsia cases and matched controls. A set of women at full term were also recruited. Fasting blood sample (~5 ml) was drawn from all the participants followed by DNA extraction, global DNA methylation and MTHFR gene specific methylation. MTHFR C677T polymorphism was analysed by PCR followed by RFLP. Results higher Global DNA methylation at maternal front (p = 0.04) and hypomethylation of MTHFR gene at fetal front (p = 0.001) might be a characteristic of preeclampsia. Recurrent miscarriage cases were having significantly (p = 0.002) hyper MTHFR gene specific methylation as compared to controls. Women carrying CT genotype were found to be having significantly (p = 0.001) higher global DNA methylation in PE cases and MTHFR gene specific methylation (p = 0.005) in RM cases. Intergenerational analysis revealed similar patterns of global DNA methylation and MTHFR gene specific methylation among both PE and RM cases at maternal and fetal fronts. Conclusion The study highlights the importance of global DNA methylation in Preeclampsia and MTHFR gene specific methylation in recurrent miscarriages. MTHFR C677T gene polymorphism in association with global and gene specific methylation seem to play a pivotal role in PE and RM respectively.

A130-day culture experiment was performed to compare the effects of rearing Litopenaeus vannamei in a biofloc system and conventional autotrophic system, supplemented with diets having graded protein levels on growth performance, non-specific immune response and immunomodulatory activity. The experiment groups consisted of four protein-level treatments with four replicates each, and was performed in 16 experimental units (7.5-Tcapacity) stocked with juvenile L. vannamei (initial average weight 1.48 ± 0.4 g) at a density of 150 juvenile shrimps /m3. Biofloc-based groups fed with supplementary feed containing varying levels of crude protein (CP) BFT40 (40% CP), BFT32 (32% CP) and BFT24 (24% CP), and a control group (CP 40%), were maintained in an autotrophic system. At the end of the experimental period, there was an improvement of 32.6–52.6% in terms of productivity, 22–27.6% average body weight; 8.7–19.6% survival rate and 10–31% feed conversion ratio (FCR) in shrimp maintained in biofloc systems as compared to control. Similarly, the protein efficiency ratio (PER) in biofloc treatment groups was32 to 83% higher than control. The shrimp also showed higher resistance to disease in the biofloc treatment when challenged with pathogenic Vibrio parahaemolyticus, as survival of juveniles was significantly higher (p

Shrimp aquaculture in India has made significant strides especially after the introduction of Pacific white shrimp in the year 2009. However, intensification of culture practice has exacerbated several disease issues. Apart from infectious diseases, the Indian shrimp aquaculture has been witnessing certain syndromes, affecting productivity. One such syndrome associated with significant morbidity and mortality is popularly termed as running mortality syndrome (RMS) by shrimp farmers. Since 2011, RMS has been widely prevalent in the shrimp farms in Andhra Pradesh (AP) and Tamil Nadu (TN). The affected shrimp show patches of whitish musculature in the abdominal segments as a clinical sign with continuous low-level mortalities, especially after about 35–40 days of shrimp culture. We tried to investigate if this kind of mortality is infectious in nature. Investigations conducted in 34 farms comprising 25 RMS affected and 9 healthy farms were tested negative for all the major OIE listed and other pathogens such as white spot syndrome virus (WSSV), infectious hypodermal and hematopoietic necrosis virus (IHHNV), monodon baculovirus (MBV), hepatopancreatic parvo virus (HPV), infectious myonecrosis (IMNV), Taura syndrome virus (TSV), yellow head virus (YHV), and Penaeus vannamei noda virus (PvNV). Bacteriological examination of haemolymph and hepatopancreas of RMS affected shrimp showed the predominance of Vibrio spp., such as Vibrio parahaemolyticus and Vibrio azureus. Histopathological examination of the hepatopancreas was found to be largely normal, except for haemocytic infiltration in the abdominal segments. Hemolymph of affected shrimp was observed to have less concentration of major and trace minerals than healthy ones. Bioassay through feeding RMS affected shrimp tissue to healthy shrimp and co-habitation experiment of healthy shrimp with the affected animals failed to induce RMS. When maintained in water with optimal physico-chemical parameters, affected shrimps showed recovery within 6–7 days. On the other hand, environmental parameters of pond waters such as total ammonia nitrogen, nitrite nitrogen and turbidity were relatively higher than the optimal values in RMS affected farms. Multiple correspondence statistical analysis of critical factors indicated running mortality to be associated with high stocking densities, high nitrite-N, and high turbidity. Though the study could not identify any specific known aetiological agent associated with RMS affected shrimp, failure to reproduce the syndrome by bioassay, the recovery of affected shrimp under the optimal environmental conditions and the positive correlation with critical environmental parameters and the stocking densities to mortality rates clearly suggest RMS to be a pond ecosystem or pond management associated syndrome rather than infectious in nature and thus can be overcome through best management practices.

