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Dopamine transporter (DAT) blockers like cocaine and many other abused and therapeutic drugs bind and stabilize an inactive form of the transporter inhibiting reuptake of extracellular dopamine (DA). The resulting increases in DA lead to the ability of these drugs to induce psychomotor alterations and addiction, but paradoxical findings in animal models indicate that not all DAT antagonists induce cocaine-like behavioral outcomes. How this occurs is not known, but one possibility is that uptake inhibitors may bind at multiple locations or in different poses to stabilize distinct conformational transporter states associated with differential neurochemical endpoints. Understanding the molecular mechanisms governing the pharmacological inhibition of DAT is therefore key for understanding the requisite interactions for behavioral modulation and addiction. Previously, we leveraged complementary computational docking, mutagenesis, peptide mapping, and substituted cysteine accessibility strategies to identify the specific adduction site and binding pose for the crosslinkable, photoactive cocaine analog, RTI 82, which contains a photoactive azide attached at the 2β position of the tropane pharmacophore. Here, we utilize similar methodology with a different cocaine analog N-[4-(4-azido-3-I-iodophenyl)-butyl]-2-carbomethoxy-3-(4-chlorophenyl)tropane , MFZ 2–24, where the photoactive azide is attached to the tropane nitrogen. In contrast to RTI 82, which crosslinked into residue Phe319 of transmembrane domain (TM) 6, our findings show that MFZ 2–24 adducts to Leu80 in TM1 with modeling and biochemical data indicating that MFZ 2–24, like RTI 82, occupies the central S1 binding pocket with the (+)-charged tropane ring nitrogen coordinating with the (−)-charged carboxyl side chain of Asp79. The superimposition of the tropane ring in the three-dimensional binding poses of these two distinct ligands provides strong experimental evidence for cocaine binding to DAT in the S1 site and the importance of the tropane moiety in competitive mechanisms of DA uptake inhibition. These findings set a structure-function baseline for comparison of typical and atypical DAT inhibitors and how their interactions with DAT could lead to the loss of cocaine-like behaviors. [ABSTRACT FROM AUTHOR]

Abstract: Valeriana jatamansi Jones. syn. V. wallichii DC (Indian valerian) is an aromatic as well as medicinal crop. It is commercially used as a substitute for V. officinalis. The valepotriates, mostly from its underground parts, possess tranquillising property. The present studies were conducted during 2001–2006 in Palampur, Himachal Pradesh in the Indian western Himalaya to study seasonal variation of plant growth, and content of enriched fraction of valepotriates and essential oil in its underground parts. The studies were conducted with V. jatamansi cultivar Himbala raised under natural shade. Fresh weight of underground parts and length of root were significantly higher during July and August, the time of maximum rains in the study area. However, dry matter in underground parts was maximum in October. Enriched fraction of valepotriates in underground parts ranged from 2.0 to 5.6%. Enriched fraction of valepotriates was significantly lower during February to June (2.4–3.6%), the time of flowering and fruiting in the crop, and was significantly higher during January, October and November (5.4, 4.7 and 4.9%, respectively). Essential oil in the underground parts ranged from 0.1 to 0.5% and was significantly higher during March to June (0.3–0.4%) attaining its peak in June (0.4%). Estimate of yield of enriched fraction of valepotriates indicated that November or January is the ideal time to harvest V. jatamansi for enriched fraction of valepotriates production, while May is appropriate harvesting time for production of essential oil in western Himalayan region in India. [ABSTRACT FROM AUTHOR]

