Nucleosome remodeler exclusion by histone deacetylation enforces heterochromatic silencing and epigenetic inheritance.

Heterochromatin enforces transcriptional gene silencing and can be epigenetically inherited, but the underlying mechanisms remain unclear. Here, we show that histone deacetylation, a conserved feature of heterochromatin domains, blocks SWI/SNF subfamily remodelers involved in chromatin unraveling, thereby stabilizing modified nucleosomes that preserve gene silencing. Histone hyperacetylation, resulting from either the loss of histone deacetylase (HDAC) activity or the direct targeting of a histone acetyltransferase to heterochromatin, permits remodeler access, leading to silencing defects. The requirement for HDAC in heterochromatin silencing can be bypassed by impeding SWI/SNF activity. Highlighting the crucial role of remodelers, merely targeting SWI/SNF to heterochromatin, even in cells with functional HDAC, increases nucleosome turnover, causing defective gene silencing and compromised epigenetic inheritance. This study elucidates a fundamental mechanism whereby histone hypoacetylation, maintained by high HDAC levels in heterochromatic regions, ensures stable gene silencing and epigenetic inheritance, providing insights into genome regulatory mechanisms relevant to human diseases.

Seafloor primary production in a changing Arctic Ocean.

Phytoplankton and sea ice algae are traditionally considered to be the main primary producers in the Arctic Ocean. In this Perspective, we explore the importance of benthic primary producers (BPPs) encompassing microalgae, macroalgae, and seagrasses, which represent a poorly quantified source of Arctic marine primary production. Despite scarce observations, models predict that BPPs are widespread, colonizing ~3 million km2 of the extensive Arctic coastal and shelf seas. Using a synthesis of published data and a novel model, we estimate that BPPs currently contribute ~77 Tg C y-1 of primary production to the Arctic, equivalent to ~20 to 35% of annual phytoplankton production. Macroalgae contribute ~43 Tg C y-1, seagrasses contribute ~23 Tg C y-1, and microalgae-dominated shelf habitats contribute ~11 to 16 Tg C y-1. Since 2003, the Arctic seafloor area exposed to sunlight has increased by ~47,000 km2 y-1, expanding the realm of BPPs in a warming Arctic. Increased macrophyte abundance and productivity is expected along Arctic coastlines with continued ocean warming and sea ice loss. However, microalgal benthic primary production has increased in only a few shelf regions despite substantial sea ice loss over the past 20 y, as higher solar irradiance in the ice-free ocean is counterbalanced by reduced water transparency. This suggests complex impacts of climate change on Arctic light availability and marine primary production. Despite significant knowledge gaps on Arctic BPPs, their widespread presence and obvious contribution to coastal and shelf ecosystem production call for further investigation and for their inclusion in Arctic ecosystem models and carbon budgets.

The Arabidopsis F-box protein SKP1-INTERACTING PARTNER 31 modulates seed maturation and seed vigor by targeting JASMONATE ZIM DOMAIN proteins independently of jasmonic acid-isoleucine.

F-box proteins have diverse functions in eukaryotic organisms, including plants, mainly targeting proteins for 26S proteasomal degradation. Here, we demonstrate the role of the F-box protein SKP1-INTERACTING PARTNER 31 (SKIP31) from Arabidopsis (Arabidopsis thaliana) in regulating late seed maturation events, seed vigor, and viability through biochemical and genetic studies using skip31 mutants and different transgenic lines. We show that SKIP31 is predominantly expressed in seeds and that SKIP31 interacts with JASMONATE ZIM DOMAIN (JAZ) proteins, key repressors in jasmonate (JA) signaling, directing their ubiquitination for proteasomal degradation independently of coronatine/jasmonic acid-isoleucine (JA-Ile), in contrast to CORONATINE INSENSITIVE 1, which sends JAZs for degradation in a coronatine/JA-Ile dependent manner. Moreover, JAZ proteins interact with the transcription factor ABSCISIC ACID-INSENSITIVE 5 (ABI5) and repress its transcriptional activity, which in turn directly or indirectly represses the expression of downstream genes involved in the accumulation of LATE EMBRYOGENESIS ABUNDANT proteins, protective metabolites, storage compounds, and abscisic acid biosynthesis. However, SKIP31 targets JAZ proteins, deregulates ABI5 activity, and positively regulates seed maturation and consequently seed vigor. Furthermore, ABI5 positively influences SKIP31 expression, while JAZ proteins repress ABI5-mediated transactivation of SKIP31 and exert feedback regulation. Taken together, our findings reveal the role of the SKIP31-JAZ-ABI5 module in seed maturation and consequently, establishment of seed vigor.

PROTEIN L-ISOASPARTYL METHYLTRANSFERASE protects enolase dysfunction by repairing isoaspartyl-induced damage and is positively implicated in agronomically important seed traits.

The protein-repairing enzyme (PRE) PROTEIN L-ISOASPARTYL METHYLTRANSFERASE (PIMT) influences seed vigor by repairing isoaspartyl-mediated protein damage in seeds. However, PIMTs function in other seed traits, and the mechanisms by which PIMT affects such seed traits are still poorly understood. Herein, through molecular, biochemical, and genetic studies using overexpression and RNAi lines in Oryza sativa and Arabidopsis thaliana, we demonstrate that PIMT not only affects seed vigor but also affects seed size and weight by modulating enolase (ENO) activity. We have identified ENO2, a glycolytic enzyme, as a PIMT interacting protein through Y2H cDNA library screening, and this interaction was further validated by BiFC and co-immunoprecipitation assay. We show that mutation or suppression of ENO2 expression results in reduced seed vigor, seed size, and weight. We also proved that ENO2 undergoes isoAsp modification that affects its activity in both in vivo and in vitro conditions. Further, using MS/MS analyses, amino acid residues that undergo isoAsp modification in ENO2 were identified. We also demonstrate that PIMT repairs such isoAsp modification in ENO2 protein, protecting its vital cellular functions during seed maturation and storage, and plays a vital role in regulating seed size, weight, and seed vigor. Taken together, our study identified ENO2 as a novel substrate of PIMT, and both ENO2 and PIMT in turn implicate in agronomically important seed traits.

The Lysosomal Calcium Channel TRPML1 Maintains Mitochondrial Fitness in NK Cells through Interorganelle Cross-Talk.

Cytotoxic lymphocytes eliminate cancer cells through the release of lytic granules, a specialized form of secretory lysosomes. This compartment is part of the pleomorphic endolysosomal system and is distinguished by its highly dynamic Ca2+ signaling machinery. Several transient receptor potential (TRP) calcium channels play essential roles in endolysosomal Ca2+ signaling and ensure the proper function of these organelles. In this study, we examined the role of TRPML1 (TRP cation channel, mucolipin subfamily, member 1) in regulating the homeostasis of secretory lysosomes and their cross-talk with mitochondria in human NK cells. We found that genetic deletion of TRPML1, which localizes to lysosomes in NK cells, led to mitochondrial fragmentation with evidence of collapsed mitochondrial cristae. Consequently, TRPML1-/- NK92 (NK92ML1-/-) displayed loss of mitochondrial membrane potential, increased reactive oxygen species stress, reduced ATP production, and compromised respiratory capacity. Using sensitive organelle-specific probes, we observed that mitochondria in NK92ML1-/- cells exhibited evidence of Ca2+ overload. Moreover, pharmacological activation of the TRPML1 channel in primary NK cells resulted in upregulation of LC3-II, whereas genetic deletion impeded autophagic flux and increased accumulation of dysfunctional mitochondria. Thus, TRPML1 impacts autophagy and clearance of damaged mitochondria. Taken together, these results suggest that an intimate interorganelle communication in NK cells is orchestrated by the lysosomal Ca2+ channel TRPML1.

PIEZO1 targeting in macrophages boosts phagocytic activity and foam cell apoptosis in atherosclerosis.

The rising incidences of atherosclerosis have necessitated efforts to identify novel targets for therapeutic interventions. In the present study, we observed increased expression of the mechanosensitive calcium channel Piezo1 transcript in mouse and human atherosclerotic plaques, correlating with infiltration of PIEZO1-expressing macrophages. In vitro administration of Yoda1, a specific agonist for PIEZO1, led to increased foam cell apoptosis and enhanced phagocytosis by macrophages. Mechanistically, PIEZO1 activation resulted in intracellular F-actin rearrangement, elevated mitochondrial ROS levels and induction of mitochondrial fragmentation upon PIEZO1 activation, as well as increased expression of anti-inflammatory genes. In vivo, ApoE-/- mice treated with Yoda1 exhibited regression of atherosclerosis, enhanced stability of advanced lesions, reduced plaque size and necrotic core, increased collagen content, and reduced expression levels of inflammatory markers. Our findings propose PIEZO1 as a novel and potential therapeutic target in atherosclerosis.

Genome-wide transcriptomic and biochemical profiling of major depressive disorder: Unravelling association with susceptibility, severity, and antidepressant response.

Identifying biomarkers for diagnosing Major Depressive Disorder (MDD), assessing its severity, and guiding treatment is crucial. We conducted whole genome transcriptomic study in North Indian population, and analyzed biochemical parameters. Our longitudinal study investigated gene-expression profiles from 72 drug-free MDD patients and 50 healthy controls(HCs) at baseline and 24 patients after 12-weeks of treatment. Gene expression analyses identified differentially expressed genes(DEGs) associated with MDD susceptibility, symptom severity and treatment response, independently validated by qPCR. Hierarchical clustering revealed distinct expression patterns between MDD and HCs, also between mild and severe cases. Enrichment analyses of significant DEGs revealed inflammatory, apoptosis, and immune-related pathways in MDD susceptibility, severity, and treatment response. Simultaneously, we assessed thirty biochemical parameters in the same cohort, showed significant differences between MDD and HCs in 13 parameters with monocytes, eosinophils, creatinine, SGPT, and total protein remained independent predictors of MDD in a multivariate-regression model. Our study supports the role of altered immune/inflammatory signaling in MDD pathophysiology, offering clinically relevant biochemical parameters and insights into transcriptomic gene regulation in MDD pathogenesis and treatment response.

Thiacalix[4]arene-Protected Silver Nanoclusters Encapsulating Different Two-Electron Superatom Oligomers.

The subvalent silver kernel represents the nascent state of silver cluster formation, yet the growth mechanism has long been elusive. Herein, two silver nanoclusters (Ag30 and Ag34) coprotected by TC4A4- (H4TC4A = p-tert-butylthiacalix[4]arene) and TBPMT- (TBPMTH = 4-tert-butylbenzenemethanethiol) containing 6e and 4e silver kernels are synthesized and characterized. The trimer of the 2e superatom Ag14 kernel in Ag30 is built from a central Ag6 octahedron sandwiched by two orthogonally oriented Ag5 trigonal bipyramids through sharing vertexes, whereas a double-octahedral Ag10 kernel in Ag34 is a dimer of 2e superatoms. They manifest disparate polyhedron fusion growth patterns at the beginning of the silver cluster formation. Their excellent solution stabilities are contributed by the multisite and multidentate coordination fashion of TC4A4- and the special valence electron structures. This work demonstrates the precise control of silver kernel growth by the solvent strategy and lays a foundation for silver nanocluster application in photothermal conversion.

Genome-wide comparative analyses highlight selection signatures underlying saline adaptation in Chilika buffalo.

Chilika, a native buffalo breed of the Eastern coast of India, is mainly distributed around the Chilika brackish water lake connected with the Bay of Bengal Sea. This breed possesses a unique ability to delve deep into the salty water of the lake and stay there to feed on local vegetation of saline nature. Adaptation to salinity is a genetic phenomenon; however, the genetic basis underlying salinity tolerance is still limited in animals, specifically in livestock. The present study explores the genetic evolution that unveils the Chilika buffalo's adaptation to the harsh saline habitat, including both water and food systems. For this study, whole genome resequencing data on 18 Chilika buffalo and for comparison 10 Murrah buffalo of normal habitat were generated. For identification of selection sweeps, intrapopulation and interpopulation statistics were used. A total of 709, 309, 468, and 354 genes were detected to possess selection sweeps in Chilika buffalo using the nucleotide diversity (θπ), Tajima's D, nucleotide diversity ratio (θπ-ratio), and FST methods, respectively. Further analysis revealed a total of 23 genes including EXOC6B, VPS8, LYPD1, VPS35, CAMKMT, NCKAP5, COMMD1, myosin light chain kinase 3 (MYLK3), and B3GNT2 were found to be common by all the methods. Furthermore, functional annotation study of identified genes provided pathways such as MAPK signaling, renin secretion, endocytosis, oxytocin signaling pathway, etc. Gene network analysis enlists that hub genes provide insights into their interactions with each other. In conclusion, this study has highlighted the genetic basis underlying the local adaptive function of Chilika buffalo under saline environment.NEW & NOTEWORTHY Indian Chilika buffaloes are being maintained on extensive grazing system and have a unique ability to convert local salty vegetation into valuable human food. However, adaptability to saline habitat of Chilika buffalo has not been explored to date. Here, we identified genes and biological pathways involved, such as MAPK signaling, renin secretion, endocytosis, and oxytocin signaling pathway, underlying adaptability of Chilika buffalo to saline environment. This investigation shed light on the mechanisms underlying the buffalo's resilience in its native surroundings.

Effect of a multicomponent quality improvement strategy on sustained achievement of diabetes care goals and macrovascular and microvascular complications in South Asia at 6.5 years follow-up: Post hoc analyses of the CARRS randomized clinical trial.

BACKGROUND: Diabetes control is poor globally and leads to burdensome microvascular and macrovascular complications. We aimed to assess post hoc between-group differences in sustained risk factor control and macrovascular and microvascular endpoints at 6.5 years in the Center for cArdiovascular Risk Reduction in South Asia (CARRS) randomized trial. METHODS AND FINDINGS: This parallel group individual randomized clinical trial was performed at 10 outpatient diabetes clinics in India and Pakistan from January 2011 through September 2019. A total of 1,146 patients with poorly controlled type 2 diabetes (HbA1c ≥8% and systolic BP ≥140 mm Hg and/or LDL-cholesterol ≥130 mg/dL) were randomized to a multicomponent quality improvement (QI) strategy (trained nonphysician care coordinator to facilitate care for patients and clinical decision support system for physicians) or usual care. At 2.5 years, compared to usual care, those receiving the QI strategy were significantly more likely to achieve multiple risk factor control. Six clinics continued, while 4 clinics discontinued implementing the QI strategy for an additional 4-year follow-up (overall median 6.5 years follow-up). In this post hoc analysis, using intention-to-treat, we examined between-group differences in multiple risk factor control (HbA1c <7% plus BP <130/80 mm Hg and/or LDL-cholesterol <100 mg/dL) and first macrovascular endpoints (nonfatal myocardial infarction, nonfatal stroke, death, revascularization [angioplasty or coronary artery bypass graft]), which were co-primary outcomes. We also examined secondary outcomes, namely, single risk factor control, first microvascular endpoints (retinopathy, nephropathy, neuropathy), and composite first macrovascular plus microvascular events (which also included amputation and all-cause mortality) by treatment group and whether QI strategy implementation was continued over 6.5 years. At 6.5 years, assessment data were available for 854 participants (74.5%; n = 417 [intervention]; n = 437 [usual care]). In terms of sociodemographic and clinical characteristics, participants in the intervention and usual care groups were similar and participants at sites that continued were no different to participants at sites that discontinued intervention implementation. Patients in the intervention arm were more likely to exhibit sustained multiple risk factor control than usual care (relative risk: 1.77; 95% confidence interval [CI], 1.45, 2.16), p < 0.001. Cumulatively, there were 233 (40.5%) first microvascular and macrovascular events in intervention and 274 (48.0%) in usual care patients (absolute risk reduction: 7.5% [95% CI: -13.2, -1.7], p = 0.01; hazard ratio [HR] = 0.72 [95% CI: 0.61, 0.86]), p < 0.001. Patients in the intervention arm experienced lower incidence of first microvascular endpoints (HR = 0.68 [95% CI: 0.56, 0.83), p < 0.001, but there was no evidence of between-group differences in first macrovascular events. Beneficial effects on microvascular and composite vascular outcomes were observed in sites that continued, but not sites that discontinued the intervention. CONCLUSIONS: In urban South Asian clinics, a multicomponent QI strategy led to sustained multiple risk factor control and between-group differences in microvascular, but not macrovascular, endpoints. Between-group reductions in vascular outcomes at 6.5 years were observed only at sites that continued the QI intervention, suggesting that practice change needs to be maintained for better population health of people with diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01212328.

Influence of planting dates and fertilizer modules on yield of chrysanthemum and soil health.

BACKGROUND: Optimum planting date and appropriate fertilizer module are essential facets of chrysanthemum cultivation, to enhance quality yield, and improve soil health. A field-based study was undertaken over multiple growing seasons in 2022 and 2023, where six different planting dates, viz., P1:June 15, P2:June 30, P3:July 15, P4:July 30, P5:August 15 and P6:August 30 and two fertilizer modules, FM1:Jeevamrit @ 30 ml plant-1 and FM2:NPK @ 30 g m-2 were systematically examined using a Randomized Block Design (factorial), replicated thrice. RESULTS: P6 planting resulted in early bud formation (44.03 days) and harvesting stage (90.78 days). Maximum plant height (79.44 cm), plant spread (34.04 cm), cut stem length (68.40 cm), flower diameter (7.83 cm), stem strength (19.38˚), vase life (14.90 days), flowering duration (24.08 days), available soil N (314 kg ha-1), available P (37 kg ha-1), available K (347 kg ha-1), bacterial count (124.87 × 107 cfu g-1 soil), actinomycetes count (60.72 × 102 cfu g-1 soil), fungal count (30.95 × 102 cfu g-1 soil), microbial biomass (48.79 µg g-1 soil), dehydrogenase enzyme (3.64 mg TPF h-1 g-1 soil) and phosphatase enzyme (23.79 mol PNP h-1 g-1 soil) was recorded in P1 planting. Among the fertilization module, minimum days to bud formation (74.94 days) and days to reach the harvesting stage (120.95 days) were recorded with the application of NPK @30 g m-2. However, maximum plant height (60.62 cm), plant spread (23.10 cm), number of cut stems m-2 (43.88), cut stem length (51.34 cm), flower diameter (6.92 cm), stem strength (21.24˚), flowering duration (21.75 days), available soil N (317 kg ha-1), available P (37 kg ha-1) and available K (349 kg ha-1) were also recorded with the application of NPK @300 kg ha-1. Maximum vase life (13.87 days), OC (1.13%), bacterial count (131.65 × 107 cfu g-1 soil), actinomycetes count (60.89 × 102 cfu g-1 soil), fungal count (31.11 × 102 cfu g-1 soil), microbial biomass (51.27 µg g-1 soil), dehydrogenase enzyme (3.77 mg TPF h-1 g-1 soil) and phosphatase enzyme (21.72 mol PNP h-1 g-1 soil) were observed with the application of Jeevamrit @ 30 ml plant-1. CONCLUSION: Early planting (P1) and inorganic fertilization (NPK @ 30 g m-2) resulted in improved yield and soil macronutrient content. The soil microbial population and enzymatic activity were improved with the jeevamrit application. This approach highlights the potential for improved yield and soil health in chrysanthemum cultivation, promoting a more eco-friendly and economically viable agricultural model.

Crystalline Porous Material-Based Nanogenerators: Recent Progress, Applications, Challenges, and Opportunities.

Nanogenerator (NG) is a potential technology that allows to build self-powered systems, sensors, flexible and portable electronics in the current Internet of Things (IoT) generation. Nanogenerators include piezoelectric nanogenerators (PENGs) and triboelectric nanogenerators (TENGs), convert different forms of mechanical motion into useful electrical signals. They have evolved and expanded their applications in various fields since their discovery in 2006 and 2012. Material selection is crucial for designing efficient NGs, with high conversion efficiencies. In the recent past, crystalline porous mat erials (metal-organic frameworks (MOFs) and covalent organic frameworks (COFs)) have been widely reported as potential candidates for nanogenerators, owing to their special properties of large surface area, porosity tailoring, ease of surface, post-synthesis modification, and chemical stability. The present organized review provides a complete overview of all the crystalline porous materials (CPMs)-based nanogenerator devices reported in the literature, including synthesis, characterization, device fabrication, and potential applications. Additionally, this review article discusses current challenges, future directions, and perspectives in the field of CPMs-NGs.

Automatic pipeline for segmentation of LV myocardium on quantitative MR T1 maps using deep learning model and computation of radial T1 and ECV values.

Native T1 mapping is a non-invasive technique used for early detection of diffused myocardial abnormalities, and it provides baseline tissue characterization. Post-contrast T1 mapping enhances tissue differentiation, enables extracellular volume (ECV) calculation, and improves myocardial viability assessment. Accurate and precise segmenting of the left ventricular (LV) myocardium on T1 maps is crucial for assessing myocardial tissue characteristics and diagnosing cardiovascular diseases (CVD). This study presents a deep learning (DL)-based pipeline for automatically segmenting LV myocardium on T1 maps and automatic computation of radial T1 and ECV values. The study employs a multicentric dataset consisting of retrospective multiparametric MRI data of 332 subjects to develop and assess the performance of the proposed method. The study compared DL architectures U-Net and Deep Res U-Net for LV myocardium segmentation, which achieved a dice similarity coefficient of 0.84 ± 0.43 and 0.85 ± 0.03, respectively. The dice similarity coefficients computed for radial sub-segmentation of the LV myocardium on basal, mid-cavity, and apical slices were 0.77 ± 0.21, 0.81 ± 0.17, and 0.61 ± 0.14, respectively. The t-test performed between ground truth vs. predicted values of native T1, post-contrast T1, and ECV showed no statistically significant difference (p > 0.05) for any of the radial sub-segments. The proposed DL method leverages the use of quantitative T1 maps for automatic LV myocardium segmentation and accurately computing radial T1 and ECV values, highlighting its potential for assisting radiologists in objective cardiac assessment and, hence, in CVD diagnostics.

Automatic removal of large blood vasculature for objective assessment of brain tumors using quantitative dynamic contrast-enhanced magnetic resonance imaging.

The presence of a normal large blood vessel (LBV) in a tumor region can impact the evaluation of quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters and tumor classification. Hence, there is a need for automatic removal of LBVs from brain tissues including intratumoral regions for achieving an objective assessment of tumors. This retrospective study included 103 histopathologically confirmed brain tumor patients who underwent MRI, including DCE-MRI data acquisition. Quantitative DCE-MRI analysis was performed for computing various parameters such as wash-out slope (Slope-2), relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF), blood plasma volume fraction (Vp), and volume transfer constant (Ktrans). An approach based on data-clustering algorithm, morphological operations, and quantitative DCE-MRI maps was proposed for the segmentation of normal LBVs in brain tissues, including the tumor region. Here, three widely used data-clustering algorithms were evaluated on two types of quantitative maps: (a) Slope-2, and (b) a new proposed combination of rCBV and Slope-2 maps. Fluid-attenuated inversion recovery-MRI hyperintense lesions were also automatically segmented using deep learning-based architecture. The accuracy of LBV segmentation was qualitatively assessed blindly by two experienced observers, and Likert scoring was also obtained from each individual and compared using Cohen's Kappa test, and multiple statistical features from quantitative DCE-MRI parameters were obtained in the segmented tumor. t-test and receiver operating characteristic (ROC) curve analysis were performed for comparing the effect of removal of LBVs on parameters as well as on tumor grading. k-means clustering exhibited better accuracy and computational efficiency. Tumors, in particular high-grade gliomas (HGGs), showed a high contrast compared with normal tissues (relative % difference = 18.5%) on quantitative maps after the removal of LBVs. Statistical features (95th percentile values) of all parameters in the tumor region showed a statistically significant difference (p < 0.05) between with and without LBV maps. Similar results were obtained for the ROC curve analysis for differentiation between low-grade gliomas and HGGs. Moreover, after the removal of LBVs, the rCBV, rCBF, and Vp maps show better visualization of tumor regions.

Folded interferometer to measure coherence-polarization matrix.

We present and experimentally demonstrate a new, to the best of our knowledge, technique to quantitatively measure coherence-polarization (BCP) matrix with correlations of only two Stokes fluctuations. The BCP matrix is a square matrix with four elements that involves two-point correlations among orthogonal polarization components. A theoretical framework of the technique is developed, and its viability is demonstrated by a proof of principle experiment. Experimental tests and measurement of the elements of the BCP matrix of statistically stationary beams are demonstrated.

Therapeutic potential of Nelumbo nucifera Linn. in systemic lupus erythematosus: Network pharmacology and molecular modeling insights.

BACKGROUND: Systemic lupus erythematosus is a chronic autoimmune inflammatory disease characterized by multiple symptoms. The phenolic acids and other flavonoids in Nelumbo nucifera have anti-oxidants, anti-inflammatory, and immunomodulatory activities that are essential for managing SLE through natural sources. This study employs network pharmacology to unveil the multi-target and multi-pathway mechanisms of Nelumbo nucifera as a complementary therapy. The findings are validated through molecular modeling, which includes molecular docking followed by a molecular dynamics study. METHODS: Active compounds and targets of SLE were obtained from IMPPAT, KNApAcKFamily and SwissTargetPrediction databases. SLE-related targets were retrieved from GeneCards and OMIM databases. A protein-protein interaction (PPI) network was built to screen out the core targets using Cytoscape software. ShinyGO was used for GO and KEGG pathway enrichment analyses. Interactions between potential targets and active compounds were assessed by molecular docking and molecular dynamics simulation study. RESULTS: In total, 12 active compounds and 1190 targets of N. nucifera's were identified. A network analysis of the PPI network revealed 10 core targets. GO and KEGG pathway enrichment analyses indicated that the effects of N. nucifera are mediated mainly by AGE-RAGE and other associated signalling pathways. Molecular docking indicated favourable binding affinities, particularly leucocianidol exhibiting less than -4.5 kcal/mol for all 10 targets. Subsequent molecular dynamics simulations of the leucocianidol-ESR1 complex aimed to elucidate the optimal binding complex's stability and flexibility. CONCLUSIONS: Our study unveiled the potential therapeutic mechanism of N. nucifera in managing SLE. These findings provide insights for subsequent experimental validation and open up new avenues for further research in this field.

Methyl jasmonate inducible UGT79A18 is a novel glycosyltransferase involved in the bacoside biosynthetic pathway in Bacopa monnieri.

Bacosides are dammarane-type triterpenoidal saponins in Bacopa monnieri and have various pharmacological applications. All the bacosides are diversified from two isomers, i.e., jujubogenin and pseudojujubogenin. The biosynthetic pathway of bacoside is not well elucidated. In the present study, we characterized a UDP-glycosyltransferase, UGT79A18, involved in the glycosylation of pseudojujubogenin. UGT79A18 shows higher expression in response to 5 h of wounding, and 3 h of MeJA treatment. The recombinant UGT79A18 shows in vitro activity against a wide range of flavonoids and triterpenes and has a substrate preference for protopanaxadiol, a dammarane-type triterpene. Secondary metabolite analysis of overexpression and knockdown lines of UGT79A18 in B. monnieri identify bacopasaponin D, bacopaside II, bacopaside N2 and pseudojujubogenin glucosyl rhamnoside as the major bacosides that were differentially accumulated. In the overexpression lines of UGT79A18, we found 1.7-fold enhanced bacopaside II, 8-fold enhanced bacopasaponin D, 3-fold enhanced pseudojujubogenin glucosyl rhamnoside, and 1.6-fold enhanced bacopaside N2 content in comparison with vector control plant, whereas in the knockdown lines of UGT79A18, we found 1.4-fold reduction in bacopaside II content, 3-fold reduction in the bacopasaponin D content, 2-fold reduction in the pseudojujubogenin glucosyl rhamnoside content, and 1.5-fold reduction in bacopaside N2 content in comparison with vector control. These results suggest that UGT79A18 is a significant UDP glycosyltransferase involved in glycosylating pseudojujubogenin and enhancing the pseudojujubogenin-derived bacosides.

Uncovering the Role of Methylmercury on DNA Lesions at Cytotoxic Concentrations in Glutathione-Depleted Cells: Insights from Experimental and Computational Studies.

Organomercurials (RHg+), especially methylmercury (MeHg+) and ethylmercury (EtHg+), are considered to be more neurotoxic than the inorganic counterpart (Hg2+). They cause massive DNA damage in cells, especially in neurons, where cellular glutathione (GSH) levels are significantly low. However, the mechanism by which RHg+ exerts massive DNA damage at cytotoxic concentrations in brain cells remains obscure. In this study, we investigated the effect of RHg+ on the structural and electronic properties of nucleosides and its effects on DNA damage. The direct interaction of RHg+ with the nucleoside significantly weakens N-glycosidic bonds, decreases the C-H bond energy of sugar moieties, and increases the electrophilicity of the C8-center of purine bases. As a consequence, RHg+-conjugated DNA molecules are extremely labile and highly sensitive to any nucleophiles/radicals present in GSH-depleted cells and, thus, undergo enhanced oxidative and unusual alkylative DNA damage. We also report a functional model of organomercurial lyase, which showed excellent cytoprotective effect against RHg+-induced cytotoxicity; this reverses the activity of glutathione reductase inhibited by MeHgCl and ceases oxidative and alkylating DNA damage. This intriguing finding provides new mechanistic insight into the mode of action of organomercurials in GSH-depleted cells and their adverse effects on individuals with neurodegenerative disorders associated with oxidative stress.

Highly Anisotropic to Isotropic Nature and Ultralow Out-of-Plane Lattice Thermal Conductivity of Layered PbClF-Type Materials.

Materials with an extreme lattice thermal conductivity (κl) are indispensable for thermal energy management applications. Layered materials provide an avenue for designing such functional materials due to their intrinsic bonding heterogeneity. Therefore, a microscopic understanding of the crystal structure, bonding, anharmonic lattice dynamics, and phonon transport properties is critically important for layered materials. Alkaline-earth halofluorides exhibit anisotropy from their layered crystal structure, which is strongly determined by axial bond(s), and it is attributed to the large axial ratio (c/a > 2) for CaBrF, CaIF, and SrIF, in which Br/I acts as a rattler, as evidenced from potential energy curves and phonon density of states. The low axial (c/a) ratio leads to relatively isotropic κl values in the BaXF (X = Cl, Br, I) series. MXF (M = Ca, Sr, Ba) compounds exhibit highly anisotropic (a large phonon transport anisotropy ratio of 10.95 for CaIF) to isotropic (a small phonon transport anisotropy ratio of 1.49 for BaBrF) κl values despite their iso-structure. Moreover, ultralow κl (<1 W/m K) values have been predicted for CaBrF, CaIF, and SrIF in the out-of-plane direction due to weak van der Waals (vdWs) bonding. Overall, this comprehensive study on MXF compounds provides insights into designing low κl layered materials with a large axial ratio by fine-tuning out-of-plane bonding from ionic to vdWs bonding.

Insights into Allosteric Inhibition of the AcrB Efflux Pump: Role of Distinct Binding Pockets, Protomer Preferences, and Crosstalk Disruption.

AcrB, a key component in bacterial efflux processes, exhibits distinct binding pockets that influence inhibitor interactions. In addition to the well-known distal binding pocket within the periplasmic domain, a noteworthy pocket amidst the transmembrane (TM) helices serves as an alternate binding site for inhibitors. The bacterial efflux mechanism involves a pