Genetic mechanism regulating diversity in the placement of eyes on the head of animals.

Despite the conservation of genetic machinery involved in eye development, there is a strong diversity in the placement of eyes on the head of animals. Morphogen gradients of signaling molecules are vital to patterning cues. During Drosophila eye development, Wingless (Wg), a ligand of Wnt/Wg signaling, is expressed anterolaterally to form a morphogen gradient to determine the eye- versus head-specific cell fate. The underlying mechanisms that regulate this process are yet to be fully understood. We characterized defective proventriculus (dve) (Drosophila ortholog of human SATB1), a K50 homeodomain transcription factor, as a dorsal eye gene, which regulates Wg signaling to determine eye versus head fate. Across Drosophila species, Dve is expressed in the dorsal head vertex region where it regulates wg transcription. Second, Dve suppresses eye fate by down-regulating retinal determination genes. Third, the dve-expressing dorsal head vertex region is important for Wg-mediated inhibition of retinal cell fate, as eliminating the Dve-expressing cells or preventing Wg transport from these dve-expressing cells leads to a dramatic expansion of the eye field. Together, these findings suggest that Dve regulates Wg expression in the dorsal head vertex, which is critical for determining eye versus head fate. Gain-of-function of SATB1 exhibits an eye fate suppression phenotype similar to Dve. Our data demonstrate a conserved role for Dve/SATB1 in the positioning of eyes on the head and the interocular distance by regulating Wg. This study provides evidence that dysregulation of the Wg morphogen gradient results in developmental defects such as hypertelorism in humans where disproportionate interocular distance and facial anomalies are reported.

Therapeutic Potential of Morin Hydrate Against Rifampicin Induced Hepato and Renotoxicity in Albino Wistar Rats: Modulation of Organ Function, Oxidative Stress and Inflammatory Response.

Tuberculosis (TB) is a challenging public health issue, particularly in poor and developing countries. Rifampicin (RIF) is one of the most common first-line anti-TB drugs but it is known for its adverse effects on the hepato-renal system. The present study investigated the efficacy of morin hydrate (MH) in protecting hepato-renal damage inflicted by RIF in rats. RIF (50 mg/kg), and a combination of RIF (50 mg/kg) and MH (50 mg/kg) were administered orally for 4 weeks in rats. Silymarin (50 mg/kg) was used as a positive control. Increased levels of serological parameters such as AST, ALT, ALP, LDH, GGT, bilirubin, triglyceride, total cholesterol, urea, uric acid, creatinine, TNF-α, IFN-γ, IL-6 along with the decreased level of IL-10, total protein and albumin were used as markers of hepatic and renal injury. Oxidative damage in the tissues was measured by the increase in lipid peroxidation and decline in GSH, SOD and catalase activities. Histopathology of liver slices was used to study hepatic architecture. Four-week RIF treatment produced altered serological parameters with an increase in pro-inflammatory cytokines in serum suggesting hepatotoxicity and nephrotoxicity. The antioxidant status of the liver and kidney (increased lipid peroxidation and decline in GSH, SOD and catalase) was compromised. Cellular damage and necrosis were observed in liver slices. MH supplementation with RIF improved hepato-renal functions by restoring the serum and tissue markers towards normal values. Histological observations authenticated the results. MH supplementation also reduced the production of pro-inflammatory cytokines. Thus, the results revealed that MH provides protection against RIF-induced hepato-renal injury.

Novel Compound Heterozygous Mutations of LIG4 Gene in an Indian LIG4 Syndrome Patient with Severe Microcephaly: Case Report, In-silico Analysis and Systematic Review.

