Novel azole-sulfonamide conjugates as potential antimicrobial candidates: synthesis and biological assessment.

Background: Azole and sulfonamide molecular frameworks are endowed with potent antimicrobial activity. Materials & methods: A series of azole-sulfonamide conjugates were synthesized using click reaction of N-propargylated imidazole with azide of sulfonamide and its antimicrobial efficacy was evaluated. Results: The compounds 7c, 7i and 7r displayed promising antibacterial activities, better than the standards sulfonamide and norfloxacin. All molecules exhibited promising antifungal activity, more potent than fluconazole. Docking studies of the active conjugates signified the importance of hydrophobic interactions in hosting the molecules in the active site of dihydrofolate reductase. Conclusion: Azole-sulfonamide conjugates are more active than single sulfonamide moieties and 7c, 7i and 7r may prove valuable leads for further optimization as novel antimicrobial agents.

An Introductory Overview on Applications of Pyrazoles as Transition Metal Chemosensors.

Utility of pyrazoles and their derivatives in constructing ordered porous materials with physicochemical characteristics such as chemosensors has undoubtedly created much interest in developing newer frameworks. A variety of pyrazole based chemosensors are known for their remarkable photophysical, pH sensitivity, solvatochromic, ion detection, high quantum yields and nonlinear optical behavior. Many of the transition metals have shown beneficial biological effects in biological systems. There is always a need of continuous monitoring to maintain an adequate range of all and specifically for the toxic ones like mercury. Pyrazoline nanoparticle probes have been reported for sensing/detection of Hg2+ions. Pyridinyl pyrazoline and benzimidazolyl pyrazole derived sensors are more selective and sensitive towards Zn2+and Fe3+ ions respectively. Pyrazole derived metal organic frameworks (MOF's) have been reported for environmental monitoring and biological imaging. Keeping in view of the enormous synthetic and biological importance of pyrazoles, herein, we are presenting an overview on applications of pyrazoles in transition metal chemosensors.

Intensive critical care and management of asthmatic and smoker patients in COVID-19 infection.

This century's most serious catastrophe, COVID-19, has been dubbed "the most life-threatening disaster ever". Asthmatic persons are even more prone to COVID-19's complex interplay with the underlying inflammatory condition. In order to protect themselves against COVID-19, asthmatic patients must be very vigilant in their usage of therapeutic techniques and drugs (e.g., bronchodilators, 5-lipoxygenase inhibitors), which may be accessed to deal with mild, moderate, and severe COVID-19 indications. People with asthma may have more severe COVID-19 symptoms, which may lead to a worsening of their condition. Several cytokines were found to be elevated in the bronchial tracts of patients with acute instances of COVID-19, suggesting that this ailment may aggravate asthma episodes by increasing inflammation. The intensity of COVID-19 symptoms is lessened in patients with asthma who have superior levels of T-cells. Several antibiotics, antivirals, antipyretics, and anti-inflammatory drugs have been suggested to suppress COVID-19 symptoms in asthmatic persons. Furthermore, smokers are more likely to have aggravated repercussions in COVID-19 infection. Being hospitalized to critical care due to COVID-19, needing mechanical breathing, and suffering from serious health repercussions, are all possible outcomes for someone who has previously smoked. Smoking damages airways and alveoli, which significantly raises the risk of COVID-19-related health complications. Patients with a previous record of smoking are predisposed to severe COVID-19 disease symptoms that essentially require a combination of bronchodilators, mucolytics, antivirals, and antimuscarinic drugs, to cope with the situation. The present review discusses the care and management of asthmatic and smoker patients in COVID-19 infection.

Synthesis and Biological Evaluation of 2-(Halophenyl)benzoxazole-5-Carboxylic Acids as Potential Anti-Inflammatory and Cytotoxic Agent with Molecular Docking Studies.

2-Halogenatedphenyl benzoxazole-5-carboxylic acids with mono-halogen (chloro, bromo and fluoro) substituted at ortho-, meta- and para-positions on the phenyl ring were designed and synthesized based on significance of presence of halogen in increasing number of marketed halogenated drugs and importance of benzoxazoles. These 2-alogenatedphenylbenzoxazole-5-carboxylic acids and their methyl esters were screened for anti-inflammatory activity, and cytotoxicity. 2-(3-Chlorophenyl)benzoxaole-5-carboxylic acid (6b) exhibited significant anti-inflammatory activity with IC50 values of 0.103 mM almost equivalent to the standard drug ibuprofen (0.101 mM). 2-(4-Chlorophenyl)benzoxaole-5-carboxylic acid (6c) showed excellent cytotoxic activity against 22Rv1 cells (human prostate carcinoma epithelial cell lines) with IC50 value of 1.54 µM better than that of standard drug doxorubicin having IC50 value of 2.32 µM. More importantly, the selectivity index of this potential molecule was found to be 57.74. Molecular docking analysis resulted in good binding interactions of these compounds with their respective biochemical targets viz. Cyclooxygenase-2 and aldo-keto reductase IC3.

