Probing and evaluating transmembrane chloride ion transport in double walled trifluorophenyl/phthalimide extended calix[4]pyrrole-based supramolecular receptors.

Therapeutic applications have sparked increased interest in the use of synthetic anion receptors for ion transport across lipid membranes. In this context, the construction of synthetic transmembrane transporters for the physiologically important chloride ion is currently of enormous interest. As a result, considerable effort is being devoted to the design and synthesis of artificial transmembrane chloride ion transporters. However, only inadequate progress has been made in developing macrocyclic chloride ion transporters using the fundamental principles of supramolecular chemistry, and hence this field entails fostering investigations. In this investigation, the synthesis of two new double walled trifluorophenyl/phthalimide extended calix[4]pyrrole (C4P) receptors (3 and 7) has been successfully reported. 1H-NMR titration and HRMS studies confirmed the 1 : 1 binding stoichiometry of the chloride ion with these receptors in the solution phase (only receptor 3b was studied by 1H-NMR). Regarding ion transport of 3b and 7, when studied in the HPTS-based vesicular system, 3b showed better activity with an EC50 value of 0.39 µM. The detailed ion transport studies on 3b have revealed that ion transport occurs through the Cl-/NO3- antiport mode.

Probing protein aggregation through spectroscopic insights and multimodal approaches: A comprehensive review for counteracting neurodegenerative disorders.

Aberrant accumulation of protein misfolding can cause aggregation and fibrillation and is one of the primary characteristic features of neurodegenerative diseases. Because they are disordered, misfolded, and aggregated proteins pose a significant setback in drug designing. The structural study of intermediate steps in these kinds of aggregated proteins will allow us to determine the conformational changes as well as the probable pathways encompassing various neurodegenerative disorders. The analysis of protein aggregates involved in neurodegenerative diseases relies on a diverse toolkit of biophysical techniques, encompassing both morphological and non-morphological methods. Additionally, Thioflavin T (ThT) assays and Circular Dichroism (CD) spectroscopy facilitate investigations into aggregation kinetics and secondary structure alterations. The collective application of these biophysical techniques empowers researchers to comprehensively unravel the intricate nature of protein aggregates associated with neurodegeneration. Furthermore, the topics covered in this review have summed up a handful of well-established techniques used for the structural analysis of protein aggregation. This multifaceted approach advances our fundamental understanding of the underlying mechanisms driving neurodegenerative diseases and informs potential therapeutic strategies.

Actinomycetes - The Repertoire of Diverse Bioactive Chemical Molecules: From Structures to Antibiotics.

The urgent need for novel antibiotics in the face of escalating global antimicrobial resistance necessitates innovative approaches to identify bioactive compounds. Actinomycetes, renowned for their prolific production of antimicrobial agents, stand as a cornerstone in this pursuit. Their diverse metabolites exhibit multifaceted bioactivities, including potent antituberculosis, anticancer, immunomodulatory, immuno-protective, antidiabetic, etc. Though terrestrial sources have been exploited significantly, contemporary developments in the field of antimicrobial drug discovery have put marine actinomycetes in a prominent light as a promising and relatively unexplored source of novel bioactive molecules. This is further boosted by post-genomic era advances like bioinformatics-based secretome analysis and reverse engineering that have totally revitalized actinomycetes antibiotic research. This review highlights actinomycetes-based chemically diverse scaffolds and clinically validated antibiotics along with the enduring significance of actinomycetes from untouched ecosystems, especially with recent advanced techniques in the quest for next-generation antimicrobials.

Deciphering Tuberculous Meningitis: From Clinical Challenges to Novel Models and Pathogenic Pathways.

