Omics-driven utilization of wild relatives for empowering pre-breeding in pearl millet.

MAIN CONCLUSION: Pearl millet wild relatives harbour novel alleles which could be utilized to broaden genetic base of cultivated species. Genomics-informed pre-breeding is needed to speed up introgression from wild to cultivated gene pool in pearl millet. Rising episodes of intense biotic and abiotic stresses challenge pearl millet production globally. Wild relatives provide a wide spectrum of novel alleles which could address challenges posed by climate change. Pre-breeding holds potential to introgress novel diversity in genetically narrow cultivated Pennisetum glaucum from diverse gene pool. Practical utilization of gene pool diversity remained elusive due to genetic intricacies. Harnessing promising traits from wild pennisetum is limited by lack of information on underlying candidate genes/QTLs. Next-Generation Omics provide vast scope to speed up pre-breeding in pearl millet. Genomic resources generated out of draft genome sequence and improved genome assemblies can be employed to utilize gene bank accessions effectively. The article highlights genetic richness in pearl millet and its utilization with a focus on harnessing next-generation Omics to empower pre-breeding.

Probing the potential of bioactive compounds of millets as an inhibitor for lifestyle diseases: molecular docking and simulation-based approach.

Millets are becoming more popular as a healthy substitute for people with lifestyle disorders. They offer dietary fiber, polyphenols, fatty acids, minerals, vitamins, protein, and antioxidants. The nutritional importance of millets leads to the present in-silico study of selective bioactive compounds docked against the targets of lifestyle diseases, viz., diabetes, hypertension, and atherosclerosis using molecular docking and molecular simulations approach. Pharmacokinetic analysis was also carried out to analyse ADME properties and toxicity analysis, drug-likeliness, and finally target prediction for new targets for uncharacterized compounds or secondary targets for recognized molecules by Swiss Target Prediction was also done. The docking results revealed that the bioactive compound flavan-4-ol, among all the 50 compounds studied, best docked to all the four targets of lifestyle diseases, viz., Human dipeptidyl peptidase IV (-5.94 kcal mol-1 binding energy), Sodium-glucose cotransporter-2 (-6.49 kcal mol-1) diabetes-related enzyme, the Human angiotensin-converting enzyme (-6.31 kcal mol-1) which plays a significant role in hypertension, and Proprotein convertase subtilisin kexin type 9 (-4.67 kcal mol-1) for atherosclerosis. Molecular dynamics simulation analysis substantiates that the flavan-4-ol forms a better stability complex with all the targets. ADMET profiles further strengthened the candidature of the flavan-4-ol bioactive compound to be considered for trial as an inhibitor of targets DPPIV, SGLT2, PCSK9, and hACE. We suggest that more research be conducted, taking Flavon-4-ol into account where it can be used as standard treatment for lifestyle diseases.

Elucidating the interactive impact of tillage, residue retention and system intensification on pearl millet yield stability and biofortification under rainfed agro-ecosystems.

Micronutrient malnutrition and suboptimal yields pose significant challenges in rainfed cropping systems worldwide. To address these issues, the implementation of climate-smart management strategies such as conservation agriculture (CA) and system intensification of millet cropping systems is crucial. In this study, we investigated the effects of different system intensification options, residue management, and contrasting tillage practices on pearl millet yield stability, biofortification, and the fatty acid profile of the pearl millet. ZT systems with intercropping of legumes (cluster bean, cowpea, and chickpea) significantly increased productivity (7-12.5%), micronutrient biofortification [Fe (12.5%), Zn (4.9-12.2%), Mn (3.1-6.7%), and Cu (8.3-16.7%)], protein content (2.2-9.9%), oil content (1.3%), and fatty acid profile of pearl millet grains compared to conventional tillage (CT)-based systems with sole cropping. The interactive effect of tillage, residue retention, and system intensification analyzed using GGE statistical analysis revealed that the best combination for achieving stable yields and micronutrient fortification was residue retention in both (wet and dry) seasons coupled with a ZT pearl millet + cowpea-mustard (both with and without barley intercropping) system. In conclusion, ZT combined with residue recycling and legume intercropping can be recommended as an effective approach to achieve stable yield levels and enhance the biofortification of pearl millet in rainfed agroecosystems of South Asia.

