Pyridine-2,6-Dicarboxamide Proligands and their Cu(II)/Zn(II) Complexes Targeting Staphylococcus Aureus for the Attenuation of In Vivo Dental Biofilm.

In the pursuit to combat stubborn bacterial infections, particularly those stemming from gram-positive bacteria, this study is an attempt to craft a precision-driven platform characterized by unparalleled selectivity, specificity, and synergistic antimicrobial mechanisms. Leveraging remarkable potential of metalloantibiotics in antimicrobial applications, herein, this work rationally designs, synthesizes, and characterizes a new library of Pyridine-2,6-dicarboxamide ligands and their corresponding transition metal Cu(II)/Zn(II) complexes. The lead compound L11 demonstrates robust antibacterial properties against Staphylococcus aureus (Minimum Inhibitory Concentration (MIC) = 2-16 µg mL-1), methicillin and vancomycin-resistant S. aureus (MIC = 2-4 µg mL-1) and exhibit superior antibacterial activity when compared to FDA-approved vancomycin, the drug of last resort. Additionally, the compound exhibits notable antimicrobial efficacy against resistant enterococcus strains (MIC = 2-8 µg mL-1). To unravel mechanistic profile, advanced imaging techniques including SEM and AFM are harnessed, collectively suggesting a mechanistic pathway involving cell wall disruption. Live/dead fluorescence studies further confirm efficacy of L11 and its complexes against S. aureus membranes. This translational exploration extends to a rat model, indicating promising in vivo therapeutic potential. Thus, this comprehensive research initiative has capabilities to transcends the confines of this laboratory, heralding a pivotal step toward combatting antibiotic-resistant pathogens and advancing the frontiers of metalloantibiotics-based therapy with a profound clinical implication.

Assessment of acceptability of black wheat flour products and factors affecting it among Anganwadi beneficiaries and workers: A mixed-method prospective observational study.

Introduction: Malnutrition is very common in India and black wheat might be an acceptable solution to this problem. The aim of the study was to assess acceptability of black wheat flour products and factors affecting it among Anganwadi beneficiaries and workers. Materials and Methods: This was a mixed-method prospective observational study. All the family members enrolled for supplementary nutrition and Anganwadi workers/helpers of three randomly selected Anganwadi centers were taken in the study. For qualitative data, in-depth interview was done, and for quantitative data, 9-point hedonic scale was administered. Braun and Clarke's six-phase data analysis framework was used for qualitative data. Results: A total of 16 pregnant females, 14 lactating females, 16 children, 2 Anganwadi workers, and 3 Anganwadi helpers participated in the study. Thematic analysis of the data revealed five significant themes. It included characteristics of black wheat flour, the process of making the product (experience of making the product), family acceptability, availability, and hygiene. Participants expressed that the black color appearance is one of the negative influencers in the acceptability of black wheat flour. Most of the participants liked the taste as well as the texture. However, kneading, rolling, and puffing were more challenging than traditional wheat flour. On the hedonic scale, the mean rank of acceptability is lowest for color (3.03), followed by puffing (3.49) and highest for texture (4.87) and taste (4.60). Conclusion: Our study results revealed that black wheat is acceptable to the Anganwadi beneficiaries and workers.

Structure and energetics guide dynamic behaviour in a T = 3 icosahedral virus capsid.

Although virus capsids appear as rigid, symmetric particles in experimentally determined structures; biochemical studies suggest a significant degree of structural flexibility in the particles. We carried out all-atom simulations on the icosahedral capsid of an insect virus, Flock House Virus, which show intriguing differences in the degree of flexibility of quasi-equivalent capsid subunits consistent with previously described biological behaviour. The flexibility of all the ß and γ subunits of the protein and RNA fragments is analysed and compared. Both γA subunit and RNA fragment exhibit higher flexibility than the γB and γC subunits. The capsid shell is permeable to the bidirectional movement of water molecules, and the movement is heavily influenced by the geometry of the capsid shell along specific symmetry axes. In comparison to the symmetry axes along I5 and I3, the I2 axis exhibits a slightly higher water content. This enriched water environment along I2 could play a pivotal role in facilitating the structural transitions necessary for RNA release, shedding some light on the intricate and dynamic processes underlying the viral life cycle. Our study suggests that the physical characterization of whole virus capsids is the key to identifying biologically relevant transition states in the virus life cycle and understanding the basis of virus infectivity.