During and after the COVID-19 pandemic,Tuberculosis (TB) has reestablished with higher figures due to interruptions in the Directly Observed Treatment Short course (DOTS) despite underreporting. The rising consequences would have extended to extra-pulmonary forms of TB as well, including Tuberculous Meningitis (TBM). Considering the fact that TBM is the most dangerous and worst form of TB, we found the need to scan the literature to highlight various aspects of TBM. Epidemiology of TBM is proportionally less frightening, but the consequent mortalities and morbidities are more alarming than pulmonary TB. Here, we address critical research gaps in Tuberculous Meningitis that warrant further investigations. The highlighted aspects encompass a comprehensive understanding of TBM's clinical presentation and improved diagnostic tools for timely detection, the exploration of innovative chemotherapies and surgical interventions, the unraveling of the role of the blood-brain barrier in disease onset, investigating of the contributions of various brain cells to TBM development, deciphering the complex inflammatory response, exploring the involvement of Matrix Metalloproteinases in tissue damage, delving into host-pathogen genetics influencing susceptibility, utilizing robust in-vivo and in-vitro models for mechanistic insights, and more importantly between TBM and SARS-COVID-19 are discussed. Addressing these gaps will substantially advance our understanding of TBM's complex pathogenesis, contributing to more effective diagnostic, therapeutic, and preventive strategies against this debilitating disease.

India's biogeochemical capacity to attain food security and remediate climate.

In order to supply wholesome food and slow down climate change, this paper covers India's agrogeological resources. The soils are the result of the weathering of rocks with ages ranging from more than a billion years to the most recent Holocene. Because they are severely deficient in vital minerals, many soils have low agricultural production. In addition to helping to fertilise soils, reduce atmospheric carbon dioxide levels, and stop the acidification of the Indian Ocean, rock powder weathering and biochar have significant positive effects on the productivity of Indian soils. The nutrient density of food is also increased which improves health and lowers the demand for and cost of medical treatment. Remineralization may help to solve Indian soil issues including soil infertility and texture. To improve soil and plant nutrition, dusts of carbonate, basic, and ultrabasic rocks are readily available at mining sites in India combined with biochar. Adding different grain sizes to the soil helps improve the texture of the soil. Silicate and carbonate rock powders enhance soil structure by promoting the creation of soil organic matter and fostering the growth of advantageous microbial communities. These processes offer a low-cost method of remineralizing soils with important macro- and micronutrients. For each significant soil/crop/climate system, an optimised application of India's rock powder resources must be determined through a national research and development programme. India's capacity to adapt to the mounting challenges of population expansion and climate change would be significantly improved by the findings of this study programme.

Applications of supramolecular assemblies in drug delivery and photodynamic therapy.

One of the world's serious health challenges is cancer. Anti-cancer agents delivered to normal cells and tissues pose several problems and challenges. In this connection, photodynamic therapy (PDT) is a minimally invasive therapeutic technique used for selectively destroying malignant cells while sparing the normal tissues. Development in photosensitisers (PSs) and light sources have to be made for PDT as a first option treatment for patients. In the pursuit of developing new attractive molecules and their formulations for PDT, researchers are working on developing such type of PSs that perform better than those being currently used. For the widespread clinical utilization of PDT, effective PSs are of particular importance. Host-guest interactions based on nanographene assemblies such as functionalized hexa-cata-hexabenzocoronenes, hexa-peri-hexabenzocoronenes and coronene have attracted increasing attention owing to less complicated synthetic steps and purification processes (gel permeation chromatography) during fabrication. Noncovalent interactions provide easy and facile approaches for building supramolecular PSs and enable them to have sensitive and controllable photoactivities, which are important for maximizing photodynamic effects and minimizing side effects. Various versatile supramolecular assemblies based on cyclodextrins, cucurbiturils, calixarenes, porphyrins and pillararenes have been designed in order to make PDT an effective therapeutic technique for curing cancer and tumours. The supramolecular assemblies of porphyrins display efficient electron transfer and fluorescence for use in bioimaging and PDT. The multifunctionalization of supramolecular assemblies is used for designing biomedically active PSs, which are helpful in PDT. It is anticipated that the development of these functionalized supramolecular assemblies will provide more fascinating advances in PDT and will dramatically expand the potential and possibilities in cancer treatments.

Recent advancement in therapeutic strategies for Alzheimer's disease: Insights from clinical trials.

Alzheimer's disease (AD) is the most prevalent form of dementia, characterized by the presence of plaques of amyloid beta and Tau proteins. There is currently no permanent cure for AD; the only medications approved by the FDA for mild to moderate AD are cholinesterase inhibitors, NMDA receptor antagonists, and immunotherapies against core pathophysiology, that provide temporary relief only. Researchers worldwide have made significant attempts to find new targets and develop innovative therapeutic molecules to treat AD. The FDA-approved drugs are palliative and couldn't restore the damaged neuron cells of AD. Stem cells have self-differentiation properties, making them prospective therapeutics to treat AD. The promising results in pre-clinical studies of stem cell therapy for AD seek attention worldwide. Various stem cells, mainly mesenchymal stem cells, are currently in different phases of clinical trials and need more advancements to take this therapy to the translational level. Here, we review research from the past decade that has identified several hypotheses related to AD pathology. Moreover, this article also focuses on the recent advancement in therapeutic strategies for AD treatment including immunotherapy and stem cell therapy detailing the clinical trials that are currently undergoing development.

