Unrevealing the multitargeted potency of 3-1-BCMIYPPA against lung cancer structural maintenance and suppression proteins through pharmacokinetics, QM-DFT, and multiscale MD simulation studies.

Lung cancer, a relentless and challenging disease, demands unwavering attention in drug design research. Single-target drugs have yielded limited success, unable to effectively address this malignancy's profound heterogeneity and often developed resistance. Consequently, the clarion call for lung cancer drug design echoes louder than ever, and multitargeted drug design emerges as an imperative approach in this landscape, which is done by concurrently targeting multiple proteins and pathways and offering a beacon of hope. This study is focused on the multitargeted drug designing approach by identifying drug candidates against human cyclin-dependent kinase-2, SRC-2 domains of C-ABL, epidermal growth factor and receptor extracellular domains, and insulin-like growth factor-1 receptor kinase. We performed the multitargeted molecular docking studies of Drug Bank compounds using HTVS, SP and XP algorithms and poses filter with MM\GBSA against all proteins and identified DB02504, namely [3-(1-Benzyl-3-Carbamoylmethyl-2-Methyl-1h-Indol-5-Yloxy)-Propyl-]-Phosphonic Acid (3-1-BCMIYPPA) as multitargeted lead with docking and MM\GBSA score range from -8.242 to -6.274 and -28.2 and -44.29 Kcal/mol, respectively. Further, the QikProp-based pharmacokinetic computations and QM-based DFT showed acceptance results against standard values, and interaction fingerprinting reveals that THR, MET, GLY, VAL, LEU, GLU and ASP were among the most interacting residues. The NPT ensemble-based 100ns MD simulation in a neutralised state with an SPC water model has also shown a stable performance and produced deviation and fluctuations <2Å with huge interactions, making it a promising multitargeted drug candidate-however, experimental studies are suggested.

Potential biomarkers in Japanese encephalitis from different hosts and geographical locations.

Japanese encephalitis (JE) is a single-stranded, mosquito-borne, positive-sense RNA flavivirus that causes one of the most severe encephalitides. There are treatments available for those who contact this illness; however, there are no known cures. This disease has a 30% fatality rate, and of the people who survive, 30-50% develops neurologic and psychiatric sequelae. The JE virus genome size is 10.98 kb and contains two coding DNA sequences (CDS), two genes, and 15 mature peptides; the CDS polyprotein is 10.3 kb. In this study, we used 29 genomics sequences of the JE virus reported from different countries and infecting different animals and analysed vast dimensions of the genomic annotation of JE comparatively to understand its evolutionary aspects. The extensive SNPs analysis revealed that KF907505.1, reported from Taiwan, has only three SNPs, similar to sequences reported from India. Repeat and polymorphism analyses revealed that the genome tends to be similar in most JE sequences.

Multitargeted inhibitory effect of Mitoxantrone 2HCl on cervical cancer cell cycle regulatory proteins: a multitargeted docking-based MM\GBSA and MD simulation study.

Cervical cancer remains a significant global health concern that starts in the cervix, the lower part of the uterus that connects to the vagina and is caused by the human papillomavirus (HPV), necessitating the development of effective multitargeted effective and resistance-proof therapies. In early-stage cervical cancer may not show any symptoms, however, as the cancer progresses, some people may experience- abnormal vaginal bleeding, watery or bloody vaginal discharge, pain in the pelvis or lower back, pain during sex, and frequent and painful urination. In this study, we screened the complete FDA-approved drug library using a multitargeted inhibitory approach against four cervical cancer proteins, namely mitotic arrest deficient -2, DNA polymerase epsilon B-subunit, benzimidazole-related -1, and threonine-protein kinase-1 which crucially plays its role for the in its development process. We employed the HTVS, SP and XP algorithms for efficient filtering and screening that helped to identify Mitoxantrone 2HCl against all of them with docking and MM\GBSA scores ranging from - 11.63 to - 7.802 kcal/mol and - 74.38 to - 47.73 kcal/mol, respectively. We also evaluated the interaction patterns of each complex and the pharmacokinetics properties that helped gain insight into interactions. Subsequently, we performed multiscale MD simulations for 100 ns to understand the dynamic behaviour and stability of the Mitoxantrone 2HCl -protein complexes that revealed the formation of stable drug-protein complexes and provided insights into the molecular interactions that contribute to Mitoxantrone's inhibitory effects on these proteins and can be a better drug for cervical cancer. However, experimental studies of these findings could pave the way for therapies to combat cervical cancer effectively.