AI-based AlphaFold2 significantly expands the structural space of the autophagy pathway.

ABBREVIATIONS: AF2: AlphaFold2; AF2-Mult: AlphaFold2 multimer; ATG: autophagy-related; CTD: C-terminal domain; ECTD: extreme C-terminal domain; FR: flexible region; MD: molecular dynamics; NTD: N-terminal domain; pLDDT: predicted local distance difference test; UBL: ubiquitin-like.

Oral versus long-acting injectable antipsychotic in first episode schizophrenia: A 12 weeks interventional study.

Background: There is underutilization of long-acting injectable (LAI) antipsychotics for first-episode schizophrenia (FES) despite having convenient dosing and treatment retention. LAIs are predominantly used for patients with poor compliance, chronic course, and multiple relapses. Materials and Methods: Seventy-two treatment naïve patients with the first episode of Schizophrenia (DSM-5) were assessed for baseline severity of psychopathology using the positive and negative syndrome scale (PANSS) and quality of life (QOL) using the WHOQOL-BREF scale. Patients were randomized to receive either oral haloperidol or LAI haloperidol for a period of 12 weeks. Results: Both the groups had a significant reduction in PANSS scores and improvement in QoL over 12 weeks period (P = 0.0001). The LAI group showed greater adherence and significantly better quality of life than the oral group (P = 0.023). The mean numbers of side effects were less in the LAI group at week 2 as compared to the oral group. Conclusion: LAI haloperidol is similar to oral haloperidol in patients with FES with respect to treatment response and offers benefits in form of a lesser number of side effects during early treatment, overall better adherence rates, and better QOL.

Expectations of caregivers of persons with severe mental illness from mental health rehabilitation services: A qualitative study.

BACKGROUND: Mental health rehabilitation services (MHRS) play an essential role in addressing the diverse and often complex needs of persons with severe mental illness (SMI). The rehabilitation services are of utmost importance in training these patients to lead an independent and meaningful life. In India, caregivers of persons with SMI play a significant role in the decision-making process concerning treatment and rehabilitation. AIM: The main objective of the present study was to understand and analyze the expectations of caregivers of persons with severe mental illness from mental health rehabilitation services in the Indian context. METHOD: The present study is qualitative in nature. A semi-structured interview schedule was used to capture the caregivers' expectations. Fifteen caregivers who met inclusion and exclusion criteria were interviewed for the study. The data obtained was analyzed using Braun and Clarke's six-phase data analysis framework. RESULTS: Thematic analysis of the data emerged into five themes, namely (1) 'proximity', (2) 'professionalism of staff', (3) 'treatment related expectations', (4) 'welfare benefits', and (5) 'infrastructure'. These themes and their sub-themes were subsequently discussed in the light of existing literature. CONCLUSION: Caregivers of persons with SMI identified the most relevant as well as generic expectations from MHRS. Understanding these expectations can help improvise the existing services delivery system and help institutes, non-government organizations (NGOs) and other concerned entities working in mental health rehabilitation to develop service user friendly rehabilitation models.

Biologic Therapy in HIV: To Screen or Not to Screen.

Biologic therapy has revolutionized the management of chronic inflammatory diseases, including inflammatory bowel disease (IBD). Before the initiation of therapy, it is critical to rule out prior infection of chronic hepatitis B virus (HBV) and tuberculosis (TB). However, screening for human immunodeficiency virus (HIV) is not as routinely completed. We present a case of a 56-year-old male on ustekinumab for the management of Crohn's disease, found to have undiagnosed human immunodeficiency virus (HIV) with progression to acquired immunodeficiency syndrome (AIDS).

Major acute cardiovascular events in patients with inflammatory bowel disease.