Aim The purpose of the present study is to evaluate and understand the association of global and MTHFR gene specific methylation in the progression of a normal pregnancy. Methods The subjects comprised of normal pregnant women and non pregnant women. Fasting blood sample (~5 ml) was drawn from all the participants followed by DNA extraction, global DNA methylation and MTHFR gene specific methylation. Results Women with normal pregnancy were having relatively lower levels of global methylation in their first trimester as compared to non pregnant women. The trend of MTHFR gene specific methylation was exactly opposite of that of global methylation in the respective three trimesters and full term. Among normal pregnant women in the first trimester, a significant increase in MTHFR gene specific methylation is observed as compared to the non pregnant controls, followed with a relative decline in the second, third trimester and full term. Conclusion The present study speculates that pregnancy is associated with decrease in global methylation levels and increase in MTHFR gene specific methylation as compared to non pregnant state. There is an inverse relationship between global and MTHFR gene specific methylation.

Background One of the candidate biochemical marker for cardio vascular disease is elevated homocysteine and the increase in homocysteine in a population is usually attributed by both environmental (vitamin B12 and folate deficiency) and genetic regions (MTHFR gene polymorphism). Nutritional deficiencies (folic acid and vitamin B12) and mutation in gene (MTHFR C677T) hamper the conversion of homocysteine into methionine which causes the elevated homocysteine in the intercellular regions. Thus one can say a typical gene-environment interaction can result into hyperhomocysteinemia. Aim The present study attempts to understand the involvement of two nutritional factors (vitamin B12 and folate) and one genetic factor (MTHFR C677T) independently and also in combination in the causation of hyperhomocysteinemia. Material and method Data were collected through house hold survey from 303 individuals belonging to age group of 25 to 65 years in the Udaipur and Sirohi districts of Rajasthan and Baljeet Nagar area of Delhi. Fasting blood samples were collected form all the recruited individuals. Analysis of biochemical variables including homocysteine, vitamin B12 and folate was done on collected blood samples. Analysis of MTHFR C6777T gene polymorphism was done through standard protocol. All the statistical tests were performed by using MS Excel 2010 and SPSS version 20.0. Results and conclusion In the present study vitamin B12 deficiency is found to be more common than folate deficiency. Majority of studied population are found to be hyperhomocysteinemic (93.06) and vitamin B12 was found to be reason for the hyperhomocysteinemia. Combination of genetic mutation (MTHFR C677T) and nutritional deficiency (vitamin B12 and folate deficiency) seems to have survival disadvantage in the hyperhomocysteinemic individuals.

BackgroundHypertension is a complex disorder affected by gene-environment interactions. Methylenetetrahydrofolate reductase (MTHFR) gene is one of the genes in One Carbon Metabolic (OCM) pathway that affects both blood pressure and epigenetic phenomenon.MTHFRC677T gene polymorphism leads to reduced methylation capacity via increased homocysteine concentrations. Global DNA methylation (5mC%) also gets affected in conditions such as hypertension. However, no study is found to understand hypertension in terms of both genetics and epigenetics. The present study aims to understand the relation between methylation,MTHFRC677T gene polymorphism and hypertension. It also tries to understand relation (if any) between methylation and anti-hypertensive drugs.MethodsThis is a cross-sectional study where data were collected from a total of 1634 individuals of either sex in age group 35–65 years. Hypertensives (SBP ≥ 140 mm Hg and DBP ≥ 90 mm Hg) (on treatment/not on treatment) and absolute controls were 236 (cases) and 307 (controls), respectively. All the samples were subjected toMTHFRC677T gene polymorphism screening (PCR–RFLP) and global DNA methylation assay (ELISA based colorimetric assay). Results of both the analyses were obtained on 218 cases, 263 controls.ResultsMedian 5mC% was relatively lower among cases (p > 0.05) compared to controls, despite controlling for confounders (age, sex, smoking, alcohol, diet) (r2-0.92, p-0.08). Cases not on medication had significantly reduced 5mC% compared to controls (p 2-0.857, p-0.01). Among cases (irrespective of treatment), there was a significant variation in 5mC% across the three genotypes i.e. CC, CT and TT, with no such variation among controls. Cases (not on medication) with TT genotype had significantly lower methylation levels compared to the TT genotype controls and cases (on medication) (p ConclusionGlobal DNA hypomethylation seems to be associated with hypertension and antihypertensive drugs seem to improve methylation. Hypertensive individuals with TT genotype but not on medication are more likely to be prone to global DNA hypomethylation. Important precursors in OCM pathway include micronutrients such as vitamin B-12, B-9 and B-6; their nutritional interventions (either dietary or supplement) may serve as strategies to prevent hypertension at population level. However, more epidemiological-longitudinal studies are needed for further validation.

The safe, highly effective measles vaccine has been recommended globally since 1974, yet in 2017 there were more than 17 million cases of measles and 83,400 deaths in children under 5 years old, and more than 99% of both occurred in low- and middle-income countries (LMICs)1–4. Globally comparable, annual, local estimates of routine first-dose measles-containing vaccine (MCV1) coverage are critical for understanding geographically precise immunity patterns, progress towards the targets of the Global Vaccine Action Plan (GVAP), and high-risk areas amid disruptions to vaccination programmes caused by coronavirus disease 2019 (COVID-19)5–8. Here we generated annual estimates of routine childhood MCV1 coverage at 5 × 5-km2 pixel and second administrative levels from 2000 to 2019 in 101 LMICs, quantified geographical inequality and assessed vaccination status by geographical remoteness. After widespread MCV1 gains from 2000 to 2010, coverage regressed in more than half of the districts between 2010 and 2019, leaving many LMICs far from the GVAP goal of 80% coverage in all districts by 2019. MCV1 coverage was lower in rural than in urban locations, although a larger proportion of unvaccinated children overall lived in urban locations; strategies to provide essential vaccination services should address both geographical contexts. These results provide a tool for decision-makers to strengthen routine MCV1 immunization programmes and provide equitable disease protection for all children., Although progress in the coverage of routine measles vaccination in children in low- and middle-income countries was made during 2000–2019, many countries remain far from the goal of 80% coverage in all districts by 2019.