Unveiling the multitargeted potency of Sodium Danshensu against cervical cancer: a multitargeted docking-based, structural fingerprinting and molecular dynamics simulation study.

Cervical Cancer (CC) is one of the most common types of cancer in women worldwide, with a significant number of deaths reported yearly. Despite the various treatment options available, the high mortality rate associated with CC highlights the need to develop new and effective therapeutic agents. In this study, we have screened the complete prepared FDA library against the Mitotic kinesin-like protein 1, Cyclin B1, DNA polymerase, and MCM10-ID using three glide-based molecular docking algorithms: HTVS, SP and XP to produce a robust calculation. All four proteins are crucial proteins that actively participate in CC development, and inhibiting them together can be a game-changer step for multitargeted drug designing. Our multitargeted screening identified Sodium (Na) Danshensu, a natural FDA-approved phenolic compound of caffeic acid derivatives isolated from Salvia miltiorrhiza. The docking score ranges from -5.892 to -13.103 Kcal/mol, and the screening study was evaluated with the pharmacokinetics and interaction fingerprinting to identify the pattern of interactions that revealed that the compound has bound to the best site it can be fitted to where maximum bonds were created to make the complex stable. The molecular dynamics simulations for 100 ns were then extended to validate the stability of the protein-ligand complexes. The results provide insight into the repurposing, and Na-danshensu exhibited strong binding affinity and stable complex formation with the target proteins, indicating its potential as a multitargeted drug against CC.Communicated by Ramaswamy H. Sarma.

Biallelic Variants in Seven Different Genes Associated with Clinically Suspected Bardet-Biedl Syndrome.

Bardet-Biedl syndrome (BBS) is a rare clinically and genetically heterogeneous autosomal recessive multi-systemic disorder with 22 known genes. The primary clinical and diagnostic features include six different hallmarks, such as rod-cone dystrophy, learning difficulties, renal abnormalities, male hypogonadism, post-axial polydactyly, and obesity. Here, we report nine consanguineous families and a non-consanguineous family with several affected individuals presenting typical clinical features of BBS. In the present study, 10 BBS Pakistani families were subjected to whole exome sequencing (WES), which revealed novel/recurrent gene variants, including a homozygous nonsense mutation (c.94C>T; p.Gln32Ter) in the IFT27 (NM_006860.5) gene in family A, a homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B, a homozygous nonsense variant (c.720C>A; p.Cys240Ter) in the WDPCP (NM_015910.7) in family C, a homozygous nonsense variant (c.505A>T; p.Lys169Ter) in the LZTFL1 (NM_020347.4) in family D, pathogenic homozygous 1 bp deletion (c.775delA; p.Thr259Leufs*21) in the MKKS/BBS5 (NM_170784.3) gene in family E, a pathogenic homozygous missense variant (c.1339G>A; p.Ala447Thr) in BBS1 (NM_024649.4) in families F and G, a pathogenic homozygous donor splice site variant (c.951+1G>A; p?) in BBS1 (NM_024649.4) in family H, a pathogenic bi-allelic nonsense variant in MKKS (NM_170784.3) (c.119C>G; p.Ser40*) in family I, and homozygous pathogenic frameshift variants (c.196delA; p.Arg66Glufs*12) in BBS5 (NM_152384.3) in family J. Our findings extend the mutation and phenotypic spectrum of four different types of ciliopathies causing BBS and also support the importance of these genes in the development of multi-systemic human genetic disorders.

Targeting Kaposi's sarcoma associated herpesvirus encoded protease (ORF17) by a lysophosphatidic acid molecule for treating KSHV associated diseases.