Structure-activity relationships of dihydropyrimidone inhibitors against native and auto-processed human neutrophil elastase.

BACKGROUND: Human neutrophil elastase (HNE) is a key driver of systemic and cardiopulmonary inflammation. Recent studies have established the existence of a pathologically active auto-processed form of HNE with reduced binding affinity against small molecule inhibitors. METHOD: AutoDock Vina v1.2.0 and Cresset Forge v10 software were used to develop a 3D-QSAR model for a series of 47 DHPI inhibitors. Molecular Dynamics (MD) simulations were carried out using AMBER v18 to study the structure and dynamics of sc (single-chain HNE) and tcHNE (two-chain HNE). MMPBSA binding free energies of the previously reported clinical candidate BAY 85-8501 and the highly active BAY-8040 were calculated with sc and tcHNE. RESULTS: The DHPI inhibitors occupy the S1 and S2 subsites of scHNE. The robust 3D-QSAR model showed acceptable predictive and descriptive capability with regression coefficient of r2 = 0.995 and cross-validation regression coefficient q2 = 0.579 for the training set. The key descriptors of shape, hydrophobics and electrostatics were mapped to the inhibitory activity. In auto-processed tcHNE, the S1 subsite undergoes widening and disruption. All the DHPI inhibitors docked with the broadened S1'-S2' subsites of tcHNE with lower AutoDock binding affinities. The MMPBSA binding free energy of BAY-8040 with tcHNE reduced in comparison with scHNE while the clinical candidate BAY 85-8501 dissociated during MD. Thus, BAY-8040 may have lower inhibitory activity against tcHNE whereas the clinical candidate BAY 85-8501 is likely to be inactive. CONCLUSION: SAR insights gained from this study will aid the future development of inhibitors active against both forms of HNE.

Achieving nutritional security in India through iron and zinc biofortification in pearl millet (Pennisetum glaucum (L.) R. Br.).

The health problems caused by iron (Fe) and zinc (Zn) deficiency plague developing and underdeveloped countries. A vegetarian person mainly depends on cereal based diet with low quantity of Fe and Zn. Biofortification is an economical and sustainable approach to challenge the micronutrient malnutrition problem globally. Pearl millet (Pennisetum glaucum (L.) R. Br.) is one of the nutri-cereals and mostly grown under hot, dry conditions on infertile soils of low water-holding capacity, where other crops generally fail. It contains anti-nutrient compounds like phytic acid and polyphenols which reduce the mineral bioavailability because of their chelating properties. Biofortification of pearl millet is like a double-edged sword which cuts down the economic burden and simultaneously supplies required nutrition to the poor, offering a great scope for food security as well as nutritional security. With this background, this review focus on biofortification of grain Fe and Zn content in pearl millet. Genetic research on Fe and Zn uptake and accumulation in pearl millet grain is crucial in identifying the 'bottlenecks' in biofortification. The review also reveals the need and strategies for increasing bioavailability of Fe and Zn in humans by increasing promoters and decreasing anti-nutritional factors in pearl millet.

No-Tillage with Residue Retention and Foliar Sulphur Nutrition Enhances Productivity, Mineral Biofortification and Crude Protein in Rainfed Pearl Millet under Typic Haplustepts: Elucidating the Responses Imposed on an Eight-Year Long-Term Experiment.

Yield limitation and widespread sulphur (S) deficiency in pearl-millet-nurturing dryland soils has emerged as a serious threat to crop productivity and quality. Among diverse pathways to tackle moisture and nutrient stress in rainfed ecologies, conservation agriculture (CA) and foliar nutrition have the greatest potential due to their economic and environmentally friendly nature. Therefore, to understand ammonium thiosulphate (ATS)-mediated foliar S nutrition effects on yield, protein content, mineral biofortification, and sulphur economy of rainfed pearl millet under diverse crop establishment systems, a field study was undertaken. The results highlighted that pearl millet grain and protein yield was significantly higher under no-tillage +3 t/ha crop residue mulching (NTCRM) as compared to no-tillage without mulch (NoTill) and conventional tillage (ConvTill), whereas the stover yield under NTCRM and ConvTill remained at par. Likewise, grain and stover yield in foliar S application using ATS 10 mL/L_twice was 19.5% and 13.2% greater over no S application. The sulphur management strategy of foliar-applied ATS 10 mL/L_twice resulted in significant improvement in grain protein content, protein yield, micronutrient fortification, and net returns (₹ 54.6 × 1000) over the control. Overall, ATS-mediated foliar S nutrition can be an alternate pathway to S management in pearl millet for yield enhancement, micronutrient biofortification and grain protein content increase under ConvTill, as well as under the new NTCRM systems.