Aqueous humor outflow (AHO) is important for supporting normal eye physiology and vision. Altered AHO occurs in glaucoma because increased AHO resistance leads to increased intraocular pressure (IOP). This increased resistance occurs at the trabecular meshwork (TM) and distal to the TM. Soluble factors such as transforming growth factor beta (TGF-β) have been implicated in this process. Numerous tools are available to structurally or functionally study AHO that are either static or real-time in nature. These methods have been instrumental to better understanding normal AHO and unveiling the pathophysiology of diseased AHO in glaucoma.

Feed ingredients and additives significantly affect the mucosal health of fish. A 3 × 2 factorial experiment was conducted to investigate the mucosal health of Atlantic salmon (Salmo salar) fed three basal feeds (namely, BG1, BG5 and BG2; marine-, plant-, and soybean meal-based feeds, respectively) or the basal feeds with (+) or without (÷) probiotics, Lactobacillus fermentum and Lactobacillus plantarum. Six diets were fed to fish distributed into 12 tanks (approximately 43 fish/tank). The average start weight of the experimental fish was about 122.6 g. After 38-days of feeding, the dorsal skin, gills and distal intestine were obtained for analysing histomorphometry and mucus-related genes. Digesta were also collected to study short chain fatty acids (SCFAs). Fish fed BG2 had significantly higher number of mucous cells/μm2 skin epithelium (SNE) than those fed BG1 and BG5. Addition of probiotics significantly increased SNE in BG5+ and BG2+ group compared to BG1÷ group. Similarly, the area and number of mucous cells/μm2 gill epithelium (GME and GNE) were significantly higher in BG2 group, followed by BG5 and BG1 fish groups. Probiotics significantly increased GME and GNE in all feed types. Concerning intestine, villi height (VH) and enterocyte height (EH) were significantly higher for BG1 group, followed by BG5 and BG2 groups. Compared to fish offered BG2, fish fed BG1 had significantly wider villi (VW) and narrower lamina propria (LPW). The number of mucous cells (NM) and intraepithelial lymphocytes (IEL) in the intestine were significantly higher in BG2 fed fish than those offered BG5 and BG1. The indices VH, VW, EH, and IEL were not affected by probiotics. Although higher NM and IEL were observed in BG2÷ fish compared to those fed the other two diets, probiotics reduced NM and IEL. Fish fed BG2÷ showed symptoms of inflammation, including disappearance of supranuclear vacuoles (SNV). Probiotics improved VH, significantly reduced LPW and aided in the reappearance of SNV in BG2+ fed fish. Some of the gene expression data supported histological findings; notably, levels of muc5ac1 in the skin and defensin3 and cathelcidin1 in the intestine were correlated with histology data. Moreover, the total SCFA concentration was significantly affected by feed ingredients. Only acetoacetic acid was affected by both factors. Our findings suggest that feed ingredients can significantly alter the mucosal protective barrier of the organs. Supplementation of probiotics alleviated the inflammatory responses and activated selected innate immune defence molecules, without affecting growth. The positive effect of the probiotics was similar regardless of the feed ingredients, suggesting that these probiotics can be utilized as immune regulators to evoke favourable responses on the skin, gills and intestine.

Microbes are known to interact with a variety of organisms belonging to different classes, genera, or species through their own diverse and specific pathways and mechanisms. Such an interaction, which exists between microbes and herbivores like insects, has become a topic of great importance for researchers far and wide. Since such interfaces occur in the form of mutual interactions, which in turn leads to the participating organisms achieving rich and important advantages that are necessary for their survival and development. Much of the research on reciprocal interactions between insects and microbes have focused on bacterial associations with insects, more or less ignoring the fact that interactions between insects and fungi are equally important which usually follow the same mechanisms and pathways as associations between insects and Bacteria.

Actinomycetes are filamentous Gram-positive spore-forming largest dominant microbial population present in the soil. They are free-living rhizosphere colonizing bacteria and producers of bioactive metabolites which helps in improving the fertility of the soil, promote plant growth and development, provide biocontrol action against phytopathogens, and have the ability to withstand various environmental stress. Entophytic Actinobacteria are characterized as those that are contained within the internal structure of plants, making no obvious changes to their hosts. Entophytic actinobacteria consitute a huge part of the rhizosphere. The symbiotic association of Actinomycetes as endophytes have gained more importance because they are considered to be reservoir for potential novel bioactive compounds which finds in important applications in pharmaceutical and agricultural sectors. A notable significant feature of actinobacteria is its ability not to contaminate the environment, take active participation in pesticide degradation, phosphate solubilization, siderophores production, and nitrogen fixation. Microbial resource possesses a wide variety of plant growth potential thereby benefiting green and sustainable agriculture.