BACKGROUND: Systemic inflammation and immune-mediated diseases have been associated with ischemic heart disease in addition to traditional risk factors. In this study, we investigate associations between inflammatory bowel disease (IBD) and acute cardiovascular events. METHODS: An observational study where patient data were extracted from our health system patient pool of 3 917 894. Propensity scores were calculated for all 15 292 patients (0.39%) with IBD to assemble a 1:1 matched cohort balanced for age, gender, race and known cardiovascular risk factors including hypertension, hyperlipidemia, diabetes mellitus and smoking (current and former). Secondary analyses were performed independently for 6658 patients with ulcerative colitis and 9406 patients with Crohn's disease. ICD-9 and ICD-10 codes were used to identify cardiovascular risk factors and outcomes. RESULTS: Matched patients (n = 30 584) had a mean age of 51 years, with 58% being women, and 63% Caucasian. During the median follow-up of 4.4 years, all-cause mortality was observed in 1.7 versus 1.2% of patients from IBD and non-IBD groups, respectively [hazard ratio, 1.31; 95% confidence interval (CI), 1.08-1.58; P = 0.005]. Combined outcome for myocardial infarction or cardiovascular mortality was noted in 2.3 and 2.1% from IBD and non-IBD groups, respectively (hazard ratio, 1.04; 95% CI, 0.90-1.21; P = 0.588), while hazard ratios for cardiovascular mortality, myocardial infarction and unstable angina were 1.04 (0.74-1.47; P = 0.833), 1.05 (0.89-1.23; P = 0.591) and 1.10 (0.83-1.46; P = 0.524), respectively. CONCLUSIONS: Among patients with IBD, incidence of acute coronary events did not show a statistically significant difference when compared to the matched cohort.

Effects of abstinence of alcohol on neurocognitive functioning in patients with alcohol dependence syndrome.

AIMS: Alcohol dependence causes impairment of neurocognitive functions. Abstinence for some time leads to improvement in neurocognitive functions. This study was conducted with the aim to observe the effects of abstinence on neurocognition. METHODS: The current study was an observational, single group with longitudinal design exploring the effect of abstinence on neuropsychological functioning and further exploring correlation of clinical factors with neuropsychological functioning in patients with Alcohol Dependence Syndrome (ADS). Sixty consecutive male patients of ADS meeting inclusion and exclusion criteria were inducted. Neurocognitive tests were applied at baseline, one month and three months of abstinence. RESULTS: All neurocognitive functions showed significant improvement at three-time intervals (p < 0.05) except for visuomotor function, for which improvement was statistically insignificant (p > 0.05) at one month. The difference for scores on verbal fluency, working memory, set-shifting (WCST total trials and perseverative errors) and visuomotor function from 0 to 3 months was significant (p < 0.05). There was significant interaction (p < 0.05) between duration of regular but non-dependent use, total duration of use, duration of dependence, average intake per day, last intake and time period with verbal fluency, working memory, set -shifting (for WCST total trials, total errors, perseverative errors and non-perseverative errors) and visuomotor function. CONCLUSION: The study showed improvement in neurocognitive functions with abstinence over three months, suggesting the need to address these cognitive deficits in the early part of abstinence. Also, correlates for drinking history were identified which may help in the future for the prevention and management of cognitive deficits in ADS patients.

Neonatal-derived IL-17 producing dermal γδ T cells are required to prevent spontaneous atopic dermatitis.

Atopic Dermatitis (AD) is a T cell-mediated chronic skin disease and is associated with altered skin barrier integrity. Infants with mutations in genes involved in tissue barrier fitness are predisposed towards inflammatory diseases, but most do not develop or sustain the diseases, suggesting that there exist regulatory immune mechanisms to prevent aberrant inflammation. The absence of one single murine dermal cell type, the innate neonatal-derived IL-17 producing γδ T (Tγδ17) cells, from birth resulted in spontaneous, highly penetrant AD with many of the major hallmarks of human AD. In Tγδ17 cell-deficient mice, basal keratinocyte transcriptome was altered months in advance of AD induction. Tγδ17 cells respond to skin commensal bacteria and the fulminant disease in their absence was driven by skin commensal bacteria dysbiosis. AD in this model was characterized by highly expanded dermal αß T clonotypes that produce the type three cytokines, IL-17 and IL-22. These results demonstrate that neonatal Tγδ17 cells are innate skin regulatory T cells that are critical for skin homeostasis, and that IL-17 has dual homeostatic and inflammatory function in the skin.