Machine Learning for Prediction of Drug Targets in Microbe Associated Cardiovascular Diseases by Incorporating Host-pathogen Interaction Network Parameters.

Host-pathogen interactions play a crucial role in invasion, infection, and induction of immune response in humans. In this work, four machine learning algorithms, namely Logistic regression, K-nearest neighbor, Support Vector Machine, and Random Forest were implemented for the classification of drug targets. The algorithms were trained using 3400 hosts and 3800 pathogen drug and non-drug target proteins as learning instances. For each protein, 68 pathogen and 73 host features were computed that included sequence, structure, biological and host-pathogen network centrality characteristics. The Random Forest classifier model achieved the best accuracy after 10-fold cross-validation. 99 % accuracy was achieved with a ROC-AUC score of 0.99±0.01 for both pathogen and host training sets. The Eigenvector Centrality of host-pathogen interactions and host-host interactions was the top feature in performing classification of pathogen and host targets respectively. Other features important for classification were the presence of catalytic and binding sites, low instability/aliphatic index, and cellular location. The Random Forest classifier was then used for prediction of drug targets involved in Microbe Associated Cardiovascular Diseases. 331 host and 743 pathogen proteins were predicted as drug targets by the random forest model and can be validated experimentally for therapeutic intervention in Microbe Associated Cardiovascular Diseases.

Deciphering Genotype-By-Environment Interaction for Target Environmental Delineation and Identification of Stable Resistant Sources Against Foliar Blast Disease of Pearl Millet.

Once thought to be a minor disease, foliar blast disease of pearl millet, caused by Magnaporthe grisea, has recently emerged as an important biotic constraint for pearl millet production in India. The presence of a wider host range as well as high pathogenic heterogeneity complicates host-pathogen dynamics. Furthermore, environmental factors play a significant role in exacerbating the disease severity. An attempt was made to unravel the genotype-by-environment interactions for identification and validation of stable resistant genotypes against foliar blast disease through multi-environment testing. A diversity panel consisting of 250 accessions collected from over 20 different countries was screened under natural epiphytotic conditions in five environments. A total of 43 resistant genotypes were found to have high and stable resistance. Interestingly, most of the resistant lines were late maturing. Combined ANOVA of these 250 genotypes exhibited significant genotype-by-environment interaction and indicated the involvement of crossover interaction with a consistent genotypic response. This justifies the necessity of multi-year and multi-location testing. The first two principal components (PCs) accounted for 44.85 and 29.22% of the total variance in the environment-centered blast scoring results. Heritability-adjusted genotype plus genotype × environment interaction (HA-GGE) biplot aptly identified "IP 11353" and "IP 22423, IP 7910 and IP 7941" as "ideal" and "desirable" genotypes, respectively, having stable resistance and genetic buffering capacity against this disease. Bootstrapping at a 95% confidence interval validated the recommendations of genotypes. Therefore, these genotypes can be used in future resistance breeding programs in pearl millet. Mega-environment delineation and desirability index suggested Jaipur as the ideal environment for precise testing of material against the disease and will increase proper resource optimization in future breeding programs. Information obtained in current study will be further used for genome-wide association mapping of foliar blast disease in pearl millet.

Multi-Environment Quantitative Trait Loci Mapping for Grain Iron and Zinc Content Using Bi-parental Recombinant Inbred Line Mapping Population in Pearl Millet.

Pearl millet is a climate-resilient, nutritious crop with low input requirements that could provide economic returns in marginal agro-ecologies. In this study, we report quantitative trait loci (QTLs) for iron (Fe) and zinc (Zn) content from three distinct production environments. We generated a genetic linkage map using 210 F6 recombinant inbred line (RIL) population derived from the (PPMI 683 × PPMI 627) cross using genome-wide simple sequence repeats (SSRs). The molecular linkage map (seven linkage groups) of 151 loci was 3,273.1 cM length (Kosambi). The content of grain Fe in the RIL population ranged between 36 and 114 mg/Kg, and that of Zn from 20 to 106 mg/Kg across the 3 years (2014-2016) at over the three locations (Delhi, Dharwad, and Jodhpur). QTL analysis revealed a total of 22 QTLs for grain Fe and Zn, of which 14 were for Fe and eight were for Zn on three consecutive years at all locations. The observed phenotypic variance (R 2) explained by different QTLs for grain Fe and Zn content ranged from 2.85 (QGFe.E3.2014-2016_Q3) to 19.66% (QGFe.E1.2014-2016_Q3) and from 2.93 (QGZn.E3.2014-2016_Q3) to 25. 95% (QGZn.E1.2014-2016_Q1), respectively. Two constitutive expressing QTLs for both Fe and Zn co-mapped in this population, one on LG 2 and second one on LG 3. Inside the QTLs candidate genes such as Ferritin gene, Al3+ Transporter, K+ Transporters, Zn2+ transporters and Mg2+ transporters were identified using bioinformatics approaches. The identified QTLs and candidate genes could be useful in pearl millet population improvement programs, seed, restorer parents, and marker-assisted selection programs.

Network analysis of host-pathogen protein interactions in microbe induced cardiovascular diseases.

Large-scale visualization and analysis of HPIs involved in microbial CVDs can provide crucial insights into the mechanisms of pathogenicity. The comparison of CVD associated HPIs with the entire set of HPIs can identify the pathways specific to CVDs. Therefore, topological properties of HPI networks in CVDs and all pathogens was studied using Cytoscape3.5.1. Ontology and pathway analysis were done using KOBAS 3.0. HPIs of Papilloma, Herpes, Influenza A virus as well as Yersinia pestis and Bacillus anthracis among bacteria were predominant in the whole (wHPI) and the CVD specific (cHPI) network. The central viral and secretory bacterial proteins were predicted virulent. The central viral proteins had higher number of interactions with host proteins in comparison with bacteria. Major fraction of central and essential host proteins interacts with central viral proteins. Alpha-synuclein, Ubiquitin ribosomal proteins, TATA-box-binding protein, and Polyubiquitin-C &B proteins were the top interacting proteins specific to CVDs. Signaling by NGF, Fc epsilon receptor, EGFR and ubiquitin mediated proteolysis were among the top enriched CVD specific pathways. DEXDc and HELICc were enriched host mimicry domains that may help in hijacking of cellular machinery by pathogens. This study provides a system level understanding of cardiac damage in microbe induced CVDs.

Cost and Utilization with Enrollment in a Medical Home for Individuals with an Autism Spectrum Disorder and/or Intellectual Disability.

Individuals with intellectual and/or developmental disabilities (IDD) tend to incur high health care costs. The Neurobehavior HOME Program (HOME) is an interdisciplinary program that cares for this population. This study will evaluate the health care costs and utilization of individuals during their first year of enrollment in HOME and identify factors associated with higher cost and utilization. Secondary analysis of claims data were used to identify cost and utilization. Generalized linear regression and negative binomial regression were used to calculate utilization and cost. The mean total cost of care during the initial year of enrollment (n=239) per individual was $11,095.87, with $4,640.83 attributed to inpatient care. Those with diabetes (p=0.01), epilepsy (p=0.02), or mood disorders (p=0.03) were more likely to be admitted to the hospital and utilize the emergency department. These findings will enable systems and payers to better construct health care delivery reforms for this high-need population.

MorCVD: A Unified Database for Host-Pathogen Protein-Protein Interactions of Cardiovascular Diseases Related to Microbes.

Microbe induced cardiovascular diseases (CVDs) are less studied at present. Host-pathogen interactions (HPIs) between human proteins and microbial proteins associated with CVD can be found dispersed in existing molecular interaction databases. MorCVD database is a curated resource that combines 23,377 protein interactions between human host and 432 unique pathogens involved in CVDs in a single intuitive web application. It covers endocarditis, myocarditis, pericarditis and 16 other microbe induced CVDs. The HPI information has been compiled, curated, and presented in a freely accessible web interface ( http://morcvd.sblab-nsit.net/About ). Apart from organization, enrichment of the HPI data was done by adding hyperlinked protein ID, PubMed, gene ontology records. For each protein in the database, drug target and interactors (same as well as different species) information has been provided. The database can be searched by disease, protein ID, pathogen name or interaction detection method. Interactions detected by more than one method can also be listed. The information can be presented in tabular form or downloaded. A comprehensive help file has been developed to explain the various options available. Hence, MorCVD acts as a unified resource for retrieval of HPI data for researchers in CVD and microbiology.

