ABSTRACT
Melanocortin 4 receptor (MC4R) mutations are the commonest cause of monogenic obesity through dysregulation of neuronal pathways in the hypothalamus and prefrontal cortex that regulate hunger and satiety. MC4R also regulates neuropathic pain pathways via JNK signaling after nerve injury. We show evidence of corneal small fiber degeneration in 2 siblings carrying a heterozygous missense variant c.508A>G, p.Ille170Val in the MC4R gene. Both children were treated with once weekly semaglutide for 6 months with no change in weight, and only a minor improvement in HbA1c and lipid profile. However, there was evidence of nerve regeneration with an increase in corneal nerve fiber density (CNFD) [child A (13.9%), child B (14.7%)], corneal nerve branch density (CNBD) [child A (110.2%), child B (58.7%)] and corneal nerve fiber length (CNFL) [child A (21.5%), child B (44.0%)].
Subject(s)
Nerve Regeneration , Receptor, Melanocortin, Type 4 , Humans , Receptor, Melanocortin, Type 4/genetics , Male , Female , Child , Nerve Regeneration/drug effects , Glucagon-Like Peptides/therapeutic use , Glucagon-Like Peptides/pharmacology , Nerve Fibers/drug effects , Nerve Fibers/pathology , Mutation , Obesity/drug therapy , Obesity/genetics , Cornea/drug effects , Cornea/innervation , Cornea/pathology , Pediatric Obesity/drug therapy , AdolescentABSTRACT
Homemade medicinal remedies used to treat both acute and chronic ailments for centuries need to be transformed into modern evidence-based dosage forms. Therefore, the present study aimed to develop buccal dispersible film, syrup and effervescent granules of an extemporaneous antigout homemade remedy. The dosage forms were prepared using holistic remedy (HR) as an active entity and excipients masking disagreeable features. The dosage forms and HR were subjected to physicochemical evaluation, and standardised by a reversed-phase HPLC method using chlorogenic acid, caffeic acid, vanillin, and ferulic acid as analytical standards. The standardised dosage forms were investigated for antigout activity using an appropriate model. The dosage forms were found to be physically elegant and phytochemically aligned with HR. The developed dosage forms contained the selected markers and possessed antigout activity. Hence, these standardised and evidence-based dosage forms may have wider acceptance in the market compared to HR.
ABSTRACT
Background Childhood obesity is recognized as a chronic illness with limited therapeutic options. Tackling obesity (BMI; the weight in kilograms divided by the square of the height in meters, at the 95th percentile or higher) with lifestyle interventions, especially in adolescents, has proven to be a daunting task, yielding only modest results. Research on the use of liraglutide for weight reduction in pediatric patients has yielded conflicting results. Notably, there is a lack of studies in the Middle East reporting on the outcomes of glucagon-like peptide 1 (GLP-1) receptor agonists in treating obesity in children and adolescents, with or without diabetes. This study, conducted in the Middle East, represents the first investigation into the utilization of liraglutide for weight reduction in this pediatric population. Methods This retrospective study collected data on 22 consecutive participants, aged 12 to 19 years, who were diagnosed with obesity (defined as having a BMI greater than the 95th percentile for their age and sex) and had either type 2 diabetes mellitus (T2DM) or were non-diabetic who attended endocrine clinics in Sidra Medicine, Doha, Qatar, between 2020 and 2022. The study protocol involved a liraglutide treatment period spanning 18 months (72 weeks), with scheduled follow-up appointments at six-month intervals. The primary endpoints were changes in weight and BMI from baseline to the 72-week mark. Secondary endpoints were safety measures and changes in HbA1c. Results Out of the initial cohort of 22 patients, 12 completed the full 72-week duration of the study, while 10 patients either discontinued treatment or did not adhere to the prescribed medication regimen due to side effects. Among the 12 patients who completed the study, six had a diagnosis of T2DM. At baseline, the weight, standard deviation score (SDS), BMI, and BMI standard deviation (SD) were 113.9 kg, 2.9, 40.9 kg/m2, and 2.6 respectively. At the 18-month follow-up, the weight, SDS, BMI, and BMI SD were 117.8kg, 2.6, 39kg/m2, and 2.5, respectively. Thus, no statistically significant change in the weight parameters was evident at 18 months compared to baseline. Dropout from the study and poor compliance were high (10 out of 22 patients) due to side effects, mainly gastrointestinal (nausea, abdominal pain, diarrhea, and vomiting). No statistically significant differences were observed between obese vs. obese with T2DM. No significant change in HbA1c was found between baseline and treatment follow-up in the diabetes patients. No adverse effects in terms of impairment of liver and kidney function or pancreatitis were observed. Conclusions The administration of liraglutide to adolescents with obesity, regardless of whether they had T2DM or not, in a real-life setting, did not yield statistically significant reductions in BMI/weight parameters, and HbA1c levels at the 72-week mark. Nevertheless, the study findings indicate that liraglutide is deemed safe for utilization within this age group, despite the presence of mild gastrointestinal side effects.
ABSTRACT
Globally, rapid climate and land-use changes in alpine environments are posing severe risks to their bountiful biodiversity and ecosystem services. Currently, nature-based solutions are fast-emerging as the preferred approach to address the challenges of environmental sustainability. In alpine environments, cushion plants owing to their unique architecture and adaptability offer a potential nature-based system to plan biodiversity conservation and habitat restoration strategies. Here, we employed an analytical framework to test whether and how the cushion plants facilitate the sustenance of alpine plant diversity in Kashmir Himalaya. We specifically aimed to answer: what are the effects of the cushion plants on the patterns of alpine species richness and phylogenetic diversity, and whether these effects vary across spatial scales (local versus landscape), cushion types, and changing elevation. We randomly selected pairs of cushion and neighbouring non-cushion plots (size 100 m2) across 34 different alpine sites in the study region. Within each plot, we randomly laid three 5 m2 quadrats for vegetation sampling, and sampled a total of 204 quadrats in 68 plots with seven cushion types along elevation ranging from 3100 to 3850 m. Our results revealed positive effects of the cushions by supporting a higher community species richness (SR) and phylogenetic diversity (PD). The effects were consistent both at the local (i.e., quadrat) and landscape (i.e., plot) scales, but varied significantly with the cushion type. Interestingly, SR and PD showed an increasing trend with increase in elevation in cushion communities, thereby supporting stress gradient hypothesis. Along the elevational gradient, the cushion communities showed phylogenetic overdispersion, but clustering by non-cushions. Overall, our study provides empirical evidence to reinforce the role of the cushions as conservation refugia for an imperilled alpine plant diversity in the Himalaya. Looking ahead, we highlight the far-reaching implications of our findings in guiding the nature-based environmental management of alpine ecosystems worldwide.
Subject(s)
Biodiversity , Conservation of Natural Resources , Ecosystem , Phylogeny , PlantsABSTRACT
Persistent congenital hyperinsulinism (HI) is a rare genetically heterogeneous condition characterised by dysregulated insulin secretion leading to life-threatening hypoglycaemia. For up to 50% of affected individuals screening of the known HI genes does not identify a disease-causing variant. Large deletions have previously been used to identify novel regulatory regions causing HI. Here, we used genome sequencing to search for novel large (>1 Mb) deletions in 180 probands with HI of unknown cause and replicated our findings in a large cohort of 883 genetically unsolved individuals with HI using off-target copy number variant calling from targeted gene panels. We identified overlapping heterozygous deletions in five individuals (range 3-8 Mb) spanning chromosome 20p11.2. The pancreatic beta-cell transcription factor gene, FOXA2, a known cause of HI was deleted in two of the five individuals. In the remaining three, we found a minimal deleted region of 2.4 Mb adjacent to FOXA2 that encompasses multiple non-coding regulatory elements that are in conformational contact with FOXA2. Our data suggests that the deletions in these three children may cause disease through the dysregulation of FOXA2 expression. These findings provide new insights into the regulation of FOXA2 in the beta-cell and confirm an aetiological role for chromosome 20p11.2 deletions in syndromic HI.
Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 20 , Congenital Hyperinsulinism , Hepatocyte Nuclear Factor 3-beta , Humans , Hepatocyte Nuclear Factor 3-beta/genetics , Hepatocyte Nuclear Factor 3-beta/metabolism , Congenital Hyperinsulinism/genetics , Congenital Hyperinsulinism/pathology , Chromosomes, Human, Pair 20/genetics , Female , Male , Regulatory Sequences, Nucleic AcidABSTRACT
Despite the high global prevalence, rheumatoid arthritis lacks a satisfactory treatment. Hence, the present study is undertaken to design and synthesize novel anti-inflammatory compounds. For this, quinoline and anthranilic acid, two medicinally-privileged moieties, were linked by pharmacophore hybridization, and following their computational assessments, three hybrids 5a-c were synthesized in good over all yields. The in vitro and in vivo anti-inflammatory potential of these hybrids was determined by anti-denaturation and anti-proteinase, and carrageenan-induced paw edema models. The computational studies of these hybrids revealed their drug-likeness, optimum pharmacokinetics, and less toxicity. Moreover, they demonstrated high binding affinity (-9.4 to -10.6 kcal mol-1) and suitable binding interactions for TNF-α, FLAP, and COX-II. A three-step synthetic route resulted in the hybrids 5a-c with 83-86% yield of final step. At 50 µg mL-1, the antiprotease and anti-denaturation activity of compound 5b was significantly higher than 5a and 5c. Furthermore, 5b significantly reduced the edema in the right paw of the rats that received carrageenan. The results of this study indicate the medicinal worth of the novel hybrids in treating inflammatory disorders such as rheumatoid arthritis.
Subject(s)
Drug Design , Edema , Molecular Docking Simulation , Quinolines , ortho-Aminobenzoates , Quinolines/chemistry , Quinolines/pharmacology , Quinolines/chemical synthesis , Animals , Edema/drug therapy , Edema/chemically induced , ortho-Aminobenzoates/chemistry , ortho-Aminobenzoates/pharmacology , ortho-Aminobenzoates/chemical synthesis , Rats , Carrageenan , Male , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/chemical synthesis , Molecular Structure , Rats, Wistar , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Dose-Response Relationship, Drug , Structure-Activity Relationship , Cyclooxygenase 2/metabolism , Cyclooxygenase 2/chemistryABSTRACT
PURPOSE: Bi-allelic pathogenic leptin gene variants cause severe early onset obesity usually associated with low or undetectable circulating leptin levels. Recently, variants have been described resulting in secreted mutant forms of the hormone leptin with either biologically inactive or antagonistic properties. METHODS: We conducted a systematic literature research supplemented by unpublished data from patients at our center as well as new in vitro analyses to provide a systematic classification of congenital leptin deficiency based on the molecular and functional characteristics of the underlying leptin variants and investigated the correlation of disease subtype with severity of the clinical phenotype. RESULTS: A total of 28 distinct homozygous leptin variants were identified in 148 patients. The identified variants can be divided into three different subtypes of congenital leptin deficiency: classical hormone deficiency (21 variants in 128 patients), biologically inactive hormone (3 variants in 12 patients) and antagonistic hormone (3 variants in 7 patients). Only 1 variant (n=1 patient) remained unclassified. Patients with biological inactive leptin have a higher percentage of 95th BMI percentile (%BMIp95) compared to patients with classical hormone deficiency. While patients with both classical hormone deficiency and biological inactive hormone can be treated with the same starting dose of metreleptin, patients with antagonistic hormone need a variant-tailored treatment approach to overcome the antagonistic properties of the variant leptin. MAIN CONCLUSIONS: Categorization of leptin variants based on molecular and functional characteristics helps to determine the most adequate approach to treatment of patients with congenital leptin deficiency.
ABSTRACT
Background and Aims: Carbohydrate counting is a well-established tool for self-management of type 1 diabetes (T1D) and can improve glycemic control and potentially reduce long-term complication risk. However, it can also be burdensome, error-prone, and complicated for the patient. A randomized controlled trial was conducted to investigate glycemic control with carbohydrate counting ("flex") versus simplified meal announcement ("fix") in adolescents with T1D using the MiniMed™ 780G system. The present study reports follow-up data to 12 months. Methods: Adolescents with T1D were randomly assigned 1:1 to use the MiniMed™ 780G system alongside the flex versus fix approaches. Participants were followed for 12 months with outcomes recorded at 3, 6, 9, and 12 months. The primary endpoint was the difference in time-in-range (TIR), and secondary endpoints included glycated hemoglobin (HbA1c) and other glucose and insulin metrics. Results: At 12 months, TIR (proportion of time with sensor glucose 70-180 mg/dL) was significantly lower in the fix versus flex group (72.9% vs. 80.1%, respectively; P = 0.001). There was no significant difference in HbA1c between the fix (6.8% ± 0.5%) and flex groups (6.5% ± 0.5%) at 12 months (P = 0.092), and mean HbA1c was below 7% at all time points in both arms. Conclusions: Glycemic control with simplified meal announcement was maintained over 12 months. On average, the international consensus targets were met in both arms for all time points. The simplified approach represents a viable alternative to carbohydrate counting, particularly in people who find the latter burdensome; however, carbohydrate counting resulted in superior TIR. This study is registered with ClinicalTrials.gov, number NCT05069727.
Subject(s)
Diabetes Mellitus, Type 1 , Humans , Adolescent , Diabetes Mellitus, Type 1/drug therapy , Glycated Hemoglobin , Blood Glucose , Follow-Up Studies , Insulin/therapeutic use , Glucose , Insulin Infusion Systems , Hypoglycemic Agents/therapeutic use , Blood Glucose Self-MonitoringABSTRACT
Under paddy soil conditions, rice plants are vulnerable to arsenic (As) accumulation, thus causing potential threat to human health. Here we investigated the influence of foliar-applied phosphorus (P: 10 and 20 mg L-1), silicon (Si: 0.6 and 1.5 g L-1) and selenium (Se: 5 and 10 mg L-1) on As accumulation, morphological and physiological attributes of two contrasting rice genotypes (KSK-133 and Super Basmati) under As stress (25 mg kg-1 as arsenate). Silicon foliar dressing significantly (p < 0.05) reduced grain As uptake (up to 67%) and improved rice growth and chlorophyll content (28-66%) in both rice genotypes over their controls. Phosphorus foliar application resulted in a notable decrease (17%) in grain As uptake of coarse rice genotype (KSK-133), while it slightly increased grain As uptake in the fine one (Super Basmati; 6%) compared to controls. However, foliar-applied Se did not show significant effects on rice plants growth attributes and As uptake in both genotypes. Similarly, biochemical and enzymatic attributes (i.e., lipid peroxidation, electrolyte leakage, peroxidase and catalase) were improved with Si application in rice plants, except for P treatment that was only effective for coarse one. Foliar-applied Si also resulted in reduced cancer risk and hazard quotient (< 0.10) for both rice genotypes. This study advances our understanding on critical role of different foliar-applied nutrients and rice genotypes, which is imperative to develop effective As remediation and management strategies in coarse and fine rice genotypes and protect human health.
This study provided new insights on the significance of foliar-applied phosphorus, silicon and selenium for the management and remediation of arsenic in fine (Super Basmati) and coarse (KSK-133) rice genotypes. Foliar-applied silicon was the most promising strategy to mitigate arsenic uptake and minimizing health risk in rice grain of both genotypes, while phosphorus was effective only for coarse one, thus showing a genotype dependent response. Interestingly, selenium foliar application had no significant effect on arsenic accumulation in both rice genotypes.