Kaposi's sarcoma associated herpesvirus (KSHV) is causative agent of Kaposi's sarcoma, Multicentric Castleman Disease and Pleural effusion lymphoma. KSHV-encoded ORF17 encodes a protease which cleaves -Ala-Ala-, -Ala-Ser- or -Ala-Thr-bonds. The protease plays an important role in assembly and maturation of new infective virions. In the present study, we investigated expression pattern of KSHV-encoded protease during physiologically allowed as well as chemically induced reactivation condition. The results showed a direct and proportionate relationship between ORF17 expression with reactivation time. We employed virtual screening on a large database of natural products to identify an inhibitor of ORF17 for its plausible targeting and restricting Kaposi's sarcoma associated herpesvirus assembly/maturation. A library of 307,814 compounds of biological origin (A total 481,799 structures) has been used as a screen library. 1-oleoyl-2-hydroxy-sn-glycero-3-phospho-(1'-myo-inositol) was highly effective against ORF17 in in-vitro experiments. The screened compound was tested for the cytotoxic effect and potential for inhibiting Kaposi's sarcoma associated herpesvirus production upon induced reactivation by hypoxia, TPA and butyric acid. Treatment of reactivated KSHV-positive cells with 1-oleoyl-2-hydroxy-sn-glycero-3-phospho-(1'-myo-inositol) resulted in significant reduction in the production of Kaposi's sarcoma associated herpesvirus. The study identified a lysophosphatidic acid molecule for alternate strategy to inhibit KSHV-encoded protease and target Kaposi's sarcoma associated herpesvirus associated malignancies.

Anti-Tumor Potential of Gymnema sylvestre Saponin Rich Fraction on In Vitro Breast Cancer Cell Lines and In Vivo Tumor-Bearing Mouse Models.

Gymnema sylvestre (GS) is a perennial woody vine native to tropical Asia, China, the Arabian Peninsula, Africa and Australia. GS has been used as a medicinal plant with potential anti-microbial, anti-inflammatory and anti-oxidant properties. This study was conceptualized to evaluate the cytotoxicity potential of Gymnema sylvestre saponin rich fraction (GSSRF) on breast cancer cell lines (MCF-7 and MDA-MB-468) by SRB assay. The anti-tumor activity of GSSRF was assessed in tumor-bearing Elrich ascites carcinoma (EAC) and Dalton's lymphoma ascites (DLA) mouse models. The anti-oxidant potential of GSSRF was assessed by DPPH radical scavenging assay. The acute toxicity of GSSRF was carried out according to OECD guideline 425. The yield of GSSRF was around 1.4% and the presence of saponin content in GSSRF was confirmed by qualitative and Fourier transform infrared spectroscopic (FTIR) analysis. The in vitro cytotoxic effects of GSSRF on breast cancer cell lines were promising and found to be dose-dependent. An acute toxicity study of GSSRF was found to be safe at 2000 mg/kg body weight. GSSRF treatment has shown a significant increase in the body weight and the life span of EAC-bearing mice in a dose-dependent manner when compared with the control group. In the solid tumor model, the doses of 100 and 200 mg/kg body weight per day have shown about 46.70% and 60.80% reduction in tumor weight and controlled the tumor weight until the 30th day when compared with the control group. The activity of GSSRF in both models was similar to the cisplatin, a standard anticancer agent used in the study. Together, these results open the door for detailed investigations of anti-tumor potentials of GSSRF in specific tumor models, mechanistic studies and clinical trials leading to promising novel therapeutics for cancer therapy.

Reporting dinaciclib and theodrenaline as a multitargeted inhibitor against SARS-CoV-2: an in-silico study.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is one of the rapid spreading coronaviruses that belongs to the Coronaviridae family. The rapidly evolving nature of SARS-CoV-2 results in a variety of variants with a capability of evasion to existing therapeutics and vaccines. So, there is an imperative need to discover potent drugs that can able to disrupt the function of multiple drug targets to tackle the SARS-CoV-2 menace. Here in this study, we took the different targets of SARS-CoV-2 prepared in the Schrodinger maestro. The library of the DrugBank database is screened against the selected crucial targets. Our molecular docking, Molecular Mechanics/Generalized Born Surface Area (MMGBSA), and molecular dynamics simulation studies led to identifying dinaciclib and theodrenaline as potential drugs against multiple drug targets: main protease, NSP15-endoribonuclease and papain-like-protease, of SARS-CoV-2. Dinaciclib with papain-like protease and NSP15-endoribonuclease show the docking score of -7.015 and -8.737, respectively, while the theodrenaline with NSP15-endoribonuclease and main protease produced the docking score of -8.507 and -7.289, respectively. Furthermore, the binding free energy calculations with MM/GBSA and molecular dynamics simulation studies of the complexes confirm the reliability of the drugs. The selected drugs are capable of binding to multiple targets simultaneously, thus withstanding their activity of target disruption in different variants of SARS-CoV-2. Although, the repurposed drugs are showing potent activity, but may need further in-vitro and in-vivo validations.Communicated by Ramaswamy H. Sarma.