Pre-polycystic ovary syndrome and polymenorrhoea as new facets of polycystic ovary syndrome (PCOS): Evidences from a single centre data set.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is a complex disorder with diverse metabolic implications. Diagnosis typically relies on oligo-amenorrhoea (OA), hyperandrogenism (HA), and polycystic ovarian morphology (PCOM). However, the role of polymenorrhoea in PCOS remains understudied. Additionally, limited information exists regarding metabolic disturbances in women with partial PCOS phenotypes that do not meet diagnostic criteria. This extensive database aims to provide substantial evidence on the metabolic implications of polymenorrhoea and partial PCOS phenotypes. DESIGN: Prospective observational study. PATIENTS AND MEASUREMENTS: In this single-centre study, 6463 women with PCOS-like characteristics and 3142 age-matched healthy women were included. The study compared clinical (anthropometry, modified Ferriman Gallwey [mFG] score), hormonal (serum testosterone), and metabolic (plasma glucose, serum lipids, insulin) characteristics between women diagnosed with PCOS, those with partial PCOS phenotypes, and the healthy control group RESULTS: In all, 5174 women met Rotterdam criteria for PCOS diagnosis, while 737 were classified as Pre-PCOS, including HA (n = 538), OA (n = 121), or PCOM (n = 78). Common clinical features included oligomenorrhoea (75.5%), hirsutism (82.9%), obesity (27.2%), hypertension (1.6%), metabolic syndrome (19.6%), and diabetes mellitus (5.6%). Women diagnosed with PCOS, HA only, and OA only exhibited higher average body mass index, plasma glucose levels (both fasting and 2 h after the oral glucose tolerance test), and lipid fractions in comparison to those with PCOM and the healthy controls. However, indices of insulin resistance were similar among women with PCOS, HA, PCOM, and OA, albeit higher than in the healthy controls. The polymenorrhoea subgroup (5.9%) had lower BMI and serum testosterone, but similar mFG score, plasma glucose, insulin, and lipid levels as the oligomenorrhoea subgroup. CONCLUSION: The metabolic disturbances observed in Pre-PCOS women highlight the need to reassess diagnostic criteria. Including the polymenorrhoea subcategory in PCOS criteria is recommended due to similar metabolic dysfunctions as the oligomenorrhoea group.

Perceived Use Behavior of Social Networking Sites Among the Healthcare Students in India.

Introduction: The use of social networking sites (SNSs) is growing among higher education students, including healthcare students. Nonetheless, limited research has examined the perceived use behavior among healthcare students in developing countries such as India. Objective: This study attempts to assess the use behavior of SNSs by undergraduate students in the fields of nursing and pharmacy in India through the lens of Connectivism and New Social Learning theories. Method: The study used a Google form to collect data through an online questionnaire. A sample of 483 participants included 258 Bachelor of Science in Nursing students, 161 General Nursing and Midwifery students, and 64 Bachelor of Pharmacy students from various Indian nursing and pharmacy schools. Results: The majority of the respondents prefer to use SNSs for several purposes such as watching academic videos on YouTube, sharing their ideas, thoughts, and current development in their respective fields through WhatsApp, getting job-related information from different Facebook pages, etc. A substantial number of nursing students believed that these SNSs help them build relationships with professionals across the country. At the same time, many students also indicated that extensive use of SNSs might cause sleep difficulties, data privacy concerns, and a lack of focus while studying. Conclusion: To have an impact on how SNSs are used in healthcare education, more attention should be paid to build connectivism between educators and their students on social learning environment, which the findings of this study's suggestions could be put into practice.

Porphyrin-based conjugated microporous adsorbent material for the efficient remediation of hexavalent chromium from the aquatic environment.