Synthesis, Biological Activity and Molecular Docking Studies of Heterocyclic Chalcones.

Nineteen heterocyclic chalcones were synthesized from 4-acetyl-5-methylquinolylpyrazole and heteroaryl (imidazole, pyrazole, thiophene, indole and triazole) aldehydes and were screened in vitro using four tumor cell lines for their cytotoxic capability and for antimicrobial activity. The chalcone 5b exhibited the highest activity with IC50 values 2.14 µM against colon (HCT-116) and 5.0 µM, against prostate (PC-3) cancer cell lines and also displayed good activity against fungal strain (A. niger) with MIC value 9.1 µM. The chalcones 5q and 5p displayed good activity against bacterial strains (S. aureus) having MIC value 2.6 µM and fungal strain (C. albicans) having MIC value 5.4 µM, respectively. The molecular docking outcome revealed that the synthesized heterocyclic chalcones demonstrated hydrogen bond, hydrophobic and electrostatic interactions with their respective biochemical targets.

Robust, Generalizable, and Interpretable Artificial Intelligence-Derived Brain Fingerprints of Autism and Social Communication Symptom Severity.

BACKGROUND: Autism spectrum disorder (ASD) is among the most pervasive neurodevelopmental disorders, yet the neurobiology of ASD is still poorly understood because inconsistent findings from underpowered individual studies preclude the identification of robust and interpretable neurobiological markers and predictors of clinical symptoms. METHODS: We leverage multiple brain imaging cohorts and exciting recent advances in explainable artificial intelligence to develop a novel spatiotemporal deep neural network (stDNN) model, which identifies robust and interpretable dynamic brain markers that distinguish ASD from neurotypical control subjects and predict clinical symptom severity. RESULTS: stDNN achieved consistently high classification accuracies in cross-validation analysis of data from the multisite ABIDE (Autism Brain Imaging Data Exchange) cohort (n = 834). Crucially, stDNN also accurately classified data from independent Stanford (n = 202) and GENDAAR (Gender Exploration of Neurogenetics and Development to Advanced Autism Research) (n = 90) cohorts without additional training. stDNN could not distinguish attention-deficit/hyperactivity disorder from neurotypical control subjects, highlighting the model's specificity. Explainable artificial intelligence revealed that brain features associated with the posterior cingulate cortex and precuneus, dorsolateral and ventrolateral prefrontal cortex, and superior temporal sulcus, which anchor the default mode network, cognitive control, and human voice processing systems, respectively, most clearly distinguished ASD from neurotypical control subjects in the three cohorts. Furthermore, features associated with the posterior cingulate cortex and precuneus nodes of the default mode network emerged as robust predictors of the severity of core social and communication deficits but not restricted/repetitive behaviors in ASD. CONCLUSIONS: Our findings, replicated across independent cohorts, reveal robust individualized functional brain fingerprints of ASD psychopathology, which could lead to more objective and precise phenotypic characterization and targeted treatments.

An evaluation of inter and intra population structure of Uttar Pradesh, inferred from 24 autosomal STRs.

AIM: The present study was designed to explore the STR diversity and genomic history of the inhabitants of the most populous subdivision of the country. A set of 24 hypervariable autosomal STRs was used to estimate the genetic diversity within the studied population. A panel of 15 autosomal STRs, which is most common in the previously reported data sets, was used to estimate the genetic diversity between the studied population, and obtained unique relations were reported here. METHOD: The genetic diversity and polymorphism among 636 individuals of different ethnic groups, residing in Bareilly, Pilibhit, Shahjahanpur, Gorakhpur, Jhansi, and Varanasi regions of Uttar Pradesh, India, was investigated. This investigation was carried out via 24 autosomal STRs. RESULT: The 24 loci studied showed the highest value of combined power of discrimination (CPD = 1), combined power of exclusion (CPE = 0.99999999985), combined paternity index (CPI = 6.10 × 109) and lowest combined matching probability (CPM = 7.90 × 10-31). CONCLUSION: The studied population showed genetic closeness with the population of Uttarakhand, the Jats of Delhi,the Jat Sikh (Punjab), and the population of Rajasthan. Among the tested loci, SE33 and Penta E were found to be most useful in terms of the highest discrimination power, lowest matching probability, the highest power of exclusion, and highest polymorphism information content for the Uttar Pradesh population .