Objective Studies on O ne C arbon M etabolism (OCM), Interleukins-10 &-17 (IL-10/-17) & βhCG in pre-eclampsia and its delivery outcome (preterm birth) reveal contradictory results, attributed to clinical heterogeneity (early/late onset pre-eclampsia) or preterm/term birth. Disturbed OCM also influences IL-10 &-17 during pregnancy. We sought to investigate the synergism between OCM and IL-10/-17 mediated immune-regulation through βhCG in Early onset pre-eclampsia (EO-PE) patients, delivering preterm, among North Indian women. Study design Case-control study with a total of 399 pregnant women (EO-PE delivering preterm = 199; Normotensives delivering at term = 200). Maternal genotypes & biochemical estimations along with fetal genotypes on subset (n = 72) pertaining to OCM and IL-10/-17 regulation were assessed. Main outcome measures Association of 1) maternal plasma levels with EO-PE 2) maternal and fetal genotypes with EO-PE. 3) Effect of Hyper-homocysteinemia (surrogate of disturbed OCM) on differential immune regulation (IL10,-17, βhCG) in EO-PE and mode of delivery. Results Hyper-homocysteinemia posed an increased risk of three folds for EO-PE. Both, folate and B12 deficiencies were associated with elevated homocysteine in EO-PE. Further, MTHFR 677TT homozygotes was present only in EO-PE indicating its detrimental role. However, maternal IL17-197AA genotype showed decreased risk for EO-PE. Furthermore, elevated maternal plasma IL-17 along with elevated IL-10 & βhCG were observed in EO-PE. Taken together, altered homocysteine metabolism was associated with high IL10 in EO-PE; and was more pronounced in spontaneous vaginal deliveries as compared to induced/caesarean section deliveries. Conclusions We report homocysteine mediated IL-10 &17 dysregulation and its influence on mode of delivery in EO-PE, possibly through initiation of cervical ripening. Further, these could serve potential biomarkers of EO-PE & its delivery outcome among vulnerable populations with similar nutritional & genetic predispositions.

Ki-67 labelling index is a biomarker which is used across the world to predict the aggressiveness of cancer. To compute the Ki-67 index, pathologists normally count the tumour nuclei from the slide images manually; hence it is timeconsuming and is subject to inter pathologist variability. With the development of image processing and machine learning, many methods have been introduced for automatic Ki-67 estimation. But most of them require manual annotations and are restricted to one type of cancer. In this work, we propose a pooled Otsu's method to generate labels and train a semantic segmentation deep neural network (DNN). The output is postprocessed to find the Ki-67 index. Evaluation of two different types of cancer (bladder and breast cancer) results in a mean absolute error of 3.52%. The performance of the DNN trained with automatic labels is better than DNN trained with ground truth by an absolute value of 1.25%.

The microbial communities inhabited inside the plants exhibit a different lifestyle and play an essential role in the plant growth, development, and diversification like endophytes. Recently they are gaining much popularity due to their capability to produce various bioactive compounds, which are useful in the management of crop diseases. Many of them are reported for plant growth promotion and disease control agents in several agriculturally important crops. These microorganisms can effectively control many plant diseases through the induction of systemic resistance without causing any impact to the environment, unlike synthetic compounds. The main processes involved in the mechanism of disease control have been discussed in different headings, namely, siderophore production, antibiosis, lytic enzyme production, and induced systemic resistance (ISR). The endophytic colonization triggers the ISR in host plants for the reduction of further pathogen attack/disease development through highly diverse mechanisms. The endophytes help plants in such a way that they trigger the defense-related enzymes like L-phenylalanine ammonia lyase, peroxidase and polyphenol oxidase, and pathogenesis-related enzymes such as chitinase and s-1,3 glucanase. This chapter summarizes endophytes and their diverse mechanisms related to the induction of disease resistance against devastating diseases in host plants. This will also describe the challenges associated to the development of bioformulation as a commercial product in the field. Finally, the recent advances made and the future challenges in the area of endophytic research will also be highlighted.

Nanoparticles exhibit different properties compared to their bulk counterpart and among many methods available for synthesis of nanoparticles, biological synthesis is a preferred green synthesis method due to their ecofriendly nature and ease in scale up. Silver Nanoparticles (AgNPs) are very significant due to their potential antimicrobial properties and can be used in wound healing applications. In this work, silver nanoparticles were synthesized with 13% (v/v) betel leaf extract and studied for the effect of pH and temperature and it was found that AGNPs were more stable at room temperature. The synthesized AgNPs were characterized by UV-Vis spectroscopy, FTIR and EDAX. PEGylated AgNPs had antibacterial activity against the pathogens like Bacillus subtilis, Klebsiella pneumonia, Pseudomonas aeruginosa, and Staphylococcus aureus.