The encapsulation and eradication of anions from water have received a lot of scrutinize and are extremely important for virtuous production and environmental treatment. To prepare extremely efficient adsorbents, a highly functionalized and conjugated microporous porphyrin-based adsorbent material (Co-4MPP) was synthesized using the Alder Longo method. Co-4MPP featured a hierarchical microporous and mesoporous layered structure containing nitrogen and oxygen-based functional groups with a specific surface area of 685.209 m2/g and a pore volume of 0.495 cm3/g. Co-4MPP demonstrated a greater Cr (VI) adsorption empathy than the pristine porphyrin-based material did. The effects of various parameters such as pH, dose, time, and temperature were explored on the Cr (VI) adsorption by Co-4MPP. The pseudo-second-order model and the Cr (VI) adsorption kinetics were in agreement (R2 = 0.999). The Langmuir isotherm model matched the Cr (VI) adsorption isotherm, demonstrating the optimum Cr (VI) adsorption capacities: 291.09, 307.42, and 339.17 mg/g at 298K, 312K, and 320K, correspondingly, with remediation effectiveness of 96.88%. The model evaluation further revealed that Cr (VI) adsorption mechanism on Co-4MPP was endothermic, spontaneous, and entropy-rising. The detailed discussion of the adsorption mechanism suggested that it could be a reduction, chelation, and electrostatic interaction, in which the protonated nitrogen and oxygen-containing functional groups on the porphyrin ring interacted with Cr (VI) anions to form a stable complex, thus remediating Cr (VI) anions efficiently. Moreover, Co-4MPP demonstrated strong reusability, maintaining 70% of its Cr (VI) elimination rate after four consecutive adsorptions.

Forthcoming Developments in Models to Study the Hepatitis B Virus Replication Cycle, Pathogenesis, and Pharmacological Advancements.

Hepatitis, liver cirrhosis, and hepatocellular carcinoma are all manifestations of chronic hepatitis B. Its pathogenesis and molecular mechanism remain mysterious. As medical science progresses, different models are being used to study the disease from the physiological and molecular levels. Animal models have played an unprecedented role in achieving in-depth knowledge of the disease while posing no risk of harming humans throughout the study. The scarcity of acceptable animal models has slowed progress in hepatitis B virus (HBV) research and preclinical testing of antiviral medicines since HBV has a narrow species tropism and exclusively infects humans and higher primates. The development of human chimeric mice was supported by a better understanding of the obstacles to interspecies transmission, which has substantially opened the way for HBV research in vivo and the evaluation of possible chronic hepatitis B therapeutics. Animal models are cumbersome to handle, not accessible, and expensive. Hence, it is herculean to investigate the HBV replication cycle in animal models. Therefore, it becomes essential to build a splendid in vitro cell culture system to demonstrate the mechanisms attained by the HBV for its multiplication and sustenance. We also addressed the advantages and caveats associated with different models in examining HBV.

Vortex nucleation in rotating Bose-Einstein condensates with density-dependent gauge potential.

We study numerically the vortex dynamics and vortex-lattice formation in a rotating density-dependent Bose-Einstein condensate (BEC), characterized by the presence of nonlinear rotation. By varying the strength of nonlinear rotation in density-dependent BECs, we calculate the critical frequency, Ω_{cr}, for vortex nucleation both in adiabatic and sudden external trap rotations. The nonlinear rotation modifies the extent of deformation experienced by the BEC due to the trap and shifts the Ω_{cr} values for vortex nucleation. The critical frequencies, and thereby the transition to vortex-lattices in an adiabatic rotation ramp, depend on conventional s-wave scattering lengths through the strength of nonlinear rotation, C, such that Ω_{cr}(C>0)<Ω_{cr}(C=0)<Ω_{cr}(C<0). In an analogous manner, the critical ellipticity (ε_{cr}) for vortex nucleation during an adiabatic introduction of trap ellipticity (ε) depends on the nature of nonlinear rotation besides trap rotation frequency. The nonlinear rotation additionally affects the vortex-vortex interactions and the motion of the vortices through the condensate by altering the strength of Magnus force on them. The combined result of these nonlinear effects is the formation of the non-Abrikosov vortex-lattices and ring-vortex arrangements in the density-dependent BECs.

Prevalence of Thiamine Deficiency in Pregnancy and its impact on fetal outcome in an area endemic for thiamine deficiency.