Development of novel anti-infective and antioxidant azole hybrids using a wet and dry approach.

Background: Considering emerging drug resistance in microbes, this work is focused on the synthesis of azole hybrids as novel antimicrobials. Materials & methods: The triazole derivatives were prepared using azide alkyne cycloaddition reaction. The antimicrobial potential of these compounds was evaluated by serial dilution method. Results: A series of azole hybrids containing benzimidazole-1,2,3-triazole skeleton was designed and synthesized via click reaction. Compound 4s showed notable antimicrobial activity against Staphylococcus aureus and Candida albicans (MIC 0.0165 µmol/ml), and 4q gives remarkable radical scavenging activity (IC50 0.0092 µmol/ml). The compounds 4a, 4k, 4o, 4s, 4x. 4m, 4n, 4s, 4t and 4x are commendable antibacterial and antifungal molecules, even better than established drugs. Molecular docking reveals that compound 4s binds with tyrosyl-tRNA synthetase residues through two H-bonds. Conclusion: Compounds 4s and 4k may be considered valuable lead compounds for further optimization as antimicrobial drugs.

Synthesis and antidiabetic evaluation of benzimidazole-tethered 1,2,3-triazoles.

Some novel benzimidazole-tethered 1,2,3-triazole derivatives (4a-r) were synthesized by a click reaction between 2-substituted 1-(prop-2-yn-1-yl)-1H-benzo[d]imidazole and in situ azide. The structures of the synthesized compounds were confirmed by spectroscopic studies (one- and two-dimensional nuclear magnetic resonance, Fourier transform infrared, and high-resolution mass spectra). The synthesized compounds were evaluated for their antidiabetic activity. Compounds 4a-r exhibited a good-to-moderate α-amylase and α-glucosidase inhibitory activity, with IC50 values ranging from 0.0410 to 0.0916 µmol/ml and 0.0146 to 0.0732 µmol/ml, respectively. Compounds 4e, 4g, and 4n were found to be most active. Furthermore, the binding conformation of the most active compounds was ascertained by docking studies.

The genetic affinities of Gujjar and Ladakhi populations of India.

The Union Territories of Jammu and Kashmir (J&K) and Ladakh in North India owing to their unique geographic location offer a wide variety of landscape from plains to high altitudes and is a congruence of many languages and cultural practices. Here, we present the genetic diversity studies of Gujjars from Jammu region of J&K and Ladakhi population based on a battery of autosomal single nucleotide polymorphisms (SNPs) and short tandem repeats (STRs), Y-chromosomal STRs and the control region of the mitochondrial genome. These two populations were observed to be genetically distant to each other as well as to other populations from India. Interestingly, Y-STR analyses showed a closer affinity of Gujjars to other nomadic populations of Pashtuns from Baghlans and Kunduz provinces of Afghanistan and Pashtuns and Sindhis of Pakistan. Gujjars exhibited lesser genetic diversity as compared to Ladakhi population. M30f and M9 were the most abundant mitochondrial haplogroups observed among Gujjars and Ladakhis, respectively. A lower matrilineal to patrilineal diversity was observed for both these populations. The current study presents the first comprehensive analysis of Gujjars and Ladakhis and reveals their unique genetic affiliations with other populations of the world.

Insightful classification of crystal structures using deep learning.

Computational methods that automatically extract knowledge from data are critical for enabling data-driven materials science. A reliable identification of lattice symmetry is a crucial first step for materials characterization and analytics. Current methods require a user-specified threshold, and are unable to detect average symmetries for defective structures. Here, we propose a machine learning-based approach to automatically classify structures by crystal symmetry. First, we represent crystals by calculating a diffraction image, then construct a deep learning neural network model for classification. Our approach is able to correctly classify a dataset comprising more than 100,000 simulated crystal structures, including heavily defective ones. The internal operations of the neural network are unraveled through attentive response maps, demonstrating that it uses the same landmarks a materials scientist would use, although never explicitly instructed to do so. Our study paves the way for crystal structure recognition of-possibly noisy and incomplete-three-dimensional structural data in big-data materials science.