BACKGROUND: LIG4 syndrome, characterized by immunodeficiency, sensitivity to ionizing radiations, intrauterine growth retardation, postnatal growth retardation, and microcephaly, is a rare genetic disorder caused by pathogenic variants of the LIG4 gene. Few patients are presented with no immune dysregulation as well. CASE STUDY: We present here a male child of 2 years and 4 months of age with severe microcephaly and short stature. His birth weight was 1.9 Kg, and his current height, weight, and head circumference are 83.2 cm (z score = -2.37), 9.5 Kg (z score = -2.76), and 36 cm (z score = -9.24), respectively. Possible causative pathogenic compound heterozygous variants of the LIG4 gene, which were inherited from the parents, were identified by whole exome sequencing of the DNA of the patient and his parents. A systematic review of the literature is also performed to summarize the patients of LIG4 syndrome reported worldwide and summarize the associated genetic mutations of the LIG4 gene. Compound heterozygous variants (c.597_600delTCAG/ c.342del) of LIG4 gene were identified. The parents were found to be heterozygous carriers of one variant each. CONCLUSION: The in-silico analysis of identified variants explains their effect on the structure and function of the LIG4 protein hence explaining the genotype-phenotype correlation.

Clinical and CBCT Assessment of Role of Bisphosphonate on Osteotomy Site and Implant Surface.

Objectives: To assess the role of bisphosphonate on osteotomy site and implant surface. Materials and Methods: Twenty patients with adequate width and height of edentulous space and a single missing posterior tooth between the ages of 25 and 55 were incorporated in this research. Ten participants received implant therapy alone; the other ten patients received implant therapy and bisphosphonate application to osteotomy site and the implant surface. Result: Changes in the crestal bone level were seen in both the study and control groups. At 1 year, crestal bone loss was less in the bisphosphonate-treated group than in the control group. Conclusion: The quantity of crestal bone loss was reduced when bisphosphonate (sodium alendronate) was applied locally near the implant and osteotomy site.

Cyclic AMP binding to a universal stress protein in Mycobacterium tuberculosis is essential for viability.

Mycobacterial genomes encode multiple adenylyl cyclases and cAMP effector proteins, underscoring the diverse ways these bacteria utilize cAMP. We identified universal stress proteins (USP), Rv1636, and MSMEG_3811 in M. tuberculosis and M. smegmatis, respectively, as abundantly expressed, novel cAMP-binding proteins. Rv1636 is secreted via the SecA2 secretion system in M. tuberculosis but is not directly responsible for the efflux of cAMP from the cell. In slow-growing mycobacteria, intrabacterial concentrations of Rv1636 were equivalent to the concentrations of cAMP present in the cell. In contrast, levels of intrabacterial MSMEG_3811 in M. smegmatis were lower than that of cAMP and therefore, overexpression of Rv1636 increased levels of 'bound' cAMP. While msmeg_3811 could be readily deleted from the genome of M. smegmatis, we find that the rv1636 gene is essential for the viability of M. tuberculosis and is dependent on the cAMP-binding ability of Rv1636. Therefore, Rv1636 may function to regulate cAMP signaling by direct sequestration of the second messenger. This is the first evidence of a 'sponge' for any second messenger in bacterial signaling that would allow mycobacterial cells to regulate the available intrabacterial 'free' pool of cAMP.

Genome-Wide Comparative Analysis of Five Amaranthaceae Species Reveals a Large Amount of Repeat Content.

Amaranthus is a genus of C4 dicotyledonous herbaceous plant species that are widely distributed in Asia, Africa, Australia, and Europe and are used as grain, vegetables, forages, and ornamental plants. Amaranth species have gained significant attention nowadays as potential sources of nutritious food and industrial products. In this study, we performed a comparative genome analysis of five amaranth species, namely, Amaranthus hypochondriacus, Amaranthus tuberculatus, Amaranthus hybridus, Amaranthus palmeri, and Amaranthus cruentus. The estimated repeat content ranged from 54.49% to 63.26% and was not correlated with the genome sizes. Out of the predicted repeat classes, the majority of repetitive sequences were Long Terminal Repeat (LTR) elements, which account for about 13.91% to 24.89% of all amaranth genomes. Phylogenetic analysis based on 406 single-copy orthologous genes revealed that A. hypochondriacus is most closely linked to A. hybridus and distantly related to A. cruentus. However, dioecious amaranth species, such as A. tuberculatus and A. palmeri, which belong to the subgenera Amaranthus Acnida, have formed their distinct clade. The comparative analysis of genomic data of amaranth species will be useful to identify and characterize agronomically important genes and their mechanisms of action. This will facilitate genomics-based, evolutionary studies, and breeding strategies to design faster, more precise, and predictable crop improvement programs.

Protocol for preparing formalin-fixed paraffin-embedded musculoskeletal tissue samples from mice for spatial transcriptomics.

Here, we present a protocol for using spatial transcriptomics in bone and multi-tissue musculoskeletal formalin-fixed paraffin-embedded (FFPE) samples from mice. We describe steps for tissue harvesting, sample preparation, paraffin embedding, and FFPE sample selection. We detail procedures for sectioning and placement on spatial slides prior to imaging, decrosslinking, library preparation, and final analyses of the sequencing data. The complete protocol takes ca. 18 days for mouse femora with adjacent muscle; of this time, >50% is required for mineralized tissue decalcification. For complete details on the use and execution of this protocol, please refer to Wehrle et al.1 and Mathavan et al.2.

Insights into the genomic features and lifestyle of B1 subcluster mycobacteriophages.

Bacteriophages infecting Mycobacterium smegmatis mc2155 are numerous and, hence, are classified into clusters based on nucleotide sequence similarity. Analyzing phages belonging to clusters/subclusters can help gain deeper insights into their biological features and potential therapeutic applications. In this study, for genomic characterization of B1 subcluster mycobacteriophages, a framework of online tools was developed, which enabled functional annotation of about 55% of the previously deemed hypothetical proteins in B1 phages. We also studied the phenotype, lysogeny status, and antimycobacterial activity of 10 B1 phages against biofilm and an antibiotic-resistant M. smegmatis strain (4XR1). All 10 phages belonged to the Siphoviridae family, appeared temperate based on their spontaneous release from the putative lysogens and showed antibiofilm activity. The highest inhibitory and disruptive effects on biofilm were 64% and 46%, respectively. This systematic characterization using a combination of genomic and experimental tools is a promising approach to furthering our understanding of viral dark matter.

Impact of surgical timing and type of operative procedure on outcomes in periprosthetic hip fractures: an observational study at an NHS trust centre in the UK.

PURPOSE: There is a global trend of increased periprosthetic fractures due to the growing number of arthroplasty procedures. The present study assessed the impact of factors such as time to surgery and type of surgery on the outcomes, which have been seldom evaluated for periprosthetic fractures. METHODS: An observational study was conducted on consecutive 87 patients within an NHS district hospital trust in the UK. Patients who underwent a complete hip replacement prior to the fracture, received fixation therapy, or underwent revision surgery within the specified time were screened. Patients were grouped in two ways: based on time to surgery and based on surgery type. Logistic regression models were performed to assess for statistically significant differences in post-operative complication, 30-day, and 1-year mortality rates between groups, whilst adjusting for age, gender, and ASA grade. RESULTS: Forty-one patients underwent open reduction and internal fixation (ORIF), 29 patients underwent revision arthroplasty, and 17 patients were subjected to both, ORIF and revision arthroplasty. Sixty of the 87 patients were operated on > 48 h of injury. The median hospital stay was significantly lower in the ORIF plus revision arthroplasty group, versus other surgical groups (p < 0.05) whilst it was significantly higher in the group of patients who underwent surgery after 48 h of injury (p < 0.05). Numerically higher mortality was noted in the revision arthroplasty group (31.03%, p > 0.05). The group that was operated after 48 h of injury showed greater mortality but was comparable to the other group (25% vs. 14.81%, p > 0.05). For post-operative complications, none of the variables were significantly predictive (p > 0.05). However, for 30-day mortality, ASA grade (p = 0.04) and intra-operative complications (p = 0.0001) were significantly predictive. Additionally, for 1-year mortality, ASA grade (p = 0.004) was noted to be significantly predictive. CONCLUSION: Revision and delayed periprosthetic fracture management (> 48 h after injury) group showed a numerically greater mortality risk; however, this finding was not statistically significant. ASA grading at baseline is predictive of mortality for periprosthetic fractures.

RelA-mediated signaling connects adaptation to chronic cardiomyocyte stress with myocardial and systemic inflammation in the ADCY8 model of accelerated aging.

Mice with cardiac-specific overexpression of adenylyl cyclase (AC) type 8 (TGAC8) are under a constant state of severe myocardial stress. They have a remarkable ability to adapt to this stress, but they eventually develop accelerated cardiac aging and experience reduced longevity. We have previously demonstrated through bioinformatics that constitutive adenylyl cyclase activation in TGAC8 mice is associated with the activation of inflammation-related signaling pathways. However, the immune response associated with chronic myocardial stress in the TGAC8 mouse remains unexplored. Here we demonstrate that chronic activation of adenylyl cyclase in cardiomyocytes of TGAC8 mice results in activation of cell-autonomous RelA-mediated NF-κB signaling. This is associated with non-cell-autonomous activation of proinflammatory and age-associated signaling in myocardial endothelial cells and myocardial smooth muscle cells, expansion of myocardial immune cells, increase in serum levels of inflammatory cytokines, and changes in the size or composition of lymphoid organs. All these changes precede the appearance of cardiac fibrosis. We provide evidence indicating that RelA activation in cardiomyocytes with chronic activation of adenylyl cyclase is mediated by calcium-protein Kinase A (PKA) signaling. Using a model of chronic cardiomyocyte stress and accelerated aging, we highlight a novel, calcium/PKA/RelA-dependent connection between cardiomyocyte stress, myocardial inflammation, and systemic inflammation. These findings suggest that RelA-mediated signaling in cardiomyocytes might be an adaptive response to stress that, when chronically activated, ultimately contributes to both cardiac and systemic aging.

Evaluation of hydrogeochemical processes and saltwater intrusion in the coastal aquifers in the southern part of Puri District, Odisha, India.

Groundwater is widely regarded as being among the freshwater natural resources with the lowest levels of contamination. Nevertheless, the saltwater intrusion has resulted in the contamination of groundwater in coastal regions with lower elevation. The rationale of the present work is to investigate the chemistry of groundwater, to identify the various facies of groundwater, to identify the processes that influence groundwater chemistry and saltwater intrusion, and to evaluate the groundwater's aptness for use in drinking and farming. In order to gain an understanding of the groundwater quality as well as the salinization process that occurs in coastal aquifers as a result of hydrogeochemical processes, a total of 108 groundwater samples (54 each in pre- and post-monsoon) were taken and analyzed for several physiochemical parameters in the southern part of the Puri district in the Indian state of Odisha. The data has undergone analysis and examination to identify the factors (such as hydrological facies, potential solute source in water, and salinization process) that contribute to groundwater salinity. The result showed the chemistry controlling processes of rock-water interaction as per Gibbs diagram. The majority of shallow aquifers exhibit the Na-Cl type of facies as per the Piper plot. A total of 37% pre-monsoon and 33% post-monsoon samples having Na+/Cl- ratio below the threshold of 0.86 indicating the influence of saltwater intrusion. In both seasons, it was observed that 74% of the samples exhibited a Na+ concentration that exceeded the permissible limit set by the World Health Organization (WHO) for drinking purposes. The findings indicate that most groundwater failed to pass safe drinking water and irrigation standards due to saltwater intrusion. Consequently, the monitoring of coastal aquifer quality has become imperative in order to ensure the sustainability of aquifers and the development of groundwater resources. This is because coastal aquifers are highly vulnerable to saltwater intrusion, primarily as a result of the extensive extraction of groundwater for diverse purposes.

Novel approach of plate assisted buttressing in Hoffa fracture.

PURPOSE: Hoffa fracture is a femoral condyle fracture in the coronal plane. The lateral condyle is more commonly involved. The diagnosis is often difficult to detect with routine radiographs. Conservative management in this type of fracture resulted in nonunion, malunion, and other complications, such as stiff knee. Therefore, surgical management is mandatory in displaced fractures. Previous studies suggest only application of cancellous screw fixation, but these are not enough to counter vertical shear stress. Therefore, this study will evaluate the clinical outcomes of open reduction and internal fixation of Letenneur type I Hoffa fracture using cancellous screws with posterior buttressing plate. METHOD: This was a prospective cohort study conducted from March 2017 to July 2022 in orthopaedics department of tertiary care center after approval of institutional ethical committee. The study included 36 patients with Letenneur type I fractures treated by open reduction and internal fixation using posterior buttress plate and cancellous screws. Radiographs and clinical outcomes, range of movement (ROM), bone union, and knee society score (KSS) of patients were assessed at the end of 4 and 12 months in the follow-ups. All statistical analysis was done using Epi info version 7.2.1.0. RESULTS: In the 36 patients with Letenneur type I fracture, the majority belong to younger age group between 25 and 54 years with 22 males and 14 females. The modes of injury were road traffic accidents in 25 patients and fall from height in 11 patients. The right knee was involved in 21 cases and left was involved in 15 cases. Lateral condyle involvement was seen in 27 cases and medial condyle in 9 cases. All 36 patients with Letenneur type I Hoffa fracture were evaluated 4 months after surgical intervention. The notable improvements were observed in terms of ROM 120.4° ± 5.0° and KSS 85.0 ± 4.2. At the 12-month follow-up, considerably better outcomes were maintained regarding ROM 128.1° ± 5.2° and KSS 89.3 ± 4.8 with p < 0.05 which was statistically significant. At the final follow-up, all patients had routine fracture healing with a union time of (3.2 ± 3.4) months. CONCLUSIONS: Fixation of Letenneur type I Hoffa fracture with cancellous screws and posterior buttress plate is effective, reliable and capable of providing adequate stability. Buttress plate assisted fixation is a valuable enhancement of the conventional technique of lag screw fixation of Hoffa fractures.

In silico strategies for identifying therapeutic candidates against Acinetobacter baumannii: spotlight on the UDP-N-acetylmuramoyl-L-alanine-D-glutamate:meso-diaminopimelate ligase (MurE).

The opportunistic bacterium Acinetobacter baumannii, which belongs to ESKAPE group of pathogenic bacteria, is leading cause of infections associated with gram-negative bacteria. Acinetobacter baumannii causes severe diseases, such as VAP (ventilator-associated pneumonia), meningitis, and UTI (urinary tract infections) among the nosocomial infections contracted in hospitals. The high infection rate and growing resistance to the vast array of antibiotics makes it paramount to look for new therapeutic strategies against this pathogen. The most promising therapeutic targets are the proteins involved in the synthesis of peptidoglycan which is chief component of bacterial cell wall, MurE is one of those enzymes and is responsible for the addition of one unit of meso-diaminopimelic acid (meso-A2pm) to the nucleotide precursor, UDPMurNAc-L-Ala-D-Glu, and aids in the formation of crosslinker pentapeptide chain. The three-dimensional structure of MurE was modelled using homology modelling technique and then vHTS was performed using this model against Approved Drug Library on DrugRep server using AutoDock Vina. Out of 500 drug molecules, two were selected based on estimated binding affinity, interaction pattern, interacting residues, etc. The selected drug molecules are DB12887 (Tazemetostat) and DB13879 (Glecaprevir). Then, MD simulations were performed on native MurE and its complexes with ligands to examine their dynamical behaviour, stability, integrity, compactness, and folding properties. The protein-ligand complexes were then subjected to binding free energy calculations using the MM/PBSA-based binding free energy analysis and the values are -109.788 ± 8.03 and -152.753 ± 11.98 kcal for MurE-DB12887 and MurE-DB13879 complex, respectively. All the analysis performed on MD trajectories for the complexes of these ligands with protein provided plenty of dependable evidences to consider these molecules for inhibition of MurE enzyme from A. baumannii. Communicated by Ramaswamy H. Sarma.

Inhibition of leukotriene-B4 signalling-mediated host response to tuberculosis is a potential mode of adjunctive host-directed therapy.

Treatment of tuberculosis (TB) is faced with several challenges including the long treatment duration, drug toxicity and tissue pathology. Host-directed therapy provides promising avenues to find compounds for adjunctively assisting antimycobacterials in the TB treatment regimen, by promoting pathogen eradication or limiting tissue destruction. Eicosanoids are a class of lipid molecules that are potent mediators of inflammation and have been implicated in aspects of the host response against TB. Here, we have explored the blood transcriptome of pulmonary TB patients to understand the activity of leukotriene B4, a pro-inflammatory eicosanoid. Our study shows a significant upregulation in the leukotriene B4 signalling pathway in active TB patients, which is reversed with TB treatment. We have further utilized our in-house network analysis algorithm, ResponseNet, to identify potential downstream signal effectors of leukotriene B4 in TB patients including STAT1/2 and NADPH oxidase at a systemic as well as local level, followed by experimental validation of the same. Finally, we show the potential of inhibiting leukotriene B4 signalling as a mode of adjunctive host-directed therapy against TB. This study provides a new mode of TB treatment along with mechanistic insights which can be further explored in pre-clinical trials.

Squamous cell carcinoma of skin in a case of post-filariasis chronic lower limb lymphedema- a case study and review of literature.

INTRODUCTION AND IMPORTANCE: Filariasis, predominantly caused by the parasite Wuchereria Bancrofti, is a key etiological factor in lymphedema development. Lymphedema, characterized by persistent lymphatic obstruction, leads to significant changes in immunological factors and protein composition. These alterations play a crucial role in the delayed diagnosis of squamous cell carcinoma within chronic lymphedema contexts. Notably, chronic lymphedema is an infrequent but significant precursor to squamous cell carcinoma, with fewer than 20 cases reported in medical literature, including only 11 cases affecting the lower limbs. The management of squamous cell carcinoma in lymphedema is challenging due to the rarity of cases and the resulting lack of experience among clinicians. CASE PRESENTATION: The report focuses on a 69-year-old woman with long-standing right lower limb lymphedema following filariasis. She underwent treatment for a non-healing ulcer in the right gluteal region, diagnosed as moderately differentiated squamous cell carcinoma. Following a wide local excision with primary closure, her lower limb swelling persisted, and subsequent diagnosis confirmed regional lymph node metastasis. The patient was then considered for immunotherapy. CLINICAL DISCUSSION: This case emphasizes the link between chronic lymphedema and squamous cell carcinoma. It highlights the necessity for a multidisciplinary approach for timely and effective treatment, addressing the rarity and complexity of such cases. CONCLUSION: The successful application of immunotherapy in this case illustrates a favorable clinical outcome, marking a significant advancement in treating similar conditions. This finding contributes to the evolving knowledge in this medical field, suggesting immunotherapy as a promising treatment option. METHODS: This case report meticulously follows the SCARE 2023 guidelines: updating consensus Surgical Case Report guidelines (Sohrabi et al., 2023) [1]. These guidelines ensure high-quality reporting in surgical case reports. The report details the evaluation, diagnosis, and a comprehensive review of the literature pertaining to a patient with squamous cell carcinoma of the skin and regional nodal metastasis, which developed in the context of post-filariasis chronic lower limb lymphedema. By employing a multidisciplinary approach, this report achieves a thorough and standardized presentation of the case, serving as a benchmark and an additional tool for raising awareness about such rare medical conditions.

Comparative transcriptome profiling of contrasting finger millet (Eleusine coracana (L.) Gaertn) genotypes under heat stress.

BACKGROUND: Eleusine coracana (L.) Gaertn is a crucial C4 species renowned for its stress robustness and nutritional significance. Because of its adaptability traits, finger millet (ragi) is a storehouse of critical genomic resources for crop improvement. However, more knowledge about this crop's molecular responses to heat stress needs to be gained. METHODS AND RESULTS: In the present study, a comparative RNA sequencing analysis was done in the leaf tissue of the finger millet, between the heat-sensitive (KJNS-46) and heat-tolerant (PES-110) cultivars of Ragi, in response to high temperatures. On average, each sample generated about 24 million reads. Interestingly, a comparison of transcriptomic profiling identified 684 transcripts which were significantly differentially expressed genes (DEGs) examined between the heat-stressed samples of both genotypes. The heat-induced change in the transcriptome was confirmed by qRT-PCR using a set of randomly selected genes. Pathway analysis and functional annotation analysis revealed the activation of various genes involved in response to stress specifically heat, oxidation-reduction process, water deprivation, and changes in heat shock protein (HSP) and transcription factors, calcium signaling, and kinase signaling. The basal regulatory genes, such as bZIP, were involved in response to heat stress, indicating that heat stress activates genes involved in housekeeping or related to basal regulatory processes. A substantial percentage of the DEGs belonged to proteins of unknown functions (PUFs), i.e., not yet characterized. CONCLUSION: These findings highlight the importance of candidate genes, such as HSPs and pathways that can confer tolerance towards heat stress in ragi. These results will provide valuable information to improve the heat tolerance in heat-susceptible agronomically important varieties of ragi and other crops.

Exploration of potential hit compounds targeting 1-deoxy-d-xylulose 5-phosphate reductoisomerase (IspC) from Acinetobacter baumannii: an in silico investigation.

The emergence of carbapenem-resistant Acinetobacter baumannii, a highly concerning bacterial species designated as a Priority 1: Critical pathogen by the WHO, has become a formidable global threat. In this study, we utilised computational methods to explore the potent molecules capable of inhibiting the IspC enzyme, which plays a crucial role in the methylerythritol 4-phosphate (MEP) biosynthetic pathway. Employing high-throughput virtual screening of small molecules from the Enamine library, we focused on the highly conserved substrate binding site of the DXR target protein, resulting in the identification of 1000 potential compounds. Among these compounds, we selected the top two candidates (Z2615855584 and Z2206320703) based on Lipinski's rule of Five and ADMET filters, along with FR900098, a known IspC inhibitor, and DXP, the substrate of IspC, for molecular dynamics (MD) simulations. The MD simulation trajectories revealed remarkable structural and thermodynamic stability, as well as strong binding affinity, for all the IspC-ligand complexes. Furthermore, binding free energy calculations based on MM/PBSA (Molecular Mechanics/Poisson-Boltzmann Surface Area) methodology demonstrated significant interactions between the selected ligand molecules and IspC. Taking into consideration all the aforementioned criteria, we suggest Z2206320703 as the potent lead candidate against IspC. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-03923-w.

A Dual Therapeutic Approach to Diabetes Mellitus via Bioactive Phytochemicals Found in a Poly Herbal Extract by Restoration of Favorable Gut Flora and Related Short-Chain Fatty Acids.

Diabetes mellitus (DM), a metabolic and endocrine condition, poses a serious threat to human health and longevity. The emerging role of gut microbiome associated with bioactive compounds has recently created a new hope for DM treatment. UHPLC-HRMS methods were used to identify these compounds in a poly herbal ethanolic extract (PHE). The effects of PHE on body weight (BW), fasting blood glucose (FBG) level, gut microbiota, fecal short-chain fatty acids (SCFAs) production, and the correlation between DM-related indices and gut microbes, in rats were investigated. Chebulic acid (0.368%), gallic acid (0.469%), andrographolide (1.304%), berberine (6.442%), and numerous polysaccharides were the most representative constituents in PHE. A more significant BW gain and a reduction in FBG level towards normal of PHE 600 mg/kg treated rats group were resulted at the end of 28th days of the study. Moreover, the composition of the gut microbiota corroborated the study's hypothesis, as evidenced by an increased ratio of Bacteroidetes to Firmicutes and some beneficial microbial species, including Prevotella copri and Lactobacillus hamster. The relative abundance of Bifidobacterium pseudolongum, Ruminococcus bromii, and Blautia producta was found to decline in PHE treatment groups as compared to diabetic group. The abundance of beneficial bacteria in PHE 600 mg/kg treatment group was concurrently associated with increased SCFAs concentrations of acetate and propionate (7.26 nmol/g and 4.13 nmol/g). The findings of this study suggest a promising approach to prevent DM by demonstrating that these naturally occurring compounds decreased FBG levels by increasing SCFAs content and SCFAs producing gut microbiota.

A critical review on fate, behavior, and ecotoxicological impact of zinc oxide nanoparticles on algae.

The rapid inclusion of zinc oxide nanoparticles (ZnO NPs) in nanotechnology-based products over the last decade has generated a new threat in the apprehension of the environment. The massive use of zinc nanosized products will certainly be disposed of and be released, eventually entering the aquatic ecosystem, posing severe environmental hazards. Moreover, nanosized ZnO particles owing the larger surface area per volume exhibit different chemical interactions within the aquatic ecosystem. They undergo diverse potential transformations because of their unique physiochemical properties and the feature of receiving medium. Therefore, assessment of their impact is critical not only for scavenging the present situation but also for preventing unintended environmental hazards. Algae being a primary producer of the aquatic ecosystem help assess the risk of massive NPs usage in environmental health. Because of their nutritional needs and position at the base of aquatic food webs, algal indicators exhibit relatively unique information concerning ecosystem conditions. Moreover, algae are presently the most vital part of the circular economy. Hence, it is imperative to understand the physiologic, metabolic, and morphologic changes brought by the ZnO NPs to the algal cells along with the development of the mechanism imparting toxicity mechanism. We also need to develop an appropriate scientific strategy in the innovation process to restrain the exposure of NPs at safer levels. This review provides the details of ZnO NP interaction with algae. Moreover, their impact, mechanism, and factors affecting toxicity to the algae are discussed.

Computational identification of candidate inhibitors for Dihydrofolate reductase in Acinetobacter baumannii.

Acinetobacter baumannii is one of the emerging causes of hospital acquired infections and this bacterium, due to multi-drug resistant and Extensive Drug resistant has been able to develop resistance against the antimicrobial agents that are being used to eliminate it. A.baumannii has been the cause of death in immune compromised patients in hospitals. Hence it is the urgent need of time to find potential inhibitors for this bacterium to cease its virulence and affect its survival inside host organisms. The Dihydrofolate reductase enzyme, which is an important biocatalyst in the conversion of Dihydrofolate to Tetrahydrofolate, is an important drug target protein. In the present study high throughput screening is used to identify the inhibitors of this enzyme. The prioritized ligand molecular candidates identified through virtual screening for the substrate binding site of the predicted model are Z1447621107, Z2604448220 and Z1830442365. The Molecular Dynamics Simulation study suggests that potential inhibitor of the Dihydrofolate reductase enzyme would prevent bacteria from completing its life cycle, affecting its survival. Finally the complexes were analysed for binding free energy of the Dihydrofolate reductase enzyme complexes with the ligands.