Attitude and perceptions of patients towards long acting depot injections (LAIs).

BACKGROUND: Despite the well-established efficacy of the long acting depot injectable (LAIs) antipsychotics, these are significantly underused and underutilized by the mental health professionals, with a belief that patients will not accept the same. AIMS & OBJECTIVES: To explore the acceptability and perception of patients towards various psychiatric treatments, with specific focus on LAIs. Additionally the study aimed to compare the acceptability of various types of treatments including LAIs between patients with severe mental disorders (Psychotic disorders and Bipolar disorder) and those with Common mental disorders (Anxiety, neurotic and depressive disorders). METHODOLOGY: A self-designed semi-structured questionnaire was used to evaluate the preferred treatment options of all the new patients attending the psychiatry outpatient clinic of a tertiary care hospital. Depending on the response, they were further probed for the reasons for accepting or rejecting the LAIs. RESULTS: 2659 patients were interviewed who were divided into two groups (Group I - 321 subjects with psychotic disorders and 120 subjects with bipolar affective disorder (BPAD) and Group II - 2218 subjects with neurotic, stress-related and unipolar depressive disorders). More than three-fourth (78.8%) of the participants in the whole study sample opted for tablets only as their first preferred choice and injectables were opted by about 5% of the participants only, with no significant difference between the 2 groups. After being explained about LAIs, one fourth of the participants (24.9%) reported that they may consider LAIs, without any significant difference between the 2 groups. Among those who refused to take LAIs even after explanation, the commonly reported reasons were difficulty in visiting hospital frequently for the injectables (41.69%), injectables being painful (19.41%), fear of injections (13.96%), no need to take LAIs (12.45%) and preference to take some other types of medicines (8.52%). CONCLUSIONS: Considering the fact that LAIs are highly underused in patients with severe mental disorders and there is lack of awareness about LAIs among patients with severe mental disorders, the present study findings suggest that there is reasonable level of acceptance of LAIs among patients with severe mental disorders when explained about the same.

Immune checkpoint inhibitor-induced colitis: A comprehensive review.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target down-regulators of the anti-cancer immune response: Cytotoxic T-lymphocyte antigen-4, programmed cell death protein-1, and its ligand programmed death-ligand 1. ICIs have revolutionized the treatment of a variety of malignancies. However, many immune-related adverse events have also been described which mainly occurs as the immune system becomes less suppressed, affecting various organs including the gastrointestinal tract and causing diarrhea and colitis. The incidence of immune-mediated colitis (IMC) ranges from 1%-25% depending on the type of ICI and if used in combination. Endoscopically and histologically there is a significant overlap between IMC and inflammatory bowel disease, however more neutrophilic inflammation without chronic inflammation is usually present in IMC. Corticosteroids are recommended for grade 2 or more severe colitis while holding the immunotherapy. About one third to two thirds of patients are steroid refractory and benefit from infliximab. Recently vedolizumab has been found to be efficacious in steroid and infliximab refractory cases. While in grade 4 colitis, the immunotherapy is permanently discontinued, the decision is controversial in grade 3 colitis.

Injury, dysbiosis, and filaggrin deficiency drive skin inflammation through keratinocyte IL-1α release.