A novel biallelic variant further delineates PRDX3-related autosomal recessive cerebellar ataxia.

Cerebellar ataxias (CAs) comprise a rare group of neurological disorders characterized by extensive phenotypic and genetic heterogeneity. In the last several years, our understanding of the CA etiology has increased significantly and resulted in the discoveries of numerous ataxia-associated genes. Herein, we describe a single affected individual from a consanguineous family segregating a recessive neurodevelopmental disorder. The proband showed features such as global developmental delay, cerebellar atrophy, hypotonia, speech issues, dystonia, and profound hearing impairment. Whole-exome sequencing and Sanger sequencing revealed a biallelic nonsense variant (c.496A > T; p.Lys166*) in the exon 5 of the PRDX3 gene that segregated perfectly within the family. This is the third report that associates the PRDX3 gene variant with cerebellar ataxia. In addition, associated hearing impairment further delineates the PRDX3 associated gene phenotypes.

PheroxyPyrabenz and Carbopyrropyridin against major proteins of SARS CoV-2: a comprehensive in-silico molecular docking and dynamics simulation studies.

The pandemic that started in 2020 left us with so much information about viruses and respiratory diseases, and the cause behind it was severe acute respiratory syndrome coronavirus-2 (SARS CoV-2). The world is still recovering, which costs so many economic and other indirect disasters; despite that, no medications are available on the market. Although the WHO approved a few vaccines on an emergency basis, the remarks and the reinfection chances are still under investigation, and a few pharmaceutical companies are also claiming that a few medications can be effective. However, there is no situation in control. SARS CoV-2 mutates and comes in different forms, making the situation unpredictable. In this study, we have screened the complete Asinex's BioDesign library, which contains 170,269 compounds, and shorted the data against the docking score that helps in the identification of 4-[5-(3-Ethoxy-4-hydroxyphenyl)-1-(2-hydroxyethyl)-1H-pyrazol-3-yl]-1, 2-benzenediol (PheroxyPyrabenz) and 1-[(3R,4R)-1-(5-Aminopentanoyl)-4-hydroxy-3-pyrrolidinyl]-1H-pyrrolo[2,3-b]pyridine-4-carboxamide (Carbopyrropyridin) as a significant drug candidate that can work against the multiple proteins of the SARS CoV-2 resulting in seizing the complete biological process of the virus. Further, the study extended to Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) and molecular dynamics (MD) simulation of both the compounds with their complexity. The complete workflow of the study has shown satisfactory results, and both drug candidates can potentially stop the hunt for drugs against this virus after its experimental validation. Further, we checked both compounds' absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, showing case-proof validatory results.Communicated by Ramaswamy H. Sarma.

Dioxinodehydroeckol: A Potential Neuroprotective Marine Compound Identified by In Silico Screening for the Treatment and Management of Multiple Brain Disorders.

Neurodegenerative disorders such as Alzheimer's disease (AD), Glioblastoma multiforme (GBM), Amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD) are some of the most prevalent neurodegenerative disorders in humans. Even after a variety of advanced therapies, prognosis of all these disorders is not favorable, with survival rates of 14-20 months only. To further improve the prognosis of these disorders, it is imperative to discover new compounds which will target effector proteins involved in these disorders. In this study, we have focused on in silico screening of marine compounds against multiple target proteins involved in AD, GBM, ALS, and PD. Fifty marine-origin compounds were selected from literature, out of which, thirty compounds passed ADMET parameters. Ligand docking was performed after ADMET analysis for AD, GBM, ALS, and PD-associated proteins in which four protein targets Keap1, Ephrin A2, JAK3 Kinase domain, and METTL3-METTL14 N6-methyladenosine methyltransferase (MTA70) were found to be binding strongly with the screened compound Dioxinodehydroeckol (DHE). Molecular dynamics simulations were performed at 100 ns with triplicate runs to validate the docking score and assess the dynamics of DHE interactions with each target protein. The results indicated Dioxinodehydroeckol, a novel marine compound, to be a putative inhibitor among all the screened molecules, which might be effective against multiple target proteins involved in neurological disorders, requiring further in vitro and in vivo validations.