Relation of body mass index to risk of developing inflammatory bowel disease amongst women in the Danish National Birth Cohort.

BACKGROUND: Crohn's disease (CD) has traditionally been associated with weight loss and low BMI, yet paradoxically obesity has recently been suggested as a risk factor for CD, but not for ulcerative colitis (UC). We therefore hypothesized that the relation between BMI and CD is U shaped. AIM: To conduct a large population-based prospective cohort study of BMI and later risk of IBD, taking age at IBD diagnosis into account. METHODS: A cohort of 74,512 women from the Danish National Birth Cohort, with BMI measured pre-pregnancy and 18 months after delivery, was followed for 1,022,250 person-years for development of IBD, according to the Danish National Patient Register. Associations were tested by Cox regression. RESULTS: Overweight subjects (25≤BMI<30 kg/m2) had the lowest risk of CD, whereas obesity (BMI≥30kg/m2) increased the risk of CD at all ages, and low BMI (BMI<18.5kg/m2) associated with CD diagnosed at age 18-<40 years. Hence, using normal weight subjects as the reference, adjusted HRs for risk of developing CD (at age 18-<40 years) were 1.8(95%CI, 0.9-3.7) for underweight, 0.6(0.3-1.2) for overweight, and 1.5(0.8-2.7) for obese individuals (pre-pregnancy BMI). HRs were greater for BMI determined 18 months after delivery. Splines for CD risk according to waist:height ratio confirmed a U-shaped relationship with CD occurring <40 years, and a linear relationship with CD diagnosed at age 40+. There was no relationship between BMI and risk of UC. CONCLUSION: For the first time, we demonstrate that both high BMI and low BMI are risk factors for CD. Underweight may be a pre-clinical manifestation of disease being present many years before onset with obesity being a true risk factor. This raises the question as to whether there may be two distinct forms of CD.

Surgical Management of Crohn Disease in Children: Guidelines From the Paediatric IBD Porto Group of ESPGHAN.

The incidence of Crohn disease (CD) has been increasing and surgery needs to be contemplated in a substantial number of cases. The relevant advent of biological treatment has changed but not eliminated the need for surgery in many patients. Despite previous publications on the indications for surgery in CD, there was a need for a comprehensive review of existing evidence on the role of elective surgery and options in pediatric patients affected with CD. We present an expert opinion and critical review of the literature to provide evidence-based guidance to manage these patients. Indications, surgical options, risk factors, and medications in pre- and perioperative period are reviewed in the light of available evidence. Risks and benefits of surgical options are addressed. An algorithm is proposed for the management of postsurgery monitoring, timing for follow-up endoscopy, and treatment options.

Faecal calprotectin: factors affecting levels and its potential role as a surrogate marker for risk of development of Crohn's Disease.

BACKGROUND: Faecal calprotectin (FC) is one of the most widely used non-invasive tests for the diagnosis and assessment of Crohn's disease (CD) activity. Despite this, factors other than disease activity which affect levels have not been extensively reviewed. This is of importance when using FC in the diagnostic setting but also may be of utility in studying the aetiology of disease. OBJECTIVES: Our review outlines environmental risk factors that affect FC levels influencing diagnostic accuracy and how these may be associated with risk of developing CD. FC as a surrogate marker could be used to validate risk factors established in case control studies where prospective studies are not feasible. Proof of this concept is provided by our identification of obesity as being associated with elevated FC, our subsequent confirmation of obesity as risk factor for CD and the subsequent verification in prospective studies, as well as associations of lack of physical activity and dietary fibre intake with elevated FC levels and their subsequent confirmation as risk factors in prospective studies. CONCLUSION: We believe that FC is likely to prove a useful surrogate marker for risk of developing CD. This review has given a theoretical basis for considering the epidemiological determinants of CD which to date has been missing.

Treatment of Crohn's Disease with an IgG4-Guided Exclusion Diet: A Randomized Controlled Trial.

BACKGROUND AND AIM: We previously reported an improvement in symptoms in Crohn's disease following an IgG4-guided exclusion diet in an open-label study. We aimed to evaluate, in a double-blinded randomized sham-controlled setting, the efficacy of IgG4-guided diet in improving quality of life in patients with Crohn's disease. METHODS: Consecutive patients with Crohn's disease and a Crohn's disease activity index (CDAI) of 80-400 attending tertiary and secondary care centers were screened. All patients had IgG4 titers tested against 16 common food types using ELISA. The true diet group excluded four food types with the highest antibody titers for 4 weeks, and the sham group excluded four foods with the lowest antibody titers. Quality of life was assessed using the Short Inflammatory Bowel Disease Questionnaire (SIBDQ) at beginning and end of the trial. Secondary outcome measures were CDAI, Harvey Bradshaw index, serum C-reactive protein, and fecal calprotectin. RESULTS: One hundred and forty-five subjects were screened and 96 subjects had initial food antibody testing performed with 76 patients completing the study. Milk, beef, pork and egg were the most commonly excluded food types in the true diet group. There was a 3.05 (0.01-6.11) p < 0.05 improvement in SIBDQ and 41 (10.4-71.5) in CDAI p = 0.009. CONCLUSION: IgG4-guided exclusion diet, as an adjunct, can improve quality of life and symptoms in patients with CD.

The wisdom of crowds and the repurposing of artesunate as an anticancer drug.

Artesunate, a semi-synthetic and water-soluble artemisinin-derivative used as an anti-malarial agent, has attracted the attention of cancer researchers due to a broad range of anti-cancer activity including anti-angiogenic, immunomodulatory and treatment-sensitisation effects. In addition to pre-clinical evidence in a range of cancers, a recently completed randomised blinded trial in colorectal cancer has provided a positive signal for further clinical investigation. Used perioperatively artesunate appears to reduce the rate of disease recurrence - and the Neo-Art trial, a larger Phase II RCT, is seeking to confirm this positive effect. However, artesunate is a generic medication, and as with other trials of repurposed drugs, the Neo-Art trial does not have commercial sponsorship. In an innovative move, the trial is seeking funds directly from members of the public via a crowd-funding strategy that may have resonance beyond this single trial.

What is known about the mechanisms of dietary influences in Crohn's disease?

Much has been written about the role of diet and risk for Crohn's disease (CD). However, the evidence is contradictory. Recent evidence has pointed to fiber playing an important role along with the possibility that dietary fat and overnutrition also have a role. Diet has a clearer place in disease modification, with some diets used in the treatment of CD. The lack of clarity stems from a poor understanding of the mechanisms underlying the relationship between diet and CD. Gut permeability is likely to play a key role in the risk for CD. Mechanisms whereby diet can affect gut permeability, including the effects of the gut microbiota, are reviewed. Modification of disease behavior is likely to be influenced by additional mechanisms, including recognition of complex food antigens. As with many other chronic diseases, a surrogate marker of CD risk would greatly aid evaluation of the dietary factors involved. Formal measures of gut permeability are too cumbersome for large-scale use, but fecal calprotectin may be a convenient measure of this. There are only preliminary data on the effect of diet and microbiota composition on fecal calprotectin and these require further investigation.

A Randomised, Double Blind, Placebo-Controlled Pilot Study of Oral Artesunate Therapy for Colorectal Cancer.

BACKGROUND: Artesunate is an antimalarial agent with broad anti-cancer activity in in vitro and animal experiments and case reports. Artesunate has not been studied in rigorous clinical trials for anticancer effects. AIM: To determine the anticancer effect and tolerability of oral artesunate in colorectal cancer (CRC). METHODS: This was a single centre, randomised, double-blind, placebo-controlled trial. Patients planned for curative resection of biopsy confirmed single primary site CRC were randomised (n = 23) by computer-generated code supplied in opaque envelopes to receive preoperatively either 14 daily doses of oral artesunate (200 mg; n = 12) or placebo (n = 11). The primary outcome measure was the proportion of tumour cells undergoing apoptosis (significant if > 7% showed Tunel staining). Secondary immunohistochemical outcomes assessed these tumour markers: VEGF, EGFR, c-MYC, CD31, Ki67 and p53, and clinical responses. FINDINGS: 20 patients (artesunate = 9, placebo = 11) completed the trial per protocol. Randomization groups were comparable clinically and for tumour characteristics. Apoptosis in > 7% of cells was seen in 67% and 55% of patients in artesunate and placebo groups, respectively. Using Bayesian analysis, the probabilities of an artesunate treatment effect reducing Ki67 and increasing CD31 expression were 0.89 and 0.79, respectively. During a median follow up of 42 months 1 patient in the artesunate and 6 patients in the placebo group developed recurrent CRC. INTERPRETATION: Artesunate has anti-proliferative properties in CRC and is generally well tolerated.