Subject(s)
Arsenic , Oryza , Selenium , Soil Pollutants , Humans , Silicon/analysis , Silicon/pharmacology , Phosphorus , Oryza/genetics , Soil Pollutants/analysis , Biodegradation, Environmental , Soil/chemistry , Genotype , Edible Grain/chemistryABSTRACT
The leptin-melanocortin pathway is pivotal in appetite and energy homeostasis. Pathogenic variants in genes involved in this pathway lead to severe early-onset monogenic obesity (MO). The MC4R gene plays a central role in leptin-melanocortin signaling, and heterozygous variants in this gene are the most common cause of MO. A targeted gene panel consisting of 52 obesity-related genes was used to screen for variants associated with obesity. Variants were analyzed and filtered to identify potential disease-causing activity and validated using Sanger sequencing. We identified two novel heterozygous variants, c.253A>G p.Ser85Gly and c.802T>C p.Tyr268His, in the MC4R gene in two unrelated patients with morbid obesity and evaluated the functional impact of these variants. The impact of the variants on the MC4R gene was assessed using in silico prediction tools and molecular dynamics simulation. To further study the pathogenicity of the identified variants, GT1-7 cells were transfected with plasmid DNA encoding either wild-type or mutant MC4R variants. The effects of allelic variations in the MC4R gene on cAMP synthesis, MC4R protein level, and activation of PKA, ERB, and CREB signaling pathways in both stimulated and unstimulated É-MSH paradigms were determined for their functional implications. In silico analysis suggested that the variants destabilized the MC4R structure and affected the overall dynamics of the MC4R protein, possibly leading to intracellular receptor retention. In vitro analysis of the functional impact of these variants showed a significant reduction in cell surface receptor expression and impaired extracellular ligand binding activity, leading to reduced cAMP production. Our analysis shows that the variants do not affect total protein expression; however, they are predicted to affect the post-translational localization of the MC4R protein to the cell surface and impair downstream signaling cascades such as PKA, ERK, and CREB signaling pathways. This finding might help our patients to benefit from the novel therapeutic advances for monogenic forms of obesity.
Subject(s)
Leptin , Obesity, Morbid , Humans , Leptin/genetics , Obesity, Morbid/genetics , Qatar , Alleles , alpha-MSH/pharmacology , Receptor, Melanocortin, Type 4/genetics , Receptor, Melanocortin, Type 4/metabolism , MutationABSTRACT
BACKGROUND: Hypoketotic hypoglycaemia with suppressed plasma fatty acids and detectable insulin suggests congenital hyperinsulinism (CHI). Severe hypoketotic hypoglycaemia mimicking hyperinsulinism but without detectable insulin has recently been described in syndromic individuals with mosaic genetic activation of post-receptor insulin signalling. We set out to expand understanding of this entity focusing on metabolic phenotypes. METHODS: Metabolic profiling, candidate gene and exome sequencing were performed in six infants with hypoketotic, hypoinsulinaemic hypoglycaemia, with or without syndromic features. Additional signalling studies were carried out in dermal fibroblasts from two individuals. RESULTS: Two infants had no syndromic features. One was mistakenly diagnosed with CHI. One had mild features of megalencephaly-capillary malformation-polymicrogyria (MCAP) syndrome, one had non-specific macrosomia, and two had complex syndromes. All required intensive treatment to maintain euglycaemia, with CHI-directed therapies being ineffective. Pathogenic PIK3CA variants were found in two individuals - de novo germline c.323G>A (p.Arg108His) in one non-syndromic infant and postzygotic mosaic c.2740G>A (p.Gly914Arg) in the infant with MCAP. No causal variants were proven in the other individuals despite extensive investigation, although rare variants in mTORC components were identified in one. No increased PI3K signalling in fibroblasts of two individuals was seen. CONCLUSIONS: We expand the spectrum of PI3K-related hypoinsulinaemic hypoketotic hypoglycaemia. We demonstrate that pathogenic germline variants activating post-insulin-receptor signalling may cause non-syndromic hypoinsulinaemic hypoketotic hypoglycaemia closely resembling CHI. This distinct biochemical footprint should be sought and differentiated from CHI in infantile hypoglycaemia. To facilitate adoption of this differential diagnosis, we propose the term "pseudohyperinsulinism".