Oleuropein as a Potent Compound against Neurological Complications Linked with COVID-19: A Computational Biology Approach.

The association of COVID-19 with neurological complications is a well-known fact, and researchers are endeavoring to investigate the mechanistic perspectives behind it. SARS-CoV-2 can bind to Toll-like receptor 4 (TLR-4) that would eventually lead to α-synuclein aggregation in neurons and stimulation of neurodegeneration pathways. Olive leaves have been reported as a promising phytotherapy or co-therapy against COVID-19, and oleuropein is one of the major active components of olive leaves. In the current study, oleuropein was investigated against SARS-CoV-2 target (main protease 3CLpro), TLR-4 and Prolyl Oligopeptidases (POP), to explore oleuropein potency against the neurological complications associated with COVID-19. Docking experiments, docking validation, interaction analysis, and molecular dynamic simulation analysis were performed to provide insight into the binding pattern of oleuropein with the three target proteins. Interaction analysis revealed strong bonding between oleuropein and the active site amino acid residues of the target proteins. Results were further compared with positive control lopinavir (3CLpro), resatorvid (TLR-4), and berberine (POP). Moreover, molecular dynamic simulation was performed using YASARA structure tool, and AMBER14 force field was applied to examine an 100 ns trajectory run. For each target protein-oleuropein complex, RMSD, RoG, and total potential energy were estimated, and 400 snapshots were obtained after each 250 ps. Docking analyses showed binding energy as -7.8, -8.3, and -8.5 kcal/mol for oleuropein-3CLpro, oleuropein-TLR4, and oleuropein-POP interactions, respectively. Importantly, target protein-oleuropein complexes were stable during the 100 ns simulation run. However, an experimental in vitro study of the binding of oleuropein to the purified targets would be necessary to confirm the present study outcomes.

Brain-Derived Neurotrophic Factor: A Connecting Link Between Nutrition, Lifestyle, and Alzheimer's Disease.

Brain-derived neurotrophic factor (BDNF) involving tropomyosin kinase B and low affinity p75 neurotropin receptors is the most abundant and researched neurotropins in mammal's brain. It is one of the potential targets for therapeutics in Alzheimer's disease (AD) owing to its key role in synaptic plasticity. Low levels of BDNF are implicated in the pathophysiology of neurological diseases including AD. However, a healthy lifestyle, exercise, and dietary modifications are shown to positively influence insulin regulation in the brain, reduce inflammation, and up-regulate the levels of BDNF, and are thus expected to have roles in AD. In this review, the relationship between BDNF, mental health, and AD is discussed. Insights into the interrelationships between nutrition, lifestyle, and environment with BDNF and possible roles in AD are also provided in the review. The review sheds light on the possible new therapeutic targets in neurodegenerative diseases.

Identification of homozygous missense variant in SIX5 gene underlying recessive nonsyndromic hearing impairment.

Hearing impairment (HI) is a heterogeneous condition that affects many individuals globally with different age groups. HI is a genetically and phenotypically heterogeneous disorder. Over the last several years, many genes/loci causing rare autosomal recessive and dominant forms of hearing impairments have been identified, involved in various aspects of ear development. In the current study, two affected individuals of a consanguineous family exhibiting autosomal recessive nonsyndromic hearing impairment (AR-NSHI) were clinically and genetically characterized. The single affected individual (IV-2) of the family was subjected to whole-exome sequencing (WES) accompanied by traditional Sanger sequencing. Clinical examinations using air conduction audiograms of both the affected individuals showed profound hearing loss across all frequencies. WES revealed a homozygous missense variant (c.44G>C) in the SIX5 gene located on chromosome 19q13.32. We report the first case of autosomal recessive NSHI due to a biallelic missense variant in the SIX5 gene. This report further supports the evidence that the SIX5 variant might cause profound HI and supports its vital role in auditory function. Identification of novel candidate genes might help in application of future gene therapy strategies that may be implemented for NSHI, such as gene replacement using cDNA, gene silencing using RNA interference, and gene editing using the CRISPR/Cas9 system.