The ultraviolet (UV) radiation triggers a pigmentation response in human skin, wherein, melanocytes rapidly activate divergent maturation and proliferation programs. Using single-cell sequencing, we demonstrate that these 2 programs are segregated in distinct subpopulations in melanocytes of human and zebrafish skin. The coexistence of these 2 cell states in cultured melanocytes suggests possible cell autonomy. Luria-Delbrück fluctuation test reveals that the initial establishment of these states is stochastic. Tracking of pigmenting cells ascertains that the stochastically acquired state is faithfully propagated in the progeny. A systemic approach combining single-cell multi-omics (RNA+ATAC) coupled to enhancer mapping with H3K27 acetylation successfully identified state-specific transcriptional networks. This comprehensive analysis led to the construction of a gene regulatory network (GRN) that under the influence of noise, establishes a bistable system of pigmentation and proliferation at the population level. This GRN recapitulates melanocyte behaviour in response to external cues that reinforce either of the states. Our work highlights that inherent stochasticity within melanocytes establishes dedicated states, and the mature state is sustained by selective enhancers mark through histone acetylation. While the initial cue triggers a proliferation response, the continued signal activates and maintains the pigmenting subpopulation via epigenetic imprinting. Thereby our study provides the basis of coexistence of distinct populations which ensures effective pigmentation response while preserving the self-renewal capacity., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: RSG is the co-founder of Vyome Biosciences Pvt Ltd., a biopharmaceutical company working in the area of dermatology. Other authors declare no competing interest., (Copyright: © 2024 Aggarwal et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

A new area of biotechnology is nanotechnology. Nanotechnology is an emerging field that aims to develope various substances with nano-dimensions that have utilization in the various sectors of pharmaceuticals, bio prospecting, human activities and biomedical applications. An essential stage in the development of nanotechnology is the creation of nanoparticles. To increase their biological uses, eco-friendly material synthesis processes are becoming increasingly important. Recent years have shown a lot of interest in nanostructured materials due to their beneficial and unique characteristics compared to their polycrystalline counterparts. The fascinating performance of nanomaterials in electronics, optics, and photonics has generated a lot of interest. An eco-friendly approach of creating nanoparticles has emerged in order to get around the drawbacks of conventional techniques. Today, a wide range of nanoparticles have been created by employing various microbes, and their potential in numerous cutting-edge technological fields have been investigated. These particles have well-defined chemical compositions, sizes, and morphologies. The green production of nanoparticles mostly uses plants and microbes. Hence, the use of microbial nanotechnology in agriculture and plant science is the main emphasis of this review. The present review highlights the methods of biological synthesis of nanoparticles available with a major focus on microbially synthesized nanoparticles, parameters and biochemistry involved. Further, it takes into account the genetic engineering and synthetic biology involved in microbial nanobiosynthesis to the construction of microbial nanofactories., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In the present scenario, growing population demands more food, resulting in the need for sustainable agriculture. Numerous approaches are explored in response to dangers and obstacles to sustainable agriculture. A viable approach is to be exploiting microbial consortium, which generate diverse biostimulants with growth-promoting characteristics for plants. These bioinoculants play an indispensable role in optimizing nutrient uptake efficiency mitigating environmental stress. Plant productivity is mostly determined by the microbial associations that exist at the rhizospheric region of plants. The engineered consortium with multifunctional attributes can be effectively employed to improve crop growth efficacy. A number of approaches have been employed to identify the efficient consortia for plant growth and enhanced crop productivity. Various plant growth-promoting (PGP) microbes with host growth-supporting characteristics were investigated to see if they might work cohesively and provide a cumulative effect for improved growth and crop yield. The effective microbial consortia should be assessed using compatibility tests, pot experimentation techniques, generation time, a novel and quick plant bioassay, and sensitivity to external stimuli (temperature, pH). The mixture of two or more microbial strains found in the root microbiome stimulates plant growth and development. The present review deals with mechanism, formulation, inoculation process, commercialization, and applications of microbial consortia as plant bioinoculants for agricultural sustainability., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Endophytic microbes are plant-associated microorganisms that reside in the interior tissue of plants without causing damage to the host plant. Endophytic microbes can boost the availability of nutrient for plant by using a variety of mechanisms such as fixing nitrogen, solubilizing phosphorus, potassium, and zinc, and producing siderophores, ammonia, hydrogen cyanide, and phytohormones that help plant for growth and protection against various abiotic and biotic stresses. The microbial endophytes have attained the mechanism of producing various hydrolytic enzymes such as cellulase, pectinase, xylanase, amylase, gelatinase, and bioactive compounds for plant growth promotion and protection. The efficient plant growth promoting endophytic microbes could be used as an alternative of chemical fertilizers for agro-environmental sustainability. Endophytic microbes belong to different phyla including Euryarchaeota, Ascomycota, Basidiomycota, Mucoromycota, Firmicutes, Proteobacteria, and Actinobacteria. The most pre-dominant group of bacteria belongs to Proteobacteria including α-, β-, γ-, and δ-Proteobacteria. The least diversity of the endophytic microbes have been revealed from Bacteroidetes, Deinococcus-Thermus, and Acidobacteria. Among reported genera, Achromobacter, Burkholderia, Bacillus, Enterobacter, Herbaspirillum, Pseudomonas, Pantoea, Rhizobium, and Streptomyces were dominant in most host plants. The present review deals with plant endophytic diversity, mechanisms of plant growth promotion, protection, and their role for agro-environmental sustainability. In the future, application of endophytic microbes have potential role in enhancement of crop productivity and maintaining the soil health in sustainable manner., (© 2023. Institute of Microbiology, Academy of Sciences of the Czech Republic, v.v.i.)

Cannabis misuse and opioid use disorder (OUD) are highly comorbid but under-treated and associated with poorer outcomes. This paper reports a double-blind, parallel-group randomized controlled trial to determine the efficacy of single-session, clinician-delivered screening and brief intervention (SBI) for reducing cannabis risk. The primary outcome was the cannabis-specific Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST) scores, measured at three-month post-intervention. The secondary objectives were to determine the efficacy of SBI in reducing the frequency of cannabis use, in risk transition from moderate to low risk, and in prescription and non-prescription opioid use. One hundred forty-three participants were randomly allocated to receive either SBI (n = 72) or control (n = 71) interventions. We performed Per-protocol (PP) (n = 125) and Intention-to-treat (ITT) analysis (n = 143). We adjusted our analysis for age, sex, and baseline ASSIST score. The ITT showed that the SBI group had a significant reduction (F = 39.46, p < .001, Effect size 0.22) in the mean ASSIST at follow-up. PP analyses too revealed a similar positive effect of SBI (F = 53.1; p < .001, Effect size 0.31). At follow-up, the SBI group had a higher number of days of cannabis abstinence. Care providers and policymakers may consider SBI for cannabis use in individuals on medications for OUD.

The leachates emanating from the landfills are high in organic loads and thus become potential sources of contamination for both surface and groundwater. As the landfill ages, the nature of leachate changes from acidic to alkaline. The change in pH level affects the chemical oxygen demand (COD)/biochemical oxygen demand (BOD) ratio and when it is less than 0.63, chemical treatments are more effective over the biological treatment methods such as upflow anaerobic sludge blankets (UASB). The existing literature suggests coagulation-flocculation and advanced oxidation process (Fenton) as effective methods for treating wastewater but no comparison of the two are available. Thus, the present study attempts to identify the most efficient coagulants out of ferric chloride (FeCl 3 ), ferrous sulphate (FeSO 4 ) and alum [Al 2 (SO 4 ) 3 ]. Ferric chloride leading to 99% colour removal, 98% COD removal, 99% decrease in total organic carbon, 94.3% removal in NH 3 -N and 91.4% removal in total Kjeldahl nitrogen is observed to be the most efficient coagulant and surprisingly, proves to be even better than Fenton. To understand the field applicability of the two treatment procedures, coagulation with FeCl 3 and Fenton are compared with the UASB method which is currently employed at Gazipur landfill site, Delhi. With lesser operational cost than UASB, both FeCl 3 and Fenton perform better on cost-efficiency scale. Switching from in-suit UASB method to the FeCl 3 method of treatment may result in decreasing the operational cost by 71.9% and to conventional Fenton may result in decreasing the operational cost by 76.8%., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Aims: Multiple substance use is a common but underrecognized problem in patients on opioid agonist treatment (OAT). Co-occurring substance misuse is associated with poor clinical and psychosocial outcomes. We aimed ( a ) to determine the effect of screening and brief intervention (SBI) for substance misuse in people on OAT and (b) to qualitatively summarize the implementation of SBI., Methods: We performed a systematic review of clinical trials on the efficacy of SBI for alcohol and drug misuse in participants on OAT. We searched 5 electronic databases and included published studies and unpublished trials. We measured the standardized mean difference in substance risk scores before and after intervention. We also estimated the standardized mean difference in alcohol consumption per day before and after intervention., Results: We included a total of 8 studies; 5 of these were included in the meta-analysis, and all were reviewed for narrative synthesis. We observed a significant change in the pre-post brief intervention substance risk scores with a medium effect size (Hedges g = 0.752, 95% confidence interval, 0.405-1.099). Sensitivity analyses with different pretest-posttest correlations did not change our result. Modest effects of SBI were found in reducing both alcohol and illicit drug risk scores, and among the population on methadone and buprenorphine treatment. We also observed a significant decrease in alcohol consumption per day 3 months after SBI. Studies showed a limited and incomplete screening for substance misuse and delivery of brief intervention in OAT settings., Conclusions: Screening and brief intervention may be a potential treatment for co-occurring substance misuse among patients on OAT., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 American Society of Addiction Medicine.)

Background: Nepal has implemented the social health security program in certain health facilities to improve access to quality health services. The aim of the study is to understand the utilization pattern of social health security schemes and community's perception of the social health security program., Method: A descriptive cross-sectional mixed-method study was conducted among 300 households of Illam district who had enrolled in the social health security scheme. A multi-stage random sampling method was used. A semi-structured questionnaire was used to collect quantitative data whereas focus group discussions (FGDs) were conducted for qualitative data. Descriptive analysis, bivariate and multivariate analysis was done. FGDs were transcribed and thematic analysis was done., Findings: The utilization rate of social health security scheme was 88.7%. Factors associated with the utilization of program included: presence of under-five children and chronic illness in households, sex and age group. Focus group discussion revealed that people were aware of social health insurance and pleased with program implemented by government. However, the hospitals under the social health insurance were not able to meet their expectations., Conclusion: Although the utilization of social health security scheme was high, people were dissatisfied with the service provided by the hospital under the social health security scheme. Therefore, the social health insurance board should closely monitor the hospitals and develop a feedback mechanism from the users., Competing Interests: The authors have declared that no competing interests exist.

Melanocytes are specialized neural crest-derived cells present in the epidermal skin. These cells synthesize melanin pigment that protects the genome from harmful ultraviolet radiations. Perturbations in melanocyte functioning lead to pigmentary disorders such as piebaldism, albinism, vitiligo, melasma, and melanoma. Zebrafish is an excellent model system to understand melanocyte functions. The presence of conspicuous pigmented melanocytes, ease of genetic manipulation, and availability of transgenic fluorescent lines facilitate the study of pigmentation. This study employs the use of wild-type and transgenic zebrafish lines that drive green fluorescent protein (GFP) expression under mitfa and tyrp1 promoters that mark various stages of melanocytes. Morpholino-based silencing of candidate genes is achieved to evaluate the phenotypic outcome on larval pigmentation and is applicable to screen for regulators of pigmentation. This protocol demonstrates the method from microinjection to imaging and fluorescence-activated cell sorting (FACS)-based dissection of phenotypes using two candidate genes, carbonic anhydrase 14 (Ca14) and a histone variant (H2afv), to comprehensively assess the pigmentation outcome. Further, this protocol demonstrates segregating candidate genes into melanocyte specifiers and differentiators that selectively alter melanocyte numbers and melanin content per cell, respectively.

The present study describes the heavy metal bioaccumulation potential of Ochrobactrum intermedium BPS-20 and Ochrobactrum ciceri BPS-26. A total of 27 isolates were retrieved from the soils of industrial areas and these two were selected based on their maximum metal tolerance. They can resist up to 2400 mg/L and 2000 mg/L of Lead and 850 mg/L and 1200 mg/L of Nickel respectively. The atomic absorption spectroscopic analysis showed considerably good bioaccumulation by O. intermedium BPS-20 (85.34% and 74.87%) and O. ciceri BPS-26 (71.20% and 88.48%) for Lead and Nickel respectively. The growth rate studies also demonstrated no inhibitory effects of heavy metals in the medium. Further the SEM analysis showed the presence of extracellular polymeric substances around bacterial cells. Moreover, the functional gene annotation confirmed the presence of ATPase, ABC, and HoxN/HupN/NixA families of transporters. Thus, both the isolates provide a better solution for the removal of metal pollutants., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: WHO addresses the infectious disease like Tuberculosis, and non- communicable disease like Diabetes among the top 10 causes of death worldwide, which collectively leads to increasing mortality and premature death especially in developing countries. Hence, the present study aims to assess the prevalence of diabetes and its associated risk factors among the tuberculosis patient of Morang, Eastern Nepal., Methods: A cross-sectional study was carried out among the 320 respondents undergoing tuberculosis treatment of Morang district. Respondents from eight randomly selected DOTS centers were selected purposively. The Fasting Blood Sugar and 2-h Post-Prandial Blood Sugar were assessed in the laboratory of respective DOTS center by the glucose oxidase method. An interview for socio-demographic and other variables was conducted using a pretested semi-structured questionnaire based on WHO-STEP Instrument for chronic disease and excerpt from DASS-21 was used for the variable stress., Results: The prevalence of diabetes, pre-diabetic and glucose intolerance among tuberculosis patient was 11.9, 17.2, and 17.8% respectively. Additionally, the univariate analysis reported, user of tobacco products, current alcohol consumers, family history of diabetes and stress level, to have positive association with diabetes, while the multivariate analysis reported, the current alcohol consumer as the significant predictor of diabetes among the tuberculosis patient., Conclusion: A significant portion of the respondents were diabetic, impaired glucose tolerance and pre-diabetic, which supports the fact of diabetes being comorbid with tuberculosis. Hence, it shifts the focus on the bidirectional screening of tuberculosis and diabetes.

Microbial secondary metabolites (SMs) have been identified as an important natural source of drugs for several metabolic and neurological diseases. Along with biomedical applications, SMs are also used in the food and biochemical industries. SMs include natural products such as pigments, alkaloids, toxins, antimicrobials obtained from cultured microorganisms, while other non-cultivable microorganisms have also acted as a rich source of SMs. But, the isolation of SMs from these sources is a very tedious task. Metabolomics provides complete identification and structural information about the entire cellular metabolome under specific conditions using highly sophisticated instrumentation. Further, gene editing techniques such as cloning and gene refactoring, including advanced CRISPR-Cas, can be used for engineering microbes that have the potential to produce natural SMs that were not produced in native microbial strain. The present review describes integrated metabolomics and gene editing approaches for the synthesis of novel microbial SMs and their potential application towards drug discovery and development.

Plants are continually facing biotic and abiotic stresses, and hence, they need to respond and adapt to survive. Plant response during multiple and combined biotic and abiotic stresses is highly complex and varied than the individual stress. These stresses resulted alteration of plant behavior through regulating the levels of microRNA, heat shock proteins, epigenetic variations. These variations can cause many adverse effects on the growth and development of the plant. Further, in natural conditions, several abiotic stresses causing factors make the plant more susceptible to pathogens infections and vice-versa. A very intricate and multifaceted interactions of various biomolecules are involved in metabolic pathways that can direct towards a cross-tolerance and improvement of plant's defence system. Systems biology approach plays a significant role in the investigation of these molecular interactions. The valuable information obtained by systems biology will help to develop stress-resistant plant varieties against multiple stresses. Thus, this review aims to decipher various multilevel interactions at the molecular level under combinatorial biotic and abiotic stresses and the role of systems biology to understand these molecular interactions.

The persistent disposal of xenobiotic compounds like insecticides, pesticides, fertilizers, plastics and other hydrocarbon containing substances is the major source of environmental pollution which needs to be eliminated. Many contemporary remediation methods such as physical, chemical and biological are currently being used, but they are not sufficient to clean the environment. The enzyme based bioremediation is an easy, quick, eco-friendly and socially acceptable approach used for the bioremediation of these recalcitrant xenobiotic compounds from the natural environment. Several microbial enzymes with bioremediation capability have been isolated and characterized from different natural sources, but less production of such enzymes is a limiting their further exploitation. The genetic engineering approach has the potential to get large amount of recombinant enzymes. Along with this, enzyme immobilization techniques can boost the half-life, stability and activity of enzymes at a significant level. Recently, nanozymes may offer the potential bioremediation ability towards a broad range of pollutants. In the present review, we have described a brief overview of the microbial enzymes, different enzymes techniques (genetic engineering and immobilization of enzymes) and nanozymes involved in bioremediation of toxic, carcinogenic and hazardous environmental pollutants., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: Fungal respiratory infections are important cause of mortality and morbidity among HIV positive individuals. They account for up to 70% of illness in Acquired Immunodeficiency Disease Syndrome cases (AIDS). The range of illness varies from asymptomatic mucosal candidiasis to overwhelming disseminated infections. In these patients dissemination of fungus leads to very serious outcomes hence, it is important to have the knowledge of prevailing profile of fungus causing infections, so that it can be treated at the onset. Low CD4+ T lymphocyte count is an excellent indicator of decreased immunity and can also be helpful to predict opportunistic fungal respiratory infections and other complications., Aim: To define the fungal aetiology of lower respiratory tract infections in HIV positive patients and to correlate the occurrence of different fungi with CD4+ T lymphocyte count., Materials and Methods: This was a cross sectional study conducted between May 2014 to April 2015, on 180 treatment naive HIV seropositive patients with lower respiratory tract infections attending the Integrated Counselling and Testing Centre, SMS Medical College, Jaipur, Rajasthan. Early morning expectorated and induced sputum samples were collected and processed for isolation and identification of fungal species. CD4+ T lymphocyte count estimation was done by BD FACS Calibur., Results: Fungal species were isolated from 155 (86.1%) patients. The most common isolate was Candida albicans (31.7%), followed by Aspergillus niger (17.7%) and Aspergillus flavus (10%). The fungal species were most commonly isolated from patients with CD4+ T lymphocyte cell less than 200 cells/μl., Conclusion: Fungal infections were seen in 86.1% of HIV positive patients with lower respiratory tract infections hence, high level of clinical suspicion for fungal aetiology of respiratory infections in HIV positive patients should be kept in mind.

Introduction: Gastrointestinal Tract (GIT) infections are among the most frequent infections in HIV/AIDS patients. The intestinal opportunistic parasitic infections in HIV-infected subjects present most commonly as diarrhoea. A study was conducted to determine the prevalence of enteric parasitic infections in HIV infected patients with diarrhoea, with different levels of immunity., Methods: This study was carried out at the HIV Lab of the Microbiology Department of a tertiary care teaching hospital in Jaipur, Rajasthan, between June-October 2009 among consecutively enrolled 75 HIV infected patients who presented with diarrhoea. Stool samples were collected and examined for enteric parasites by using microscopy and special staining methods. The CD4 (+) cell counts were estimated by using the FACS count system., Results: Intestinal parasitic pathogens were detected in 38.66% patients, Cryptosporidium species was the most common enteric opportunistic parasite which accounted for 37.93 % of the total parasites, followed by Isospora belli 31.03 %. In the HIV infected patients with CD4 (+) counts of < 200 cells/μl, parasites were identified in 56.25 % patients and in HIV patients with CD4 (+) counts between 200-499 cells /μl, parasites could be identified in 27.5 % of the patients . No parasite was detected in the patients with CD4 (+) counts of >500 cells/ μl., Conclusion: Parasitic infections were detected in 38.66% HIV infected patients with diarrhoea and a low CD4 (+) count was significantly associated with opportunistic infections. Identification of the aetiological agent of diarrhoea in an HIV patient is very important, as it can help in the institution of the appropriate therapy and the reduction of the morbidity and the mortality in these patients.