Highly stereoselective synthesis of α-glycosylated carboxylic acids by phenanthroline catalysis.

Carbohydrate molecules with an α-glycosylated carboxylic acid motif provide access to biologically relevant chemical space but are difficult to synthesize with high selectivity. To address this challenge, we report a mild and operationally simple protocol to synthesize a wide range of functionally and structurally diverse α-glycosylated carboxylic acids in good yields with high diastereoselectivity. Although there is no apparent correlation between reaction conversion and pK a of carboxylic acids, we found that carboxylic acids with a pK a of 4-5 provide high selectivity while those of a pK a of 2.5 or lower do not. Our strategy utilizes readily available 2,9-dibutyl-1,10-phenanthroline as an effective nucleophilic catalyst to displace a bromide leaving group from an activated sugar electrophile in a nucleophilic substitution reaction, forming phenanthrolinium intermediates. The attack of the carboxylic acid takes place from the α-face of the more reactive intermediate, resulting in the formation of α-glycosylated carboxylic acid. Previous calculations suggested that the hydroxyl group participates in the hydrogen bond interaction with the basic C2-oxygen of a sugar moiety and serves as a nucleophile to attack the C1-anomeric center. In contrast, our computational studies reveal that the carbonyl oxygen of the carboxylic acid serves as a nucleophile, with the carboxylic acid-OH forming a hydrogen bond with the basic C2-oxygen of the sugar moiety. This strong hydrogen bond (1.65 Å) interaction increases the nucleophilicity of the carbonyl oxygen of carboxylic acid and plays a critical role in the selectivity-determining step. In contrast, when alcohol acts as a nucleophile, this scenario is not possible since the -OH group of the alcohol interacts with the C2-oxygen and attacks the C1-anomeric carbon of the sugar moiety. This is also reflected in alcohol-OH's weak hydrogen bond (1.95 Å) interaction with the C2-oxygen. The O(C2)-HO (carboxylic acid) angle was measured to be 171° while the O(C2)-HO (alcohol) angle at 122° deviates from linearity, resulting in weak hydrogen bonding.

Anti-solvent materials enhanced structural and optical properties on ambiently fabricated perovskite thin films.

Perovskite solar cells (PSCs) hold potential for low-cost, high-efficiency solar energy, but their sensitivity to moisture limits practical application. Current fabrication requires controlled environments, limiting mass production. Researchers aim to develop stable PSCs with longer lifetimes under ambient conditions. In this research work, we investigated the stability of perovskite films and solar cells fabricated and annealed in natural air using four different anti-solvents: toluene, ethyl acetate, diethyl ether, and chlorobenzene. Films (about 300 nm thick) were deposited via single-step spin-coating and subjected to ambient air-atmosphere for up to 30 days. We monitored changes in crystallinity, electrical properties, and optics over time. Results showed a gradual degradation in the films' crystallinity, morphology, and electro-optical properties. Notably, films made with ethyl acetate exhibited superior stability compared to other solvents. These findings contribute to advancing stable and high-performance PSCs manufactured under normal ambient conditions. In addition, we also discuss the possible machine learning (ML) approach to our future work direction to optimize the materials structures, and synthesis process parameters for future high-efficient perovskite solar cells fabrication.

A probabilistic risk assessment of heavy metal in water and sediment: An industrially affected urban river in Bangladesh.

Human welfare and biodiversity are at risk due to the deterioration of water and sediment quality. Particularly, in last few decades, global water and sediment quality degraded due to the rapid industrialization and urbanization. This study aimed to determine the concentration of nine heavy metals and metalloid (Pb, Cr, Cd, Hg, As, Mn, Ni, Cu, and Zn) and assess the ecological risks using different pollution indices (e.g., heavy metal pollution index [HPI], Nemerow pollution index [NI], geo-accumulation index [Igeo], contamination factor [CF], degree of contamination [CD] and pollution load index [PLI], ecological risk index [ERI]) in water and sediment of the Shitalakshya River, an industrially affected urban river of Bangladesh. For the first time, 20 water and sediment samples were collected across a wider geographical area of the Shitalakshya River during both monsoon and dry seasons and analyzed using the atomic absorption spectrometer. Average concentrations of heavy metals and metalloid in water were within the Bangladesh standard except for Cr (51.69 ppb) and Mn (228.20 ppb) during monsoon season, portraying potential ecological and human health risks. Besides, average concentration of Mn (549.75 and 370.93 ppb), Ni (549.75 and 370.93 ppb), and Cu (45.34 and 36.09 ppb) in sediment during both seasons were above international standard, implying risk to aquatic sediment biota. The average HPI values indicated moderate to high contamination, whereas the NI values implied polluted water in monsoon season with severe pollution in port area of the river. Similarly, Igeo, CF, CD, and PLI elucidated different levels of contamination in the sediment, particularly during dry season. The ERI values also referred moderate ecological risk in the sediment during dry season. Overall, our findings highlight the alarming level of heavy metal pollution in the Shitalakshya River, necessitating immediate action to protect the aquatic environment, sediment biota, and human health. PRACTITIONER POINTS: This study determined the concentration of heavy metals and metalloid in water and sediment of the Shitalakshya River, Bangladesh. The study revealed that the average concentration of Cr and Mn in water exceeded national standard, whereas Mn, Ni, and Cu in sediment exceeded international limit. Potential ecological risk of heavy metals was also assessed using different pollution indices. Calculated pollution indices indicated different degree of pollution, implying critical ecological condition due to heavy metal pollution in aquatic environment and sediment biota.

Mechanistic insight into the mode of inhibition of dietary flavonoids; targeting macrophage migration inhibitory factor.

Introduction: The Macrophage Migration Inhibitory Factor (MIF), a key pro-inflammatory mediator, is responsible for modulating immune responses. An array of inflammatory and autoimmune diseases has been linked to the dysregulated activity of MIF. The significance in physiological as well as pathophysiological phenomena underscores the potential of MIF as an attractive target with pharmacological relevance. Extensive research in past has uncovered a number of inhibitors, while the ISO-1, or (S, R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester being recognized as a benchmark standard so far. Recent work by Yang and coworkers identified five promising dietary flavonoids, with superior activity compared to the standard ISO-1. Nevertheless, the exact atomic-level inhibitory mechanism is still elusive. Methods: To improve the dynamic research, and rigorously characterize, and compare molecular signatures of MIF complexes with ISO-1 and flavonoids, principal component analysis (PCA) was linked with molecular dynamics (MD) simulations and binding free energy calculations. Results: The results suggest that by blocking the tautomerase site these small molecule inhibitors could modify the MIF activity by disrupting the intrinsic dynamics in particular functional areas. The stability matrices revealed the average deviation values ranging from 0.27-0.32 nm while the residue level fluctuations indicated that binding of the selected flavonoids confer enhanced stability relative to the ISO-1. Furthermore, the gyration values extracted from the simulated trajectories were found in the range of 1.80-1.83 nm. Discussion: Although all the tested flavonoids demonstrated remarkable results, the one obtained for the potent inhibitors, particularly Morin and Amentoflavone exhibited a good correlation with biological activity. The PCA results featured relatively less variance and constricted conformational landscape than others. The stable ensembles and reduced variation in turns might be the possible reasons for their outstanding performance documented previously. The results from the present exploration provide a comprehensive understanding of the molecular complexes formed by flavonoids and MIF, shedding light on their potential roles and impacts. Future studies on MIF inhibitors may benefit from the knowledge gathered from this investigation.

Exposure to Waterpipe Smoke Disrupts Erythrocyte Homeostasis of BALB/c Mice.

The prevalence of waterpipe tobacco smoking (WPS) is increasing worldwide and is relatively high among youth and young adults. It has been shown, both experimentally and clinically, that WPS exposure adversely affects the cardiovascular and hematological systems through the generation of oxidative stress and inflammation. Our study aimed to evaluate the impact of WPS exposure on erythrocytes, a major component of the hematological system, of BALB/c mice. Here, we assessed the effect of nose-only WPS exposure for four consecutive weeks on erythrocyte inflammation, oxidative stress, and eryptosis. The duration of the session was 30 min/day, 5 days/week. Control mice were exposed to air. Our results showed that the levels of C-reactive protein, lipid peroxidation (LPO), superoxide dismutase, and total nitric oxide (NO) were significantly increased in the plasma of WPS-exposed mice. The number of erythrocytes and the hematocrit were significantly decreased in WPS-exposed mice compared with the control group. Moreover, there was an increase in the erythrocyte fragility in mice exposed to WPS compared with those exposed to air. The levels of lactate dehydrogenase, LPO, reduced glutathione, catalase, and NO were significantly increased in the red blood cells (RBCs) of WPS-exposed mice. In addition, erythrocytes of the WPS-exposed group showed a significant increase in ATPase activity, Ca2+, annexin V binding, and calpain activity. Taken together, our findings suggest that WPS exposure elevated inflammation and oxidative stress in the plasma and induced hemolysis in vivo. It also caused alterations of RBCs oxidative stress and eryptosis in vitro. Our data confirm the detrimental impact of WPS on erythrocyte physiology.

Impact of mutations in SARS-CoV-2 recombinant sub-variant XBB.1.16 on the binding affinity with human ACE2 receptor.

Despite the waning threat of the COVID-19 pandemic, its detrimental impact on global health persists. Regardless of natural immunity or immunity obtained through vaccination, emerging variants of the virus continue to undergo mutations and propagate globally. The persistent mutations in SARS-CoV-2, along with the subsequent formation of recombinant sub-variants has become a challenge for researchers and health professionals, raising concerns about the efficacy of current vaccines. Gaining a better understanding of the biochemical interactions between the Spike Protein (RBD) of SARS-CoV-2 variants and the human ACE2 receptor can prove to be beneficial in designing and developing antiviral therapeutics that are equally effective against all strains and emerging variants. Our objective in this study was to investigate the interfacial binding pattern of the SARS-CoV-2 RBD-ACE2 complex of the Wild Type (WT), Omicron, and the Omicron recombinant sub-variant XBB.1.16. We aimed to examine the atomic level factors and observe how mutations influence the interaction between the virus and its host using Molecular Dynamics simulation, MM/GBSA energy calculations, and Principal Component Analysis. Our findings reveal a higher degree of structural deviation and flexibility in XBB.1.16 compared to WT and Omicron. PCA indicated a wider cluster and significant flexibility in the movements of XBB.1.16 which can also be observed in free energy landscapes, while the normal mode analysis revealed converging motions within the RBD-ACE2 complexes which can facilitate the interaction between them. A pattern of decreased binding affinity was observed in case of XBB.1.16 when compared to the WT and Omicron. These observed deviations in XBB.1.16 when compared to its parent lineage Omicron, and WT can be attributed to the mutations specific to it. Collectively, these results enhance our understanding of the impact of mutations on the interaction between this strain and the host, taking us one step closer to designing effective antiviral therapeutics against the continually mutating strains.

Exploring the reproductive features of Clupisoma garua from Ganges River, Bangladesh: insights into eco-climatic factors for sustainable management and advancements in aquaculture practices.

The Garua bacha, Clupisoma garua, holds considerable commercial and nutritional significance as a fish species. This study investigates the relationships between GSI (gonadosomatic index) and eco-climatic conditions, and provides comprehensive insights into several facets of reproduction, such as size at first sexual maturity (Lm), spawning season, peak spawning period, and proposes sustainable management strategies for C. garua in the Ganges River, northwestern, Bangladesh. Since January to December 2017, 570 female individuals have been gathered from the Ganges River using cast nets, gill nets, and square lift nets on a monthly basis. The total length (TL) of the specimens varied from 3.90 to 26.30 cm. Lm was estimated as 14.30 cm based on the results of the TL vs. GSI, MGSI (modified gonadosomatic index), DI (Dobriyal index), 14.00 cm through TL-FL regressions, and 15.18 cm depending on Lmax for this species. Furthermore, the spawning period was observed from May to August, peaking in June and July, based on greater GSI, MGSI, and DI values. Throughout the peak spawning season, there was not a significant differ from a value of 100 in the relative weight (WR) of the female species. During the spawning season, a substantial association between temperature and GSI (p = 0.0038); rainfall and GSI (p = 0.0043); DO and GSI (p = 0.0043); pH and GSI (p = 0.0002); and alkalinity and GSI (p = 0.0001) was detected. Analyzing a 55-year data series (1964-2018), it became clear that an increase in average air temperature of 0.0289 °C and a decrease in rainfall of 2.988 mm per year might possibly delay the spawning season of this species. As a consequence, the results of this study provide crucial information for developing management strategies to safeguard C. garua populations in the Ganges River and its adjacent ecosystems.

Band gap tuning of perovskite solar cells for enhancing the efficiency and stability: issues and prospects.

The intriguing optoelectronic properties, diverse applications, and facile fabrication techniques of perovskite materials have garnered substantial research interest worldwide. Their outstanding performance in solar cell applications and excellent efficiency at the lab scale have already been proven. However, owing to their low stability, the widespread manufacturing of perovskite solar cells (PSCs) for commercialization is still far off. Several instability factors of PSCs, including the intrinsic and extrinsic instability of perovskite materials, have already been identified, and a variety of approaches have been adopted to improve the material quality, stability, and efficiency of PSCs. In this review, we have comprehensively presented the significance of band gap tuning in achieving both high-performance and high-stability PSCs in the presence of various degradation factors. By investigating the mechanisms of band gap engineering, we have highlighted its pivotal role in optimizing PSCs for improved efficiency and resilience.

Assessment of Heavy Metal Contamination and Health Risk Associated with Cultivated Vegetables along Dhaka-Mymensingh Highway, Bangladesh.

The purpose of this research work is to evaluate the degree of eight heavy metals (Fe, Mn, Cu, Zn, Cd, Pb, Cr, and Ni) contamination and health risks of three regularly consumed vegetables (papaya, bottle gourd, and esculent) near one of Bangladesh's busiest roadways, the Dhaka-Mymensingh highway. The heavy metal concentrations in 45 vegetable samples were analyzed using an atomic absorption spectrometer (AAS). These samples were collected from five different sampling sites based on various land use patterns adjacent to the highway. The average concentrations (mg/kg) of Cu, Fe, Mn, Zn, Cr, and Ni were found to be 9.86, 246.8, 16.9, 28.0, 9.02, and 2.02, respectively, for papaya; 14.9, 281.2, 387.6, 49.0, 10.1, and 2.92, respectively, for bottle gourd; and 17.6, 183.4, 107.2, 80.7, 7.98, and 2.34, respectively, for esculent. The mean concentrations of Cr, Zn, and Mn in papaya, bottle gourd, and esculent were higher than the acceptable limit. Correlation analysis revealed a significant positive correlation between Fe-Cu, Zn-Fe, Cu-Fe, and Fe-Zn in papaya; Cu-Zn, Fe-Cr, Zn-Ni, and Cr-Fe in bottle gourd; and Mn-Cr, Mn-Ni, Mn-Fe, and Cr-Ni in esculent, thereby indicating their common anthropogenic sources like agricultural activities, waste from the commercial area, filling station, and vehicular emissions. Health risk assessment through target hazard quotient (THQ) revealed the highest THQ of 9.52 for Cr in bottle gourd, which poses a high non-carcinogenic health risk to the localities upon the intake of these contaminated vegetables. Target cancer risk (TCR) was found to be highest for Cr in papaya (0.013) and bottle gourd (0.014). TCR trends were found for Cr in the following order: bottle gourd > esculent > papaya. This study contributed the greatest concern for both carcinogenic and non-carcinogenic health impacts through ingesting contaminated vegetables.

Awareness of HPV vaccine and its socio-demographic determinants among the parents of eligible daughters in Bangladesh: A nationwide study.

Background: Vaccination against Human papillomavirus (HPV) is recommended to avoid HPV infections and its associated diseases, including cervical cancer. However, there is no awareness study among Bangladeshi population. Hence, this nationwide study was conducted to explore HPV vaccine awareness and its determinants among parents of eligible adolescent girls. Methods: This study was conducted among the parents of daughters aged 9-15 years from 42 out of 64 randomly selected districts of Bangladesh between June 28 to August 2, 2023. A multistage sampling method was used to enroll 2151 study participants from all eight divisions of Bangladesh. A semi-structured questionnaire was used for face-to-face interviews in this study. The statistical software Stata (Version 17) was used for statistical analyses. Results: The average age of the participants was 38.18 (±5.86) years. Only 22.32 % of the participants were aware of the HPV vaccine. Every additional year of age increased the likelihood of being aware of the HPV vaccine by 3 % (AOR: 1.03; 95%CI: 1.00-1.06). Participants residing in the urban area had 3.56 times higher odds of awareness than rural and semi-urban people. Businessmen and housewives had 60 % (AOR: 0.40; 95 % CI: 0.22-0.69) and 77 % (AOR: 0.23; 95 % CI: 0.16-0.33) lower odds in comparison to job holders. The lower-income group exhibited significantly higher odds of awareness (AOR: 0.25, 95%CI: 0.16-0.39) compared to the middle and the higher-income group. Participants who never went through routine health check-ups had 77 % lower odds of being aware than those who availed of regular routine check-ups (AOR: 0.23; 95%CI: 0.16-0.34). Conclusion: Awareness of the HPV vaccine among the general population of Bangladesh is very low. Age, residence, occupation, monthly income, and routine medical check-ups were associated with HPV vaccine awareness. A nationwide awareness campaign would increase this awareness level among the Bangladeshi population, especially among the parents of daughters.

Males conditionally inseminate at three female body locations according to female mating history and female maturity status in a squid.

In some squids, such as those in the family Loliginidae, upon copulation, females receive and store male-delivered sperm capsules, spermatangia, at two different body locations: the buccal membrane and the distal end of the oviduct. This insemination site dimorphism is associated with alternative reproductive strategies. However, in Loliolus sumatrensis, a species of Loliginidae, the females possess three insemination sites: buccal membrane (BM), basal left IV arm (ARM) and lateral head behind the left eye (EYE), therefore we studied such the unusual phenomena. We developed microsatellite markers and genotyped the paternity of each spermatangium on three sites. We found multiple paternity at every single site and simultaneous usage of all three sites by a few males. The seasonal dynamics of a population in the Seto Inland Sea revealed a set priority for the initial use of insemination sites as BM, followed by ARM and then EYE, whereas the maximum number of stored spermatangia was greater in EYE > ARM > BM. Female maturity status was correlated with the usage pattern of insemination sites but not with the number of stored spermatangia at any insemination site. These results suggest that a male squid inseminates at different locations according to female mating history and female maturity status.

Exploring the mechanism of action of spirooxindoles as a class of CDK2 inhibitors: a structure-based computational approach.

Cyclin-dependent kinase 2 (CDK2) regulates cell cycle checkpoints in the synthesis and mitosis phases and plays a pivotal role in cancerous cell proliferation. The activation of CDK2, influenced by various protein signaling pathways, initiates the phosphorylation process. Due to its crucial role in carcinogenesis, CDK2 is a druggable hotspot target to suppress cancer cell proliferation. In this context, several studies have identified spirooxindoles as an effective class of CDK2 inhibitors. In the present study, three spirooxindoles (SOI1, SOI2, and SOI3) were studied to understand their inhibitory mechanism against CDK2 through a structure-based approach. Molecular docking and molecular dynamics (MD) simulations were performed to explore their interactions with CDK2 at the molecular level. The calculated binding free energy for the spirooxindole-based CDK2 inhibitors aligned well with experimental results regarding CDK2 inhibition. Energy decomposition (ED) analysis identified key binding residues, including I10, G11, T14, R36, F82, K89, L134, P155, T158, Y159, and T160, in the CDK2 active site and T-loop phosphorylation. Molecular mechanics (MM) energy was identified as the primary contributor to stabilizing inhibitor binding in the CDK2 protein structure. Furthermore, the analysis of binding affinity revealed that the inhibitor SOI1 binds more strongly to CDK2 compared to the other inhibitors under investigation. It demonstrated a robust interaction with the crucial residue T160 in the T-loop phosphorylation site, responsible for kinase activation. These insights into the inhibitory mechanism are anticipated to contribute to the development of potential CDK2 inhibitors using the spirooxindole scaffold.

Predicting FFAR4 agonists using structure-based machine learning approach based on molecular fingerprints.

Free Fatty Acid Receptor 4 (FFAR4), a G-protein-coupled receptor, is responsible for triggering intracellular signaling pathways that regulate various physiological processes. FFAR4 agonists are associated with enhancing insulin release and mitigating the atherogenic, obesogenic, pro-carcinogenic, and pro-diabetogenic effects, normally associated with the free fatty acids bound to FFAR4. In this research, molecular structure-based machine-learning techniques were employed to evaluate compounds as potential agonists for FFAR4. Molecular structures were encoded into bit arrays, serving as molecular fingerprints, which were subsequently analyzed using the Bayesian network algorithm to identify patterns for screening the data. The shortlisted hits obtained via machine learning protocols were further validated by Molecular Docking and via ADME and Toxicity predictions. The shortlisted compounds were then subjected to MD Simulations of the membrane-bound FFAR4-ligand complexes for 100 ns each. Molecular analyses, encompassing binding interactions, RMSD, RMSF, RoG, PCA, and FEL, were conducted to scrutinize the protein-ligand complexes at the inter-atomic level. The analyses revealed significant interactions of the shortlisted compounds with the crucial residues of FFAR4 previously documented. FFAR4 as part of the complexes demonstrated consistent RMSDs, ranging from 3.57 to 3.64, with minimal residue fluctuations 5.27 to 6.03 nm, suggesting stable complexes. The gyration values fluctuated between 22.8 to 23.5 nm, indicating structural compactness and orderliness across the studied systems. Additionally, distinct conformational motions were observed in each complex, with energy contours shifting to broader energy basins throughout the simulation, suggesting thermodynamically stable protein-ligand complexes. The two compounds CHEMBL2012662 and CHEMBL64616 are presented as potential FFAR4 agonists, based on these insights and in-depth analyses. Collectively, these findings advance our comprehension of FFAR4's functions and mechanisms, highlighting these compounds as potential FFAR4 agonists worthy of further exploration as innovative treatments for metabolic and immune-related conditions.

Synthesis of Competitive and Noncompetitive Inhibitors of Alpha-Glucosidase and Anticancer Agents.

Imidazoles and phenylthiazoles are an important class of heterocycles that demonstrate a wide range of biological activities against various types of cancers, diabetes mellitus and pathogenic microorganisms. The heterocyclic structure having oxothiazolidine moiety is an important scaffold present in various drugs, with potential for enzyme inhibition. In an effort to discover new heterocyclic compounds, we synthesized 26 new 4,5-diphenyl-1H-imidazole, phenylthiazole, and oxothiazolidine heterocyclic analogues that demonstrated potent α-glucosidase inhibition and anticancer activities. Majority of the compounds noncompetitively inhibited α-glucosidase except for two that exhibited competitive inhibition of the enzyme. Docking results suggested that the noncompetitive inhibitors bind to an apparent allosteric site on the enzyme located in the vicinity of the active site. Additionally, the analogues also exhibited significant activity against various types of cancers including non-small lung cancer. Since tubulin protein plays an important role in the pathogenesis of non-small lung cancer, molecular docking with one of the target compounds provided important clues to its binding mode. The current work on imidazoles and phenylthiazole derivatives bears importance for designing of new antidiabetic and anticancer drugs.

Uncovering PPAR-γ agonists: An integrated computational approach driven by machine learning.

Peroxisome proliferator-activated receptor gamma (PPAR-γ) serves as a nuclear receptor with a pivotal function in governing diverse facets of metabolic processes. In diabetes, the prime physiological role of PPAR-γ is to enhance insulin sensitivity and regulate glucose metabolism. Although PPAR-γ agonists such as Thiazolidinediones are effective in addressing diabetes complications, it is vital to be mindful that they are associated with substantial side effects that could potentially give rise to health challenges. The recent surge in the discovery of selective modulators of PPAR-γ inspired us to formulate an integrated computational strategy by leveraging the promising capabilities of both machine learning and in silico drug design approaches. In pursuit of our objectives, the initial stage of our work involved constructing an advanced machine learning classification model, which was trained utilizing chemical information and physicochemical descriptors obtained from known PPAR-γ modulators. The subsequent application of machine learning-based virtual screening, using a library of 31,750 compounds, allowed us to identify 68 compounds having suitable characteristics for further investigation. A total of four compounds were identified and the most favorable configurations were complemented with docking scores ranging from -8.0 to -9.1 kcal/mol. Additionally, the compounds engaged in hydrogen bond interactions with essential conserved residues including His323, Leu330, Phe363, His449 and Tyr473 that describe the ligand binding site. The stability indices investigated herein for instance root-mean-square fluctuations in the backbone atoms indicated higher mobility in the region of orthosteric site in the presence of agonist with the deviation peaks in the range of 0.07-0.69 nm, signifying moderate conformational changes. The deviations at global level revealed that the average values lie in the range of 0.25-0.32 nm. In conclusion, our identified hits particularly, CHEMBL-3185642 and CHEMBL-3554847 presented outstanding results and highlighted the stable conformation within the orthosteric site of PPAR-γ to positively modulate the activity.

Spatial distribution of heavy metal abundance at distance gradients of roadside agricultural soil from the busiest highway in Bangladesh: A multi-index integration approach.

Bangladesh is currently experiencing significant infrastructural development in road networking system through the construction or reconstruction of multiple roads and highways. Consequently, there is a rise in traffic intensity on roads and highways, along with a significant contamination of adjacent agricultural soils with heavy metals. The purpose of this study was to evaluate the ecological risk, health risk and the abundance of seven heavy metals (Cu, Mn, Pb, Cd, Cr, As, and Ni) in three distance gradients (0, 300, and 500 m) of agricultural soil along the Dhaka-Chattogram highway. The concentration of heavy metals was measured with an Atomic Absorption Spectrophotometer (AAS) on a total of 36 soil samples that were taken from 12 different sampling sites. Based on the findings, Cd had a high contamination factor for all distance gradients, whereas Cr had a moderate contamination factor in 67% of the study areas. According to the Pollution Load Index (PLI), Cd, Cr, and Pb were the predominant pollutants. Principal component analysis (PCA) result shows these metals mainly came from anthropogenic sources. The considerable positive correlations between Cu-Pb, Cu-Cd, Pb-Cd, and Cr-Ni all pointed to shared anthropogenic origins. As per Potential Ecological Risk Assessment (PERI) analysis, Pb, Cd, Cr, and Ni each contribute significantly and pose a moderate threat. The Target Hazard Quotient (THQ) values for all pathways of exposure to Pb and Cr in soils were more than 1, which would pose a significant risk to human health in the following order: THQadult female > THQadult male > THQchildren. This study will help to evaluate the human health risk and develop a better understanding of the heavy metal abundance scenario in the agricultural fields adjacent to this highway.

Perovskite materials in X-ray detection and imaging: recent progress, challenges, and future prospects.

Perovskite materials have attracted significant attention as innovative and efficient X-ray detectors owing to their unique properties compared to traditional X-ray detectors. Herein, chronologically, we present an in-depth analysis of X-ray detection technologies employing organic-inorganic hybrids (OIHs), all-inorganic and lead-free perovskite material-based single crystals (SCs), thin/thick films and wafers. Particularly, this review systematically scrutinizes the advancement of the diverse synthesis methods, structural modifications, and device architectures exploited to enhance the radiation sensing performance. In addition, a critical analysis of the crucial factors affecting the performance of the devices is also provided. Our findings revealed that the improvement from single crystallization techniques dominated the film and wafer growth techniques. The probable reason for this is that SC-based devices display a lower trap density, higher resistivity, large carrier mobility and lifetime compared to film- and wafer-based devices. Ultimately, devices with SCs showed outstanding sensitivity and the lowest detectable dose rate (LDDR). These results are superior to some traditional X-ray detectors such as amorphous selenium and CZT. In addition, the limited performance of film-based devices is attributed to the defect formation in the bulk film, surfaces, and grain boundaries. However, wafer-based devices showed the worst performance because of the formation of voids, which impede the movement of charge carriers. We also observed that by performing structural modification, various research groups achieved high-performance devices together with stability. Finally, by fusing the findings from diverse research works, we provide a valuable resource for researchers in the field of X-ray detection, imaging and materials science. Ultimately, this review will serve as a roadmap for directing the difficulties associated with perovskite materials in X-ray detection and imaging, proposing insights into the recent status, challenges, and promising directions for future research.

Taming the cytokine storm: small molecule inhibitors targeting IL-6/IL-6α receptor.

Given the increasing effectiveness of immune-based therapies, management of their associated toxicities is of utmost importance. Cytokine release syndrome (CRS), characterized by elevated levels of cytokine, poses a significant challenge following the administration of antibodies and CAR-T cell therapies. CRS also contributes to multiple organ dysfunction in severe viral infections, notably in COVID-19. Given the pivotal role of IL-6 cytokine in initiating CRS, it has been considered a most potential therapeutic target to mitigate hyperactivated immune responses. While monoclonal antibodies of IL-6 show promise in mitigating cytokine storm, concerns about immunotoxicity persist, and small molecule IL-6 antagonists remain unavailable. The present study employed sophisticated computational techniques to identify potential hit compounds as IL-6 inhibitors, with the aim of inhibiting IL-6/IL-6R protein-protein interactions. Through ligand-based pharmacophore mapping and shape similarity in combination with docking-based screening, we identified nine hit compounds with diverse chemical scaffolds as potential binders of IL-6. Further, the MD simulation of 300 ns of five virtual hits in a complex with IL-6 was employed to study the dynamic behavior. To provide a more precise prediction, binding free energy was also estimated. The identified compounds persistently interacted with the residues lining the binding site of the IL-6 protein. These compounds displayed low binding energy during MMPBSA calculations, substantiating their strong association with IL-6. This study suggests promising scaffolds as potential inhibitors of IL-6/IL-6R protein-protein interactions and provides direction for lead optimization.

A deep learning-based theoretical protocol to identify potentially isoform-selective PI3Kα inhibitors.

Phosphoinositide 3-kinase alpha (PI3Kα) is one of the most frequently dysregulated kinases known for their pivotal role in many oncogenic diseases. While the side effects linked to existing drugs against PI3Kα-induced cancers provide an avenue for further research, the significant structural conservation among PI3Ks makes it extremely difficult to develop new isoform-selective PI3Kα inhibitors. Embracing this challenge, we herein designed a hybrid protocol by integrating machine learning (ML) with in silico drug-designing strategies. A deep learning classification model was developed and trained on the physicochemical descriptors data of known PI3Kα inhibitors and used as a screening filter for a database of small molecules. This approach led us to the prediction of 662 compounds showcasing appropriate features to be considered as PI3Kα inhibitors. Subsequently, a multiphase molecular docking was applied to further characterize the predicted hits in terms of their binding affinities and binding modes in the targeted cavity of the PI3Kα. As a result, a total of 12 compounds were identified whereas the best poses highlighted the efficiency of these ligands in maintaining interactions with the crucial residues of the protein to be targeted for the inhibition of associated activity. Notably, potential activity of compound 12 in counteracting PI3Kα function was found in a previous in vitro study. Following the drug-likeness and pharmacokinetic characterizations, six compounds (compounds 1, 2, 3, 6, 7, and 11) with suitable ADME-T profiles and promising bioavailability were selected. The mechanistic studies in dynamic mode further endorsed the potential of identified hits in blocking the ATP-binding site of the receptor with higher binding affinities than the native inhibitor, alpelisib (BYL-719), particularly the compounds 1, 2, and 11. These outcomes support the reliability of the developed classification model and the devised computational strategy for identifying new isoform-selective drug candidates for PI3Kα inhibition.

Evaluation of essential and trace metals/metalloids distribution and probable human health risk implications from branded liquid and powder milks available in Dhaka City, Bangladesh.

The processed forms of milk, branded liquid, and power milk available in Dhaka city, the capital of Bangladesh, were investigated for essential and trace metal/metalloids regarding nutritional and human health risk aspects. For this, the potential nutritional contribution, estimated daily intake (EDI) and non-carcinogenic risk for six different life stages with male and female categories, as well as the carcinogenic risk for children and adults of both genders, were addressed. In total, 46 branded liquid and powder milk samples were considered for this analysis employing atomic absorption spectroscopy. The concentration of essential elements showed the trends of K > Ca > Na > Mg > Fe > Zn > Mn > Cu and K > Ca > Na > Mg > Fe > Cu > Mn > Zn for liquid and powder milk samples, respectively, but the potentially hazardous one showed the same trends (Cr > Pb > Hg > As > Cd) for both items. Except for Cr, Hg, and Fe, the elemental compositions of both milk categories differed considerably (< 0.05). Compared to the threshold values for milk samples (liquid and powder), Fe (19% and 27%), Mn (100% and 63%), Cu (0% and 23%), Zn (94% and 0%), Pb (25% and 13%), and Cr (0% and 3%) showed above the permissible limits. The nutrient input was the highest for Ca (27.2% and 18.7%), followed by Mg, K, and Na. The EDI of studied elements was within the daily permissible limit in both the milk category (except age group (≤ 3) and the female category). The non-carcinogenic risk assessment showed that the age groups ≤ 3 for liquid milk and ≤ 3 and 3 < X ≤ 14 with female categories for powder milk exceeded the threshold level (> 1) in the case of Cr, Cd, As, Zn, and Mn. The probable carcinogenic risks indicated an unacceptable risk level (< 1.00E-04) for the ingestion of Cr through powder milk samples for children in male and female categories. Finally, it believes that green cow farming practices and green milk processing technology, as well as continuous monitoring of toxic metals, can limit the ultimate risk worldwide.