BACKGROUND: Atopic dermatitis (AD) is associated with epidermal barrier defects, dysbiosis, and skin injury caused by scratching. In particular, the barrier-defective epidermis in patients with AD with loss-of-function filaggrin mutations has increased IL-1α and IL-1ß levels, but the mechanisms by which IL-1α, IL-1ß, or both are induced and whether they contribute to the aberrant skin inflammation in patients with AD is unknown. OBJECTIVE: We sought to determine the mechanisms through which skin injury, dysbiosis, and increased epidermal IL-1α and IL-1ß levels contribute to development of skin inflammation in a mouse model of injury-induced skin inflammation in filaggrin-deficient mice without the matted mutation (ft/ft mice). METHODS: Skin injury of wild-type, ft/ft, and myeloid differentiation primary response gene-88-deficient ft/ft mice was performed, and ensuing skin inflammation was evaluated by using digital photography, histologic analysis, and flow cytometry. IL-1α and IL-1ß protein expression was measured by means of ELISA and visualized by using immunofluorescence and immunoelectron microscopy. Composition of the skin microbiome was determined by using 16S rDNA sequencing. RESULTS: Skin injury of ft/ft mice induced chronic skin inflammation involving dysbiosis-driven intracellular IL-1α release from keratinocytes. IL-1α was necessary and sufficient for skin inflammation in vivo and secreted from keratinocytes by various stimuli in vitro. Topical antibiotics or cohousing of ft/ft mice with unaffected wild-type mice to alter or intermix skin microbiota, respectively, resolved the skin inflammation and restored keratinocyte intracellular IL-1α localization. CONCLUSIONS: Taken together, skin injury, dysbiosis, and filaggrin deficiency triggered keratinocyte intracellular IL-1α release that was sufficient to drive chronic skin inflammation, which has implications for AD pathogenesis and potential therapeutic targets.

SOX4 controls invariant NKT cell differentiation by tuning TCR signaling.

Natural killer T (NKT) cells expressing the invariant T cell receptor (iTCR) serve an essential function in clearance of certain pathogens and have been implicated in autoimmune and allergic diseases. Complex effector programs of these iNKT cells are wired in the thymus, and upon thymic egress, they can respond within hours of antigenic challenges, classifying iNKT cells as innate-like. It has been assumed that the successful rearrangement of the invariant iTCRα chain is the central event in the divergence of immature thymocytes to the NKT cell lineage, but molecular properties that render the iTCR signaling distinct to permit the T cell lineage diversification remain obscure. Here we show that the High Mobility Group (HMG) transcription factor (TF) SOX4 controls the production of iNKT cells by inducing MicroRNA-181 (Mir181) to enhance TCR signaling and Ca2+ fluxes in precursors. These results suggest the existence of tailored, permissive gene circuits in iNKT precursors for innate-like T cell development.

RORα-expressing T regulatory cells restrain allergic skin inflammation.

Atopic dermatitis is an allergic inflammatory skin disease characterized by the production of the type 2 cytokines in the skin by type 2 innate lymphoid cells (ILC2s) and T helper 2 (TH2) cells, and tissue eosinophilia. Using two distinct mouse models of atopic dermatitis, we show that expression of retinoid-related orphan receptor α (RORα) in skin-resident T regulatory cells (Tregs) is important for restraining allergic skin inflammation. In both models, targeted deletion of RORα in mouse Tregs led to exaggerated eosinophilia driven by interleukin-5 (IL-5) production by ILC2s and TH2 cells. Expression of RORα in skin-resident Tregs suppressed IL-4 expression and enhanced expression of death receptor 3 (DR3), which is the receptor for tumor necrosis factor (TNF) family cytokine, TNF ligand-related molecule 1 (TL1A), which promotes Treg functions. DR3 is expressed on both ILC2s and skin-resident Tregs Upon deletion of RORα in skin-resident Tregs, we found that Tregs were no longer able to sequester TL1A, resulting in enhanced ILC2 activation. We also documented higher expression of RORα in skin-resident Tregs than in peripheral blood circulating Tregs in humans, suggesting that RORα and the TL1A-DR3 circuit could be therapeutically targeted in atopic dermatitis.

Substance use and dependence in the Union Territory of Chandigarh: Results of a household survey using a multistage stratified random sample.