BACKGROUND: Pregnancy is a metabolically challenging state with increased nutritional demand. Thiamine is an important cofactor in various metabolic pathways and thus its deficiency could have a serious impact on both maternal and fetal outcomes. Kashmir has thiamine deficiency in endemic proportions, with multiple reports of infantile beriberi, postpartum neuropathy, and gastric beriberi. This prompted us to assess the extent of the burden of thiamine deficiency during pregnancy. METHODS: This cross-sectional study was conducted for a period of two years in pregnant women attending the antenatal clinic. A demographic, clinical, biochemical, and dietary assessment was done in all participants. The whole blood thiamine levels were assessed by high-performance liquid chromatography. RESULTS: A total of 492 participants were included in the study with a mean age of 30.30±4.57 years and a mean BMI of 24.25±3.32 Kg/m2. The mean whole blood thiamine level of all participants was 133.29±14.32 nmol/L. Low thiamine status was present in 38.2% (n = 188) of participants. Participants with low thiamine had poor perinatal outcomes, with 3.1% (n = 6) reporting early infant death. CONCLUSION: A high prevalence of thiamine deficiency occurs in pregnant women of Kashmir. Low thiamine is associated with poor nutritional status as well as poor perinatal outcomes. TRIAL REGISTRATION: CTRI/2022/07/044217.

Androgen receptor signaling and pyrethroids: Potential male infertility consequences.

Infertility is a global health concern inflicting a considerable burden on the global economy and a severe socio-psychological impact. Approximately 15% of couples suffer from infertility globally, with a male factor contribution of approximately 50%. However, male infertility remains largely unexplored, as the burden of infertility is mostly assigned to female people. Endocrine-disrupting chemicals (EDCs) have been proposed as one of the factors causing male infertility. Pyrethroids represent an important class of EDCs, and numerous studies have associated pyrethroid exposure with impaired male reproductive function and development. Therefore, the present study investigated the potentially toxic effects of two common pyrethroids, cypermethrin and deltamethrin, on androgen receptor (AR) signaling. The structural binding characterization of cypermethrin and deltamethrin against the AR ligand-binding pocket was performed using Schrodinger's induced fit docking (IFD) approach. Various parameters were estimated, such as binding interactions, binding energy, docking score, and IFD score. Furthermore, the AR native ligand, testosterone, was subjected to similar experiments against the AR ligand-binding pocket. The results revealed commonality in the amino acid-binding interactions and overlap in other structural parameters between the AR native ligand, testosterone, and the ligands, cypermethrin and deltamethrin. The estimated binding energy values of cypermethrin and deltamethrin were very high and close to those calculated for AR native ligand, testosterone. Taken together, the results of this study suggested potential disruption of AR signaling by cypermethrin and deltamethrin, which may result in androgen dysfunction and subsequent male infertility.

Nephroprotective effects of honokiol in a high-fat diet-streptozotocin rat model of diabetic nephropathy.

AIMS: Diabetic nephropathy (DN) is the foremost basis of end-stage kidney failure implicating endoplasmic reticulum (ER) stress and dysregulation of Rho kinase/Rock pathway. Magnolia plants are used in traditional medicine systems in Southeast Asia owing to bioactive phytoconstituents. Earlier, honokiol (Hon) exhibited therapeutic potential in experimental models of metabolic, renal, and brain disorders. In the present study, we evaluated potential of Hon against DN and possible molecular mechanisms. MAIN METHODS: In the existing experiments, high-fat diet (HFD) (17 weeks) and streptozotocin (STZ) (40 mg/kg once) induced DN rats were orally treated with Hon (25, 50, 100 mg/kg) or metformin (150 mg/kg) for 8 weeks. KEY FINDINGS: Hon attenuated albuminuria, blood biomarkers (e.g., urea nitrogen, glucose, C-reactive protein, and creatinine) and ameliorated lipid profile, electrolytes levels (Na+/K+), and creatinine clearance against DN. Hon significantly decreased renal oxidative stress and inflammatory biomarkers against DN. Histomorphometry and microscopic analysis revealed nephroprotective effects of Hon marked by a decrease in leukocyte infiltration, renal tissue damage, and urine sediments. RT-qPCR showed that Hon treatment attenuated mRNA expression of transforming growth factor-ß1 (TGF-ß1), endothelin-1 (ET-1), ER stress markers (GRP78, CHOP, ATF4, and TRB3), and Rock 1/2 in DN rats. Data from ELISA supported a decrease in levels of TGF-ß1, ET-1, ER stress markers, and Rock1/2 by Hon. SIGNIFICANCE: Hon attenuated hyperglycemia, redox imbalance, and inflammation and improved renal functions in rats. Hon alleviates DN pathogenesis possibly by attenuating ER stress and Rock pathway.