Subject(s)
Congenital Hyperinsulinism , Proto-Oncogene Proteins c-akt , Infant , Humans , Proto-Oncogene Proteins c-akt/genetics , Insulin , Congenital Hyperinsulinism/genetics , Phosphatidylinositol 3-Kinases/metabolismABSTRACT
BACKGROUND: Early leaf spot disease, caused by Cercospora arachidicola, is a devastating peanut disease that has severely impacted peanut production and quality. Chemical fungicides pollute the environment; however, Bacillus bacteria can be used as an environmentally friendly alternative to chemical fungicides. To understand the novel bacterial strain and unravel its molecular mechanism, De novo whole-genome sequencing emerges as a rapid and efficient omics approach. RESULTS: In the current study, we identified an antagonistic strain, Bacillus amyloliquefaciens TA-1. In-vitro assay showed that the TA-1 strain was a strong antagonist against C. arachidicola, with an inhibition zone of 88.9 mm. In a greenhouse assay, results showed that the TA-1 strain had a significant biocontrol effect of 95% on peanut early leaf spot disease. De novo whole-genome sequencing analysis, shows that strain TA-1 has a single circular chromosome with 4172 protein-coding genes and a 45.91% guanine and cytosine (GC) content. Gene function was annotated using non-redundant proteins from the National Center for Biotechnology Information (NCBI), Swiss-Prot, the Kyoto Encyclopedia of Genes and Genomes (KEGG), clusters of orthologous groups of proteins, gene ontology, pathogen-host interactions, and carbohydrate-active enZYmes. antiSMASH analysis predicted that strain TA-1 can produce the secondary metabolites siderophore, tailcyclized peptide, myxochelin, bacillibactin, paenibactin, myxochelin, griseobactin, benarthin, tailcyclized, and samylocyclicin. CONCLUSION: The strain TA-1 had a significant biological control effect against peanut early leaf spot disease in-vitro and in greenhouse assays. Whole genome analysis revealed that, TA-1 strain belongs to B. amyloliquefaciens and could produce the antifungal secondary metabolites.
Subject(s)
Bacillus amyloliquefaciens , Fungicides, Industrial , Arachis/genetics , Bacillus amyloliquefaciens/genetics , MycosphaerellaABSTRACT
Cyberattacks in the modern world are sophisticated and can be undetected in a dispersed setting. In a distributed setting, DoS and DDoS attacks cause resource unavailability. This has motivated the scientific community to suggest effective approaches in distributed contexts as a means of mitigating such attacks. Syn Flood is the most common sort of DDoS assault, up from 76% to 81% in Q2, according to Kaspersky's Q3 report. Direct and indirect approaches are also available for launching DDoS attacks. While in a DDoS attack, controlled traffic is transmitted indirectly through zombies to reflectors to compromise the target host, in a direct attack, controlled traffic is sent directly to zombies in order to assault the victim host. Reflectors are uncompromised systems that only send replies in response to a request. To mitigate such assaults, traffic shaping and pushback methods are utilised. The SYN Flood Attack Detection and Mitigation Technique (SFaDMT) is an adaptive heuristic-based method we employ to identify DDoS SYN flood assaults. This study suggested an effective strategy to identify and resist the SYN assault. A decision support mechanism served as the foundation for the suggested (SFaDMT) approach. The suggested model was simulated, analysed, and compared to the most recent method using the OMNET simulator. The outcome demonstrates how the suggested fix improved detection.
ABSTRACT
Hormone absence or inactivity is common in congenital disease, but hormone antagonism remains controversial. Here, we characterize two novel homozygous leptin variants that yielded antagonistic proteins in two unrelated children with intense hyperphagia, severe obesity, and high circulating levels of leptin. Both variants bind to the leptin receptor but trigger marginal, if any, signaling. In the presence of nonvariant leptin, the variants act as competitive antagonists. Thus, treatment with recombinant leptin was initiated at high doses, which were gradually lowered. Both patients eventually attained near-normal weight. Antidrug antibodies developed in the patients, although they had no apparent effect on efficacy. No severe adverse events were observed. (Funded by the German Research Foundation and others.).