BACKGROUND: Substance misuse is a global health and social problem with major adverse consequences. A number of regional studies on prevalence of substance use and dependence have been carried out in India; but methodologically robust data from Chandigarh are sparse. METHODOLOGY: A house-to-house survey was carried out to estimate the prevalence of substance use and dependence in an adequate multistage-stratified random sample in the Union Territory (UT) of Chandigarh, using standardized instruments and predefined measures. Two thousand individuals (1000 each from urban and rural sites) from 743 households were interviewed. RESULTS: Lifetime use of any substance was reported in 21.26% households (8.01% of all respondents; 13.6% males and 1.01% females). Current use was reported in 6.55% of respondents. Prevalence rates of both lifetime and annual/current substance dependence were 2.96% (4.74% for males and 0.72% for females). Alcohol (6.72%) was the most common substance to be ever used by respondents, followed by tobacco (3.34%), opioids (0.17%), and hypnotics (0.04%). Lifetime dependence rates were found to be 1.76%, 2.28%, 0.04% and 0.17% for alcohol, tobacco, hypnotics, and opioids, respectively. None reported the use of cannabinoids, inhalants, or stimulants. Substance users were more likely to be married, employed, and in higher income group as compared to those who never used substance. Only 3.78% substance users had ever sought treatment for the same. CONCLUSION: Substance use is prevalent in the UT of Chandigarh, with a higher prevalence in males. Substance users hardly ever seek treatment for substance use. This highlights the need of awareness and community-level services for the treatment of substance use disorders.

Pattern and prevalence of substance use and dependence in the Union Territory of Chandigarh: Results of a rapid assessment survey.

BACKGROUND: Substance misuse is a matter of major public health concern in India. House-to-house survey, though an appealing method to generate population-level estimates, has limitations for estimating prevalence rates of use of illicit and rare substances. MATERIALS AND METHODS: In this rapid assessment survey (RAS), respondent-driven sampling was used to recruit substance-using individuals from the field. Size of the substance-using population was estimated using the "benchmark-multiplier" method. This figure was then projected to the entire population of the Union Territory (U.T) of Chandigarh. Focused group discussions were used to study the perceptions and views of the substance users regarding various aspects of substance use. RESULTS: Prevalence of any substance dependence in the U.T of Chandigarh was estimated to be 4.65%. Dependence rates on opioids, cannabinoids, and sedative hypnotics were found to be 1.53%, 0.52%, and 0.015%, respectively. Prevalence of injectable opioids was calculated to be 0.91%. Injectable buprenorphine was the most commonly used opioid, followed by bhukhi/doda/opium and heroin. A huge gap was found between the prevalence rates of substance-using population and those seeking treatment. CONCLUSION: RAS can be a useful method to determine the prevalence of illicit and rare substances. Our survey shows that the use of substance including that of opioids is highly prevalent in the U.T of Chandigarh. The findings of this survey can have implications for policymaking.

IL-22 derived from γδ T cells restricts Staphylococcus aureus infection of mechanically injured skin.

BACKGROUND: Staphylococcus aureus is an opportunistic pathogen that colonizes the skin of patients with atopic dermatitis (AD) and aggravates their disease. Neutrophils and the cytokines IL-17A and IL-17F, which drive the expression of the neutrophil-attracting chemokines, are important for the clearance of S aureus infection. The cytokine IL-22 is often coproduced by IL-17-secreting cells. The levels of IL-22 are elevated in AD skin lesions. OBJECTIVE: We sought to determine the role of IL-22 in the clearance of S aureus infection of mouse skin subjected to tape stripping, a surrogate for scratching, a cardinal feature of AD. METHODS: S aureus was applied to the tape-stripped skin of wild-type and Il22-/- mice. Bacterial burden was evaluated by enumerating colony-forming units. Quantitative PCR and ELISA were performed to quantify Il22 mRNA and IL-22 protein in mouse and human skin. Flow cytometry was used to enumerate neutrophils in the skin. RESULTS: Scratching the skin of healthy adults and tape stripping of mouse skin induced local expression of Il22 mRNA and IL-22 protein. Induction of Il22 expression by tape stripping was dependent on IL-23 and γδ T cells. Clearance of S aureus from tape-stripped skin was significantly impaired in Il22-/- mice. Neutrophil infiltration and upregulation of expression of genes encoding the antimicrobial peptides antigen-6/urokinase-type plasminogen activator receptor related protein-1 and ß-DEFENSIN 14 and the chemokine (C-X-C motif) ligand following tape stripping were significantly impaired in Il22-/- mice. CONCLUSIONS: These findings show that IL-22 is important for limiting the growth of S aureus on mechanically injured skin and caution that IL-23 and IL-22 blockade in patients with AD may enhance susceptibility to staphylococcal skin infection.