Case Report: Biallelic Variant in the tRNA Methyltransferase Domain of the AlkB Homolog 8 Causes Syndromic Intellectual Disability.

Intellectual disability (ID) has become very common and is an extremely heterogeneous disorder, where the patients face many challenges with deficits in intellectual functioning and adaptive behaviors. A single affected family revealed severe disease phenotypes such as ID, developmental delay, dysmorphic facial features, postaxial polydactyly type B, and speech impairment. DNA of a single affected individual was directly subjected to whole exome sequencing (WES), followed by Sanger sequencing. Data analysis revealed a novel biallelic missense variant (c.1511G>C; p.(Trp504Ser)) in the ALKBH8 gene, which plays a significant role in tRNA modifications. Our finding adds another variant to the growing list of ALKBH8-associated tRNA modifications causing ID and additional phenotypic manifestations. The present study depicts the key role of the genes associated with tRNA modifications, such as ALKBH8, in the development and pathophysiology of the human brain.

Targeting Cytotoxin-Associated Antigen A, a Virulent Factor of Helicobacter pylori-Associated Gastric Cancer: Structure-Based In Silico Screening of Natural Compounds.

Gastric cancer is the fifth most frequent cancer and the third major cause of mortality worldwide. Helicobacter pylori, a bacterial infection linked with GC, injects the cytotoxin-associated antigen A (CagA; an oncoprotein) into host cells. When the phosphorylated CagA protein enters the cell, it attaches to other cellular components, interfering with normal cellular signaling pathways. CagA plays an important role in the progression of GC by interacting with phosphatidylserine of the host cell membrane. Therefore, disrupting the CagA-phosphatidylserine connection using small molecules appears to be a promising therapeutic approach. In this report, we screened the natural compounds from ZINC database against the CagA protein using the bioinformatics tools. Hits were initially chosen based on their physicochemical, absorption, distribution, metabolism, excretion, and toxicity (ADMET) characteristics, as well as other drug-like characteristics. To locate safe and effective hits, the PAINS filter, binding affinities estimation, and interaction analysis were used. Three compounds with high binding affinity and specificity for the CagA binding pocket were discovered. The final hits, ZINC153731, ZINC69482055, and ZINC164387, were found to bind strongly with CagA protein, with binding energies of -11.53, -10.67, and -9.21 kcal/mol, respectively, which were higher than that of the control compound (-7.25 kcal/mol). Further, based on binding affinity and interaction pattern, two leads (ZINC153731, ZINC69482055) were chosen for molecular dynamics (MD) simulation analysis. MD results showed that they displayed stability in their vicinity at 100 ns. This study suggested that these compounds could be used as possible inhibitors of CagA protein in the fight against GC. However, additional benchwork tests are required to validate them as CagA protein inhibitors.

Isolation and drug susceptibility pattern of uropathogens in Saudi diabetic and non-diabetic patients with urinary tract infection.

Urinary tract infection (UTI), contribute substantially to healthcare burden. Diabetes predispose to UTI with high glycosuria being fertile medium for bacterial growth. With changing bacterial drug resistance patterns; the problem needs to be studied periodically to ensure a rational therapy, minimize adverse effects, and cost. Therefore, it is of interest to compare the profile and susceptibility pattern of uropathogens isolated from diabetic and non-diabetic patients with UTI. Mid-stream urine samples of 1100 patients (diabetic and non-diabetic), presenting with UTI symptoms were aseptically collected and inoculated into CLED medium. Colony counts of 105cfu/ml or 104cfu/ml and >5 pus cells per high power microscopic field were regarded as significant bacteriuria. Colonies from CLED were sub-cultured onto sheep blood agar and MacConkey agar. Bacterial identification was performed on the basis of colony morphology, gram staining, and series of biochemical tests though Analytical Profile Index (API) test strips. Drug susceptibility was done by standard Kirby-Bauer disk diffusion. Data was analyzed by SPSS ver. 25.Clinically significant bacteriuria was 32.8% and 19.2% in diabetics and non-diabetics respectively. The frequency of male and female patients was 153 and 208 in diabetic group; and 69 and 142 respectively in non-diabetic group. Diabetics were twice at risk of UTI; [Odds ratio; 2.04 (CI: 1.68-2.48, p<0.05)]. .Escherichia coli and klebsiella were most common gram-negative, while Staphylococcus aureus and Coagulase-negative staphylococci (CoNS) were most common gram-positive bacteria in both the groups. Most effective antibiotics against gram-negative bacteria were carbapenems, amikacin, colistin, and piperacillin/tazobactam; while ampicillin/amoxicillin, fluoroquinolones and cephalexin were least effective. For gram-positives, vancomycin, linezolid and tigecycline were most effective. No significant difference in bacterial profile and susceptibility pattern was found between diabetics and non-diabetics. However, diabetics were twice at risk of UTI compared to non-diabetics.