Subject(s)
Leptin , Obesity, Morbid , Child , Humans , Antibodies , Homozygote , Leptin/genetics , Obesity, Morbid/genetics , Signal TransductionABSTRACT
Soil microbial communities, being situated at the interface of aboveground plant and belowground soil systems, can play a pivotal role in determining ecosystem response to the drivers of global environmental change, including invasive species. In mountains, invasive plants occurring along elevational gradients offer a unique natural experimental system to investigate the impact of invasions in determining patterns and relationships of soil microbial diversity and nutrient pools at much shorter spatial distances. Here, we studied the impact of a global plant invader, Leucanthemum vulgare, on the diversity of soil microbiome and physico-chemical attributes along an elevational gradient (1760-2880 m) in Kashmir Himalaya. We used Illumina MiSeq platform to characterize the soil microbiome in pair-wise invaded and uninvaded plots at four different sites along the gradient. We found a total of 1959 bacterial operational taxonomic units (OTUs) belonging to 152 species, and a relatively higher number of 2475 fungal OTUs belonging to 589 species. The α-diversity of soil microbiome showed a gradual increase from low to high elevation and differed significantly (p < 0.05) between the invaded and uninvaded plots. The ß-diversity revealed distinct microbiome clustering among the sampling sites. Plant invasion also altered soil physico-chemical attributes along the elevational gradient. Overall, our findings suggest that the L. vulgare-induced shifts in soil microbiome and nutrient pools may be a belowground self-reinforced mechanism to facilitate its successful invasion along the elevational gradient. Our study provides new insights into invasive plant-microbe relationships with wide implications for climate warming-driven elevational range shifts in mountains.
Subject(s)
Ecosystem , Microbiota , Soil/chemistry , Biodiversity , Introduced Species , Bacteria , PlantsABSTRACT
Vaccine hesitancy (VH) is not a new phenomenon in Pakistan and is regarded as one of the primary causes of unsatisfactory vaccination campaigns. This study determined post-vaccination COVID-19 VH, factors influencing COVID-19 vaccine uptake, and public's intent to receive booster vaccinations. A cross-sectional study was conducted among adult population of Lahore, Pakistan. Participants were recruited via convenience sampling between March and May 2022. SPSS version 22 was used for the data analysis. A total of 650 participants were included in the study (age = 28.1 ± 9.7 years; male-to-female ratio nearly 1: 1). The majority of participants received Sinopharm followed by Sinovac vaccine. The top three reasons of vaccine uptake were "only vaccinated individuals are allowed at the workplace, and educational institutes" (Relative importance index (RII) = 0.749), "only vaccinated people are allowed to go to markets, malls and other public places" (RII = 0.746), and "protect myself from the infection" (RII = 0.742). The mean COVID-19 VH score was 24.5 ± 6.2 (95% CI 23.9-24.9), with not being pro-vaccines and poor economic status were the significant predictors of COVID-19 vaccine hesitancy among immunized individuals (p < .05). Acceptance of booster vaccines was negatively associated with younger age and a lower level of education. Furthermore, being pro-vaccine was associated with a greater likelihood of accepting booster vaccines (p = .001). The Pakistani public continues to express VH toward COVID-19 vaccines. Therefore, aggressive measures must be taken to combat the community factors that contribute to it.
Subject(s)
COVID-19 , Vaccines , Adult , Female , Male , Humans , Adolescent , Young Adult , COVID-19 Vaccines , Cross-Sectional Studies , Intention , COVID-19/prevention & control , VaccinationABSTRACT
CONTEXT: Monogenic obesity is a rare form of obesity due to pathogenic variants in genes implicated in the leptin-melanocortin signaling pathway and accounts for around 5% of severe early-onset obesity. Mutations in the genes encoding the MC4R, leptin, and leptin receptor are commonly reported in various populations to cause monogenic obesity. Determining the genetic cause has important clinical benefits as novel therapeutic interventions are now available for some forms of monogenic obesity. OBJECTIVE: To unravel the genetic causes of early-onset obesity in the population of Qatar. METHODS: In total, 243 patients with early-onset obesity (above the 95% percentile) and age of onset below 10 years were screened for monogenic obesity variants using a targeted gene panel, consisting of 52 obesity-related genes. RESULTS: Thirty rare variants potentially associated with obesity were identified in 36 of 243 (14.8%) probands in 15 candidate genes (LEP, LEPR, POMC, MC3R, MC4R, MRAP2, SH2B1, BDNF, NTRK2, DYRK1B, SIM1, GNAS, ADCY3, RAI1, and BBS2). Twenty-three of the variants identified were novel to this study and the rest, 7 variants, were previously reported in literature. Variants in MC4R were the most common cause of obesity in our cohort (19%) and the c.485C>T p.T162I variant was the most frequent MC4R variant seen in 5 patients. CONCLUSION: We identified likely pathogenic/pathogenic variants that seem to explain the phenotype of around 14.8% of our cases. Variants in the MC4R gene are the commonest cause of early-onset obesity in our population. Our study represents the largest monogenic obesity cohort in the Middle East and revealed novel obesity variants in this understudied population. Functional studies will be required to elucidate the molecular mechanism of their pathogenicity.
Subject(s)
Leptin , Obesity , Humans , Child , Leptin/genetics , Qatar/epidemiology , Obesity/epidemiology , Obesity/genetics , Obesity/pathology , Mutation , Phenotype , Receptor, Melanocortin, Type 4/genetics , Adaptor Proteins, Signal Transducing/geneticsABSTRACT
Endocrine disrupter chemicals (EDCs) are both natural and man-made chemicals that mimic, block or interfere with human hormonal system. In the present manuscript, QSAR modeling was performed for the androgen disruptors that interfere with biosynthesis, metabolism or action of androgens that causes adverse effects on male reproductive system. A set of 96 EDCs that exhibited affinity towards androgen receptors (Log RBA) in rats were employed for carrying out QSAR studies using Hybrid descriptors (combination of HFG and SMILES) through Monte Carlo Optimization. Using index of ideality of correlation (TF2), five splits were formed and predictability of five models resulting from these splits was assessed by various validation parameters. Models resulted from first split was the top most one with R2validation = 0.7878. Structural attributes responsible for change in endpoint were studied by employing correlation weights of structural attributes. In order to further validate the model, new EDCs were designed using these attributes. In silico molecular modelling studies were performed to assess the detailed interactions with the receptor. The binding energies of all the designed compounds were observed to be better than lead and are in the range of -10.46 to -14.80. Molecular dynamics simulation of 100 ns was performed for ED01 and NED05. The results revealed that the protein-ligand complex bearing NED05 was more stable than lead ED01 exhibiting better interactions with the receptor. Further, in an attempt to assess their metabolism, ADME studies were evaluated using SwissADME. The developed model enables to predict the characteristics of designed compounds in an authentic way.Communicated by Ramaswamy H. Sarma.
Subject(s)
Endocrine Disruptors , Molecular Dynamics Simulation , Humans , Male , Animals , Rats , Molecular Docking Simulation , Quantitative Structure-Activity Relationship , Receptors, Androgen , AndrogensABSTRACT
In an era of global environmental change, conservation of threatened biodiversity and ecosystem restoration are formidable ecological challenges. The forest understory strata and the belowground soil environment including rhizospheric microbial communities, which are crucial for ecosystem functioning and overall forest biodiversity maintenance, have remained understudied. Here, we investigate the soil microbiome of Trillium govanianum - an endangered Himalayan Forest herb, to unravel the underground diversity, drivers, and potential indicators of the microbial community. We collected rhizospheric and bulk soil samples for microbiome and physicochemical analysis at three sites along an elevation gradient (2500-3300 m) in Kashmir Himalaya. Amplicon sequencing of 16 S rRNA and ITS was used to identify the bacterial and fungal soil microorganisms. We found significant differences in the structure and diversity of microbial community (bacterial and fungal) between the rhizosphere and bulk soil along the altitudinal gradient, and noticeable shifts in the nutrient level in dominant microbial phyla associated with T. govanianum. A significant difference between soil physicochemical parameters and increasing altitude suggests that microbial community structure is determined by altitude and soil type. Similarly, the microbial communities showed a significant (P < 0.05) correlation with soil physicochemical variables along the altitudinal gradient. The moisture content in bacterial and total organic carbon in fungal communities showed the most substantial impact on the physiochemical drivers. We also identify potential bacterial and fungal plant growth promoter indicator species in the soil microbiome of T. govanianum. Overall, our findings provide novel research insights that can be pivotal in designing integrated species recovery programs and long-term restoration plans for T. govanianum, with learnings for biodiversity conservation elsewhere.