An Analysis of the Structural Relationship between Thyroid Hormone-Signaling Disruption and Polybrominated Diphenyl Ethers: Potential Implications for Male Infertility.

Polybrominated diphenyl ethers (PBDEs) are a common class of anthropogenic organobromine chemicals with fire-retardant properties and are extensively used in consumer products, such as electrical and electronic equipment, furniture, textiles, and foams. Due to their extensive use, PBDEs have wide eco-chemical dissemination and tend to bioaccumulate in wildlife and humans with many potential adverse health effects in humans, such as neurodevelopmental deficits, cancer, thyroid hormone disruption, dysfunction of reproductive system, and infertility. Many PBDEs have been listed as chemicals of international concern under the Stockholm Convention on Persistent Organic Pollutants. In this study, the aim was to investigate the structural interactions of PBDEs against thyroid hormone receptor (TRα) with potential implications in reproductive function. Structural binding of four PBDEs, i.e., BDE-28, BDE-100, BDE-153 and BDE-154 was investigated against the ligand binding pocket of TRα using Schrodinger's induced fit docking, followed by molecular interaction analysis and the binding energy estimation. The results indicated the stable and tight binding of all four PDBE ligands and similarity in the binding interaction pattern to that of TRα native ligand, triiodothyronine (T3). The estimated binding energy value for BDE-153 was the highest among four PBDEs and was more than that of T3. This was followed by BDE-154, which is approximately the same as that of TRα native ligand, T3. Furthermore, the value estimated for BDE-28 was the lowest; however, the binding energy value for BDE-100 was more than BDE-28 and close to that of TRα native ligand, T3. In conclusion, the results of our study suggested the thyroid signaling disruption potential of indicated ligands according to their binding energy order, which can possibly lead to disruption of reproductive function and infertility.

Aryl- and Superaryl-Extended Calix[4]pyrroles: From Syntheses to Potential Applications.

The incorporation of aryl substituents at the meso-positions of calix[4]pyrrole (C4P) scaffolds produces aryl-extended (AE) and super-aryl-extended (SAE) calix[4]pyrroles. The cone conformation of the all-α isomers of "multi-wall" AE-C4Ps and SAE-C4Ps displays deep aromatic clefts or cavities. In particular, "four-wall" receptors feature an aromatic polar cavity closed at one end with four convergent pyrrole rings and fully open at the opposite end. This makes AE- and SAE-C4P scaffolds effective receptors for the molecular recognition of negatively charged ions and neutral guest molecules with donor-acceptor and hydrogen bonding motifs. In addition, adequately functionalized all-α isomers of multi wall AE- and SAE-C4P scaffolds self-assemble into uni-molecular and supra-molecular aggregates displaying capsular and cage-like structures. The self-assembly process requires the presence of template ions or molecules that lock the C4P cone conformation and complementing the inner polar functions and volumes of their cavities. We envisioned performing an in-depth revision of AE- and SAE-C4P scaffolds owing to their importance in different domains such as supramolecular chemistry, biology, material sciences and pharmaceutical chemistry. Herewith, besides the synthetic details on the elaboration of their structures, we also draw attention to their diverse applications. The organization of this review is mainly based on the number of "walls" present in the AE-C4P derivatives and their structural modifications. The sections are further divided based on the C4P functions and applications. The authors are convinced that this review will be of interest to researchers working in the general area of supramolecular chemistry as well as those involved in the study of the binding properties and applications of C4P derivatives.

Identification of a survival associated gene trio in chemical induced breast cancer.