Molecular docking analysis of phytochemicals with estrogen receptor alpha.

Breast cancer (BC) is linked to estrogen receptor alpha (ER-α) positive. Tamoxifen and other estrogen selective modulators have proven to be beneficial in slowing the progression of ER-α BC. However, tamoxifen resistance emerges as a result of long-term treatment and cancer development. Therefore, it is of interest to document data on the molecular docking analysis of phytochemicals targeting with Estrogen Receptor-alpha. The screening of the phytochemicals from the ZINC database (a total of 87133 compounds) against ER-α protein was completed. We show that ZINC69481841 and ZINC95486083bind strongly to ER- with binding energies of 10.47 and 11.88 Kcal/mol, respectively, which were significantly greater than the control compound (-8.32Kcal/mol). ZINC69481841 and ZINC95486083 were found to bind with the key residues (Leu387, Arg394, Glu353, and Thr347) of ER-α protein. Data shows that the lead compounds (ZINC69481841 and ZINC95486083) have an acceptable range of ADMET and drug-likeness properties for further consideration in drug discovery.

Effect of rifampicin combination-regimens against multi-drug resistant strains in North India.

It is well-acknowledged that 'combination therapy' of antibiotics is indispensable for the treatment of patients suffering from serious bacterial infections. Therefore, it is of interest to collect data from the in vitro tests using 'rifampicin-cefotaxime' and 'rifampicin-tetracycline' combination regimens against multi drug resistant Escherichia coli and Klebsiella pneumoniae strains of nosocomial source in order to determine the effectiveness of the combination therapy. The minimum inhibitory concentration (MIC) values for cefotaxime, tetracycline and rifampicin antibiotics were found to be comparatively high for each of the antibiotics when given individually. However, carefully prepared combination-regimens exhibited significant inhibitory effect on the same bacterial isolates. DNA fragmentation study confirmed that 'rifampicin-cefotaxime' and 'rifampicin-tetracycline' combination-regimens could cause breakage of the bacterial DNA. Thus, we show that combination-regimens namely, 'rifampicin-cefotaxime' and 'rifampicin-tetracycline' were found to be capable of maintaining rifampicin susceptibility in the E. coli and K. pneumoniae strains. However, this susceptibility was not maintained by only rifampicin. More data using animal model experiments are needed for confirming and deriving translational benefits from these findings in future.

Case report: A novel de novo loss of function variant in the DNA-binding domain of TBX2 causes severe osteochondrodysplasia.

Background: T-box family members are transcription factors characterized by highly conserved residues corresponding to the DNA-binding domain known as the T-box. TBX2 has been implicated in several developmental processes, such as coordinating cell fate, patterning, and morphogenesis of a wide range of tissues and organs, including lungs, limbs, heart, kidneys, craniofacial structures, and mammary glands. Methods: In the present study, we have clinically and genetically characterized a proband showing a severe form of chondrodysplasia with developmental delay. Whole-exome sequencing (WES), Sanger sequencing, and 3D protein modeling were performed in the present investigation. Results: Whole-exome sequencing revealed a novel nonsense variant (c.529A>T; p.Lys177*; NM_005994.4) in TBX2. 3D-TBX2 protein modeling revealed a substantial reduction of the mutated protein, which might lead to a loss of function (LOF) or nonsense-mediated decay (NMD). Conclusion: This study has not only expanded the mutation spectrum in the gene TBX2 but also facilitated the diagnosis and genetic counseling of related features in affected families.