Comparative study of qualitative and quantitative methods to determine toxicity level of Aspergillus flavus isolates in maize.

An attempt was made to compare between easy and inexpensive qualitative method (ammonia vapour test) and analytical methods (thin layer chromatography and enzyme-linked immunosorbent assay) for identification of aflatoxigenic isolates of Aspergillus flavus in maize. In this comparative study the toxicity level of A. flavus isolates exhibited 100% agreement among ammonia vapour test, ELISA and TLC for highly toxigenic (>2000 ppb) and toxigenic (501-2000 ppb) isolates while 88.5% agreement observed for least toxic (<20 ppb) isolates. In ammonia vapour test 51% of A. flavus isolates showed creamish or no colour change corresponding to least toxic/atoxic (<20ppb) category estimated by ELISA. Similarly 22% highly toxic isolates exhibited plum red colour, 12% moderately toxic indicated pink colour and 10% toxic isolates showed red colour. However, 11.5% isolates were found to be false positive in cream colour category (least toxic) and 28.5% false negatives in pink colour (moderately toxic) category. The isolates from different agroclimatic zones of maize in India showed high variability for aflatoxin B1 (AFB1) production potential ranging from 0.214-8116.61 ppb. Toxigenic potential of Aspergillus flavus isolates in culture was further validated by inoculating maize grain sample with four different isolates with varied toxin producing ability. With good agreement percentage between cultural and analytical methods the study concludes the ammonia vapour test to be easy, inexpensive, reliable and time saving method that can be used for segregating or pre-screening of contaminated samples from bulk food/feed stock.

Costs of management of bile duct injuries.

BACKGROUND: Only a few studies address the financial impact of the management of bile duct injuries (BDI). This study was aimed to assess the cost of BDI sustained during cholecystectomy. METHODS: Patients who underwent surgical repair for post cholecystectomy BDI and due for routine follow up between August 2006 and September 2007 were called for an interview. RESULTS: 47 patients were interviewed. There were 39 (83%) women and 8 (17%) men. The median direct cost was US$ 1626 (451-11,009); 73,983 (20,521-500,910). The median indirect cost was US$ 312 (26-2,708); 14,196 (1,183-123,214). Total median cost was US$ 2,045 (488-12,369); 93,046 (22,204-562,790). The median total costs of management of BDI was 9.98 times the costs of a cholecystectomy at our centre (US$ 205); (9,328) and was 8.41 times the median monthly income of the patients (US$ 243); (11,057). CONCLUSIONS: Our results will help the hospital administrators and the insurance agencies to calculate and revise the packages and premium for cholecystectomy so that the extra cost of a possible BDI is evenly distributed.

Synthesis, anti-inflammatory, analgesic and kinase (CDK-1, CDK-5 and GSK-3) inhibition activity evaluation of benzimidazole/benzoxazole derivatives and some Schiff's bases.

A series of N-(acridin-9-yl)-4-(benzo[d]imidazol/oxazol-2-yl) benzamides has been synthesized by the condensation of 9-aminoacridine derivatives with benzimidazole or benzoxazole derivatives. Condensation of 2-hydroxy naphthaldehyde with functionalized diamines leads to the formation of Schiff's bases and not imidazole derivatives. All these compounds were characterized by correct FT-IR, (1)H NMR, MS and elemental analyses. These compounds were screened for anti-inflammatory, analgesic and kinase (CDK-1, CDK-5 and GSK-3) inhibition activities. Compounds 11 and 7e(f) showed good anti-inflammatory (35.8% at 50 mg/kg po) activity and good analgesic activity (60% at 50 mg/kg po), respectively. Compound 3b showed significant in vitro activity against CDK-5 (IC(50)=4.6 microM) and CDK-1(IC(50)=7.4 microM) and compound 3a showed moderate CDK-5 inhibitory activity (IC(50)=7.5 microM). The other compounds showed moderate anti-inflammatory and analgesic activities.