A 60 days nursery-based co-culture of Indian white shrimp, Penaeus indicus along with seaweed, Gracilaria tenuistipitata trial was carried out in Recirculatory Aquaculture System (RAS) of 6000 Liters capacity tank (FRP, reinforced fibre plastics) by using biofloc technology (BFT) to evaluate the growth, survival performance and immune potential. Accordingly a completely randomized experiment was designed with six treatments. These treatments were: T1- Static system (Control), T2 - RAS with BFT, T3 - RAS with Gracilaria, T4 - RAS and BFT customized with bacterial consortium, T5 - RAS with BFT + Gracilaria + bacterial consortium, T6 - Static + Gracilaria + BFT (without consortium and without RAS). Shrimp post larvae (0.08 ± 0.03 g) were stocked at a density of 3000 nos./ton. RAS with BFT along with the seaweed and bacterial consortium showed significantly higher growth and survival compared to control (T1) and treatments without BFT (T3). The control (T1) exhibited significantly lower growth, weight gain, specific growth rate, yield and higher FCR value than that of the RAS + BFT (T2), RAS+ seaweed (T3) and RAS + BFT or their combinations with bacterial consortium (T4 and T5). The treatment having seaweed without BFT (T3) showed higher survival than the static control (T1), but no significant difference in growth. The highest ABW of 4.23 ± 0.39 was obtained in T4 (BFT customized with consortium) followed by T5 (BFT + seaweed + bacterial consortium) and lowest was observed in T1 (2.14 ± 0.4). Similarly, the highest survival (92.33 ± 1.52) and production (10.39 ± 0.24 kg/ton) was observed in T5. Significantly higher NH4-N and NO2-N was accumulated in the control (T1) in comparison with other treatment like T4 and T5. Immune parameters viz., PPO activity, Total Serum Protein and Total Hemocyte Count (THC) showed significantly higher values in all the treatments compared to control. This study establishes the novel concept of incorporation of macroalgae in biofloc based RAS improving the production performance and immune response of shrimp during nursery as well as grow-out phase.

PON1 is an High Density Lipoprotein (HDL)-associated esterase. Two common polymorphisms in the PON1 gene, Q192R and L55M substitutions, determine the inter-individual variation in PON1 activity. The association of these polymorphisms with the risk of ischemic stroke remains controversial. In the present study, the role of PON1 Q192R gene polymorphism in ischemic stroke was studied in the Indian population.In the present case-control study, the PON1 Q192R gene polymorphism was screened in ischemic stroke patients (The mean age of stroke presentation was 58.11 ± 15.4 years. A total of 17.4% cases presented with young stroke (45 years age) and 9.52% cases were seen to have a recurrent stroke. The distribution of -192Q/R PON1 gene polymorphism was not seen to differ between cases and controls. The traditional stroke risk factors did not have any effect on the PON1 genotype expression. A multivariate logistic regression analysis was done in order to assess an independent association of age, gender, traditional stroke risk factors, and PON1 polymorphism with acute ischemic stroke. However, neither the RR genotype nor the presence of the R allele was associated with an increase in the risk of acute ischemic stroke (OR [RR genotype]-4.76,PON1 Q192R gene polymorphism is not associated with an increased risk of acute ischemic stroke in the North Indian population. Further studies with a larger sample size are needed before PON1 Q192R gene polymorphism can be considered as a genetic risk factor for ischemic stroke.

Background: Impaired homocysteine me­tabolism (IHM; hyperhomocysteinemia) has been linked with many complex disorders like cardiovascular diseases and immu­nological disturbances. However, studies understanding IHM in light of pro- and anti-atherogeneic markers like Interleukin-17A & -10 (IL-17A & IL-10) and Forkhead box p3 (Foxp3, a master transcription factor) are scarce.Aim: In our present study, we aimed to understand the relation of IHM with plasma IL-17A and IL-10 levels and Foxp3 mRNA expression in peripheral blood mononuclear cells (PBMCs) from an endogamous popula­tion (Jats of Haryana, North India) with high prevalence of IHM without the concur­rence of significant adverse cardiovascular outcomes.Methods: Forty (40) clinically healthy individuals, unrelated up to first cousins, were recruited and were subjected to demographic, physiological and anthropometric profiling, followed by intravenous blood sample collection (fasting) and lipid profiling. Plasma homocysteine levels were estimated and individuals with homocysteine levels ≥ 15umol/L and

Astrocytes, the “star-shaped” glial cells, are appealing gene-delivery targets to treat neurological diseases due to their diverse roles in brain homeostasis and disease. Cationic polymers have successfully delivered genes to mammalian cells and hence present a viable, non-immunogenic alternative to widely used viral vectors. In this study, we investigated the gene delivery potential of a series of arginine- and polyethylene glycol-modified, siloxane-based polyethylenimine analogs in primary cultured human neural cells (neurons and astrocytes) and in mice. Plasmid DNAs encoding luciferase reporter were used to measure gene expression. We hypothesized that polyplexes with arginine would help in cellular transport of the DNA, including across the blood-brain barrier; polyethylene glycol will stabilize polyethylenimine and reduce its toxicity while maintaining its DNA-condensing ability. Polyplexes were non-toxic to human neural cells and red blood cells. Cellular uptake of polyplexes and sustained gene expression were seen in human astrocytes as well as in mouse brains post-intravenous-injections. The polyplexes also delivered and expressed genes driven by astrocyte-restricted glial fibrillary acidic protein promoters, which are weaker than viral promoters. To our knowledge, the presented work validates a biocompatible and effective polymer-facilitated gene-delivery system for both human brain cells and mice for the first time. Keywords: human neural cells, polyplexes, GFAP promoters, intravenous gene delivery, gene therapy, blood-brain barrier

The fat mass and obesity associated (FTO) rs9939609 gene polymorphism is most widely studied in terms of obesity in various populations. Recently, the prevalence of obesity has been reported to be very high among the North-Eastern State of India. The major aim of the present study is to understand the extent of FTO rs9939609 gene polymorphism and its association with obesity among the two North-East Indian tribal populations with similar East Asian ancestry. Somatometric data and fasting blood sample were collected from 521 tribal individuals (258 Liangmai and 263 Mizo) of Manipur after obtaining written informed consent. Genotyping of FTO rs9939609 single nucleotide polymorphism (SNP) was done using restriction fragment length polymorphism method for PCR-amplified fragments. Both the presently studied populations were not following Hardy-Weinberg law. The prevalence of obesity and minor allele frequency of FTO rs9939609 polymorphism was found to be significantly higher among the Mizo tribe compared to that of Liangmai. The selected polymorphism was found to be significantly associated with obesity (BMI) only among the Liangmai tribe (Odds ratio-3.0; 95% CI-1.4, 6.4; p-0.003), after adjusting for age and occupation. Age-cohort wise distribution and absolute fitness analysis indicated the lower fitness of minor allele in the higher age group among the Liangmai tribe. To the best of the author's knowledge this is the first study, associating FTO rs9939609 gene polymorphism and obesity in the North-eastern Indian tribal populations with East-Asian ancestry. This study revealed the FTO rs9939609 polymorphism is observed to be associated with obesity only among the Liangmai tribe not among the Mizo tribe. The differential distribution and association observed in the two selected tribes, inhabited in a similar geographical region, could be attributed to differences in their migratory histories in terms of both route and time of settlement.

L-Glutaminase is majorly produced by microorganism including bacteria, yeast and fungi. It mainly catalyzes the hydrolysis of gamma-amido bond of L-glutamine. In the present investigation, the potent marine isolate, Bacillus subtilis JK-79 producing L-glutaminase was evaluated for the maximum L-glutaminase production by solid state fermentation (SSF). In this context, different agro-industrial residues reported in literature were tested and among them, wheat bran gave maximum L-glutaminase production (236.67 U/ml) and protein concentration (6.89 mg/ml). Statistical optimization of media components and culture conditions were successfully employed to markedly enhance the L-glutaminase production under SSF by marine B. subtilis JK-79. Optimization was sequentially performed from one factor at a time (OFAT), followed by Plackett and Burman Design (PBD) and response surface methodology (RSM). With the help of PB design, three significant factors such as moisture content, pH and L-glutamine were identified to significantly affect the L-glutaminase production. These three independent variables were then optimized by central composite design (CCD) of RSM. Maximum L-glutaminase production of 672.28 U/ml under flask condition was obtained at the predicted optimal values of moisture content of 62.5% (w/w), pH of 7.1 and glutamine of 2.44% (w/v). The maximum experimental L-glutaminase production was 680.8 U/ml, whereas the predicted value for L-glutaminase production was 672.28 U/ml, indicating a strong agreement between them. Statistical optimization has enhanced the production of the enzyme up to 2.88 fold as compared to the basal wheat bran medium. Thus, application of PBD and RSM for optimization studies proves to be an effective method for improving the L-glutaminase production and also understanding the interaction effects between the factors with minimum number of experiments. Key words: Bacillus subtilis JK-79, L-glutaminase, Plackett-Burman design, response surface methodology, wheat bran.

Objective The objective of the study is to investigate the association of interleukin-6 (IL6) promoter single-nucleotide polymorphisms rs1800797 (-597 G/A) and rs1800796 (-572 G/C) with obesity or metabolic syndrome in Mexican-Americans. Methods The rs1800797 and rs1800796 single-nucleotide polymorphisms were genotyped in Mexican-Americans (n = 437) from South Texas, and results were correlated with measures of obesity and metabolic syndrome including body mass index, waist circumference, blood pressure, cholesterol, triglycerides, glucose, liver enzymes, plasma IL6 and high-sensitive C-reactive protein (hs-CRP). Results Significant associations were found for the rs1800796 variant with increased waist circumference, insulin resistance, lower IL6 levels and higher hs-CRP levels. The rs1800797 variant showed no associations with metabolic traits but was associated with higher IL6 levels and lower hs-CRP levels. Conclusions Findings in this study support the anti-inflammatory, anti-obesity and glucose homeostatic roles of IL6 in Mexican-American youth.

Aim The present study aims to understand the role of methylenetetrahydrofolate reductase (MTHFR C677T) gene polymorphism in preterm premature rupture of membranes. Methods The preterm premature rupture of membranes (N = 90) cases and their gestation matched controls (N = 122) were recruited from Lady Hardinge Medical College and Smt. Sucheta Kriplani Hospital. Fasting blood sample (~5 ml) was drawn and genotypic analysis of MTHFR C677T polymorphism was performed by PCR-RFLP in all the PPROM cases and controls. Fetal genotypic analysis of MTHFR C677T was performed using placental DNA in PPROM cases (N = 16) and controls (N = 23). Results The genotypic frequency distribution of MTHFR C677T gene polymorphism of normal homozygous CC genotype was found to be similar among cases (76.67%) and controls (72.27%). Further, the analysis revealed a lower percentage of mutant heterozygotes (CT = 23.33%) among cases as compared to controls (CT = 27.73%). The cases and controls were not found to carry homozygous mutant TT genotype. Conclusion MTHFR C677T gene polymorphism does not seem to play a major role in association with preterm premature rupture of membranes in the North Indian women.

Background : Hyperglycemia and oxidative stress are hallmarks of diabetes mellitus (DM). Excessive oxidative stress is implicated in diabetic pathogenesis when endogenous antioxidants are defective. Objective: The present study evaluates the effects of anthocyanins present in the petals of Hibiscus rosa- sinensis on oxidative stress and antioxidant status in streptozotocin-induced diabetic rats. Materials and methods: Diabetes was induced in male Sprague-Dawley rats by a single intraperitoneal injection (30mg/kg) of streptozotocin. Hibiscus rosa sinensis anthocyanins (HA) extract (50 mg/kg body weight) orally administered to diabetic rats for 30 days. Results compared with diabetic rats provided with the standard drug metformin (150 mg/kg body weight). Results: Altered levels of glucose, glycated hemoglobin, toxicity markers and lipid profile in serum were significantly modulated upon the administration of HA in diabetic rats. A supplementation of HA to diabetic rats reduced oxidative stress, as well as increased the levels of antioxidant enzymes in the liver. The present study demonstrates that HA has a protective effect on diabetic rats Conclusion: The present study indicates that Hibiscus anthocyanin supplementation could protect diabetic rats' livers by protecting the hepatocytes from oxidative stress and increasing the antioxidant enzymes' activity. Keywords: Diabetes mellitus, Hibiscus rosa sinensis anthocyanins, Oxidative stress

Advances in molecular genetical research have revealed a new platform for studying the configuration and activity correlations of dopamine receptor D4 (DRD4) gene in the non-human primates and human. Among the other five dopamine receptor genes, dopamine receptor D4 (DRD4) gene has variable number of tandem repeats which are polymorphic and located in the third cytoplasmic loop of the receptor. These polymorphism are expressed in the repeat numbers of 48-base pair (bp) sequence coding for 16 amino acids. This study is designed to observe the genetic polymorphism of dopamine receptor D4 gene within the ten Indian rhesus macaques (Macaca mulatta mulatta). This research is also planned to compare the genetic sequences among the Indian rhesus macaque DRD4 genetic sequences of our recent study, rhesus macaque DRD4 gene reference sequence provided by ENSEMBL genome browser and human DRD4 gene reference sequence provided by National Center for Biotechnology Information (NCBI), USA. In our study, only DRD4 5-repeat allele variant is observed in all the ten selected Indian rhesus macaques. Sequencing data of DRD4 gene of these rhesus macaques indicate that rhesus macaques exhibit 48-bp tandem repeats in the DRD4 receptor gene which is similar to humans and there is intraspecies variability within the rhesus macaque DRD4 genetic sequences.

A novel bio-physical approach for treating well water contaminated with perchlorate (ClO4¯) at 15 mg/L is reported in this study. In this process, the ClO4¯ was initially treated in an anaerobic fixed-film bioreactor (55 L), followed by a ceramic Micro-Filtration (MF) unit (1.5 μm pore size, 0.12 m2 surface area) and a Reverse Osmosis (RO) unit (0.38 m2 surface area) connected in series. The bioreactor inoculated with a ClO4¯ reducing bacterium Serratia marcescens (Gen bank no. JQ807993) removed ~97% of the ClO4¯ using acetate as substrate (acetate/ClO4¯ ratio = 4). Subsequently, the MF and RO units removed ClO4¯ to

Nowadays, the area under onion production through seeds is increasing in India and especially in Tamil Nadu. Onion (Allium cepa L.) seeds are naturally less viable and more hygroscopic than seeds of most common vegetables. Moreover, in most areas, storage of onion seeds in improper or adverse conditions results in a serious problem called seed deterioration, which is characterised by loss of viability, loss of vigour, and loss of seed quality. Therefore, there is a significant demand for quality onion seeds in the seed chain. Hence, here, the literature pertaining to onion seed viability, seed deterioration and seed quality improvements have been reviewed. Scrutiny of the literature reveals that storage of onion seeds at low seed moisture content, low storage temperature and low relative humidity and exploitation of seed invigoration treatments like hydration-dehydration would significantly help in delaying the seed deteriorative processes and, thereby, increasing the viability and longevity of se...

Peroxisome proliferated receptors (PPARs) are important targets for drugs used in the treatment of various metabolic disorders. We have reported 4-hydroxy benzylidene derivatives of thiazolidine-2,4-diones with reversed orientation in the active site of PPARγin our earlier communication. With the reversed conformation of TZD, fitting the established pharmacophore was discussed. The current simulation studies revolves around the 2,4-dihydroxy benzylidene derivatives expecting H-bonding interactions similar to Rosiglitazone’s acidic head. The docking protocol was validated by enrichment studies using decoys and actives from DUD. Designed compounds were showing interactions similar to the actives in the top 10%, 5% and 1%. They also exhibited H-bonding interactions similar to their monohydroxy counterparts without any additional H-bonding interactions due to introduction of additional hydroxy functional groups. Predicted ADMET report reveals that 5 molecules show favourable hERG-I and -II properties and nine compounds show best metabolic stability.

Advancement of RNAi-based therapeutics depends on effective delivery to the site of protein synthesis. Although intravenously administered, multi-component delivery vehicles have enabled small interfering RNA (siRNA) delivery and progression into clinical development, advances of single-component, systemic siRNA delivery have been challenging. In pre-clinical models, attachment of a triantennary N -acetylgalactosamine (GalNAc) ligand to an siRNA mediates hepatocyte uptake via the asialoglycoprotein receptor enabling RNAi-mediated gene silencing. In this phase 1 study, we assessed translation of this delivery approach by evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of a GalNAc-siRNA conjugate, revusiran, targeting transthyretin (TTR). Subjects received a placebo or ascending doses of revusiran subcutaneously ranging from 1.25–10 mg/kg in the single and 2.5–10 mg/kg in the multiple ascending dose phases. Revusiran was generally well tolerated, with transient, mild to moderate injection site reactions the most common treatment-emergent adverse events. Doses of 2.5–10 mg/kg revusiran elicited a significant reduction of serum TTR versus the placebo (p 0.01), with mean TTR reductions of approximately 90% observed with multiple dosing. These results demonstrate translation of this novel delivery platform, enabling clinical development of subcutaneously administered GalNAc-siRNAs for liver-based diseases.

The mitochondria are highly dynamic organelles specialized in metabolizing energy for the proper functioning of all cells. These organelles go through biogenesis cycles alternating between the fusion and fission of mitochondrial compartments, and adapt their morphology to the metabolic status of the cell, optimizing its function. During fusion, the mitochondria create networks that are essential during high mitochondrial function and energy usage. Conversely, fission is predominant in resting cells, during low energy demand and accountable for the removal of damaged mitochondria. Interleukin-6 (IL-6), a widely known inflammatory cytokine, has begun to be recognized for its role in the regulation of metabolism and mitochondrial function. Since normally functioning adipocytes are crucial in promoting metabolic health, in this study, we investigated the direct effect of IL-6 on mitochondrial morphology in adipocytes. To study the effect of IL-6 on mitochondria, we used 3T3-L1 pre-adipocytes and adipocytes as our cell culture model. On the 10th day after inducing differentiation, when majority of the cells showed the rounded, lipid droplet laden characteristics of adipocytes, the cells were treated with 200 mg/mL of IL-6 for 48 and 96 hours. The fluorescent dye, MitoTracker, was used to stain the mitochondria for imaging using confocal laser microscopy. Pre-adipocytes and adipocytes treated with IL-6 presented a more fragmented and punctate mitochondrial morphology compared to the control, suggesting that IL-6 promotes the fission rather than the fusion state of mitochondrial dynamics. A decrease in florescence intensity, which indicates decreased mitochondrial membrane potential, was observed preliminarily in some of the treatments. Overall, our results demonstrate that IL-6 may affect mitochondrial biogenesis, mitochondrial function and thus metabolic function in pre-adipocytes and adipocytes. In future, we will investigate IL-6 effects on mitochondrial function and gene expression.

The overall lethality/morbidity of ionizing radiation exposure involves multiple forms of inhibitory or cytotoxic effects that may manifest in different tissues with a varying dose and time response. One of the major systemic effects leading to lethality of radiation includes its suppressive effect on hematopoiesis, which could be observed even at doses as low as 1-2 Gy, whereas effects on gastrointestinal and nervous systems appear at relatively higher doses in the same order. This article reviews the effects of radiation on the three distinct stages of erythropoiesis-formation of erythroid progenitor cells, differentiation of erythroid precursor cells, and terminal maturation. During these stepwise developmental processes, erythroid progenitor cells undergo rapid expansion to form terminally differentiated red blood cells that are continuously replenished from bone marrow into the circulating peripheral blood stream. Cellular radiation response depends upon many factors such as cell lineage, rate of proliferation, and differentiation status. Therefore, we discuss radiation-induced alterations during the progenitor, precursor, and terminal maturation stages and the implications thereof. Since biomarkers of ionizing radiation exposure in human populations are of great interest for assessing normal tissue injury as well as for biodosimetry in the event of accidental or incidental radiation exposures, we also highlight blood-based biomarkers that have potential utility for medical management.

The morphogenesis of the nervous system requires coordinating the specification and differentiation of neural precursor cells, the establishment of neuroepithelial tissue architecture and the execution of specific cellular movements. How these aspects of neural development are linked is incompletely understood. Here we inactivate a major regulator of embryonic neurogenesis - the Delta/Notch pathway - and analyze the effect on zebrafish central nervous system morphogenesis. While some parts of the nervous system can establish neuroepithelial tissue architecture independently of Notch, Notch signaling is essential for spinal cord morphogenesis. In this tissue, Notch signaling is required to repress neuronal differentiation and promote neuroepithelial apico-basal polarity. Concomitant with a loss of their neuroepithelial properties, Notch signaling deficient cells also alter their morphogenetic behavior. In the wild-type zebrafish neural tube, cells divide at the organ midline to contribute one daughter cell to each organ half. Notch deficient animals fail to display this behavior and therefore form a misproportioned spinal cord. Taken together, our findings show that Notch signaling governs not only the cellular composition but also the morphogenetic shaping of the zebrafish spinal cord.