Sporadic cases of breast cancer being more prevalent than the hereditary cases, can be largely attributed to environmental pollutants like polycyclic aromatic hydrocarbons (PAHs). The aim of the present study was to identify gene dysregulations and the associations in DMBA (a PAH) induced breast cancer. A breast cancer model was developed in Wistar rats (n = 40), using DMBA. Serum proteomics (2D electrophoresis and MALDI-TOF MS) followed by relative gene expression analysis in mammary glands were conducted to reach to the differential gene signatures. The candidate genes were subjected to survival analysis (by GEPIA2 and KM plotter) and infiltration analysis (by ImmuCellAI) for correlating gene expression with patient survival and immune cell infiltration respectively. Further, the regulatory network investigation (by Cytoscape) was performed to find out the transcription factors (TFs) and miRNAs of the concerned genes. A gene trio (ANXA5, MTG1, PPP2R5B), expressing differentially in early mammary carcinogenesis at 4 months (precancerous stage) till full-fledged cancerous stage (post 6 months) was identified. The altered gene expression was associated with less survival among breast cancer patients (n = 4019). The dysregulated expression also has a correlation with enhanced mammary infiltration of immune cells. Moreover, a regulatory network (comprising of 77 transcription factors and 50 miRNAs) involved in the regulation of candidate genes was also deciphered. The deregulated target genes can therefore be explored for reregulation via identified TFs and miRNAs, and survival thereby improved.

How do researchers perceive research misbehaviors? A case study of Indian researchers.

Despite ample evidence of increasing research misconduct in India, little attention has been paid to understanding researchers' perception of research integrity and research misconduct among young Indian researchers. Interviews among 30 research scholars were conducted at Pondicherry University in India to understand their experience and perception of research misconduct. The top three influencing factors for scientific misconduct, according to the participants, were unavailability of adequate funds (35%), pressure from research supervisors (29%), and desperation to publish articles (25%). The participants had witnessed research misconduct in different forms i.e., data fabrication, falsification, and plagiarism. However, plagiarism was the most often cited cause of misbehavior in our interviews. Majority of participants have witnessed or personally encountered multiple instances where authorship conflicts occurred. The other questionable research practices highlighted in the study were improper citations, authorship disputes like gift and ghost authorships, misrepresentation of statistical data, failure to publish negative results. In an increasingly diverse and changing research environment, our research calls for practical research guidelines based on honesty, openness, and accountability that can help articulate and strengthen scientists' core values. More importantly, scientific misconduct can only be prevented by using a multifaceted strategy that includes identifying instances of scientific misconduct and implementing suitable deterrents and treatments that could change the behavior associated with such misconduct.

Efficacy and safety of various oral regimens (three oral doses) and schedules (daily v. monthly) of cholecalciferol in North Indian adults with low vitamin D status: evidence from a randomised controlled trial.

Vitamin D (VD) deficiency (serum 25 hydroxy vitamin D (25(OH)D) concentration of < 20 ng/ml), in endemic proportions, demands a supplementation strategy with optimal dosing regimens. A randomised parallel-group, active-controlled trial was conducted among apparently healthy, VD-deficient subjects, aged 18-60 years who received 600 µg/d (Group A), 1000 µg/d (Group B), 2000 µg/d (Group C) and 60 000 µg/month (Group D) of oral cholecalciferol. The intervention was carried in two phases (I and II) of 12 weeks each, with same dose, separated by a washout phase of 12 weeks. Serum 25(OH)D, intact parathyroid hormones (iPTH), Ca, phosphorous (PO4), alkaline phosphatase (ALP) and spot urine Ca/Cr were measured at baseline, 12, 24 and 36 weeks following the intervention, and adverse events were recorded at each occurrence and at 12, 24 and 36 weeks. A statistically significant time-group interaction was found in serum 25(OH)D concentration (P < 0·05). Serum 25(OH)D concentration increased significantly from baseline to 12 weeks (P < 0·05) in all the groups with no change at 24 weeks but further increase at 36 weeks (P < 0·05). At the end of the study, Group C had maximum increment in serum 25(OH)D concentration, while as Groups C and D (95 %, and 90 %) had higher proportion of subjects VD sufficient than Groups A and B (65 % and 78 %) (P < 0·05). No significant time-dose interactions were observed in serum iPTH, Ca, PO4 and ALP or urine Ca/Cr ratio. Three subjects (two in Group C and one in Group D) developed transient hypercalciuria. Supplementation with daily 2000 µg or monthly 60 000 µg of oral cholecalciferol among adults seems optimal and safe.