Synthesis, anti-inflammatory and analgesic activities evaluation of some mono, bi and tricyclic pyrimidine derivatives.

3-Aminobenzonitrile and 2-amino-4-phenyl thiazole on condensation with 4-isothiocyanato-4-methyl pentane-2-one gave condensed monocyclic pyrimidine derivatives 1 and 2, 3, respectively. Condensation of 3-aminopropyl imidazole with 3-isothiocyantobutanal gave condensed monocyclic pyrimidine derivative 4. Bicyclic pyrimidine derivatives 5a and 5b have been synthesized by the condensation of diaminomaleonitrile with 4-isothiocyanto-4-methylpentane-2-one and 3-isothiocyanatobutanal, respectively. Condensation of 4-isothiocyanato-4-methyl pentane-2-one with 2,3-diaminopropionic acid hydrochloride yielded another bicyclic compound 7. 4-Isothiocyanato-4-methyl pentane-2-one, 3-isothiocyanatobutanal and 4-isothiocyanatobutan-2-one on condensation with 2-amino-4-nitro phenol gave tricyclic pyrimidine derivatives 8a, 8b and 8c, respectively. Structures of all the synthesized pyrimidine derivatives are supported by correct IR, 1H NMR and mass spectral data. The anti-inflammatory activity evaluation was carried out using carrageenin-induced paw oedema assay, and compounds 1, 3 and 5b exhibited good anti-inflammatory activity, that is, 27.9, 34.5 and 34.3% at 50 mg/kg po, respectively. Analgesic activity evaluation was carried out using phenylquinone writhing assay and compounds 5a, 5b and 8b showed good analgesic activity, that is, 50, 70 and 50% at 50 mg/kg po, respectively.

Synthesis of acridinyl-thiazolino derivatives and their evaluation for anti-inflammatory, analgesic and kinase inhibition activities.

Variety of N-(4-phenyl-3-(2',3',4'(un)substituted phenyl)thiazol-2(3H)-ylidene)-2,4(un)substituted acridin-9-amine (4a-o) and 1-[(2,4-(un)substituted acridin-9-yl)-3-(4-phenyl-3-(2',3',4'(un)substituted phenyl)thiazol-2(3H)-ylidene)]isothiourea (5a-h) derivatives have been synthesized by condensation of 4-phenyl-3-(2',3',4'(un)substituted phenyl)thiazol-2(3H)-imine (3a-g) with 9-chloro-2,4-(un)substituted acridine (1a-c) and 9-isothiocyanato-2,4-(un)substituted acridine (2a-d), respectively. All these compounds were characterized by correct 1H NMR, FT-IR, MS and elemental analyses. These compounds were screened for anti-inflammatory, analgesic and kinase (CDK1, CDK5 and GSK3) inhibition activities. Some compounds exhibited good anti-inflammatory (25-32%) and potent analgesic (50-75%) activities, at 50 mg/kg p.o. A compound, 4o (R1 = H, R2 = OCH3, R3 = CH3, R4 = CH3, R5 = H) exhibited moderate CDK1 (IC50 = 8.5 microM) inhibition activity.

Synthesis and biological evaluation of 2-thiopyrimidine derivatives.

Various 2-thiopyrimidine derivatives have been synthesized by an efficient, one-pot reaction of functionalized amines with either 4-isothiocyanato-4-methyl-2-pentanone or 3-isothiocyanatobutanal. All the synthesized compounds were fully characterized by elemental analysis (CHN), FT-IR, (1)H NMR, and mass spectral data. One of the compounds, 7,7,8a-trimethyl-hexahydro-thiazolo[3,2-c]pyrimidine-5-thione (17) showed good anti-inflammatory (37.4% at 100 mg/kg p.o.) and analgesic activity (75% at 100 mg/kg p.o.). 7-(1-Mercapto-3,3,4a-trimethyl-4,4a,5,9b-tetrahydro-3H-pyrido[4,3-b]indol-7-yl)-3,3,4a-trimethyl-3,4,4a,5-tetrahydro-benzo[4,5]imidazo[1,2-c]pyrimidine-1-thiol (3) showed moderate activity against CDK-1 (IC(50)=5 microM). The other compounds showed moderate anti-inflammatory (5-20%), analgesic (25-75%) and protein kinase (CDK-5, GSK-3) inhibitory activities (IC(50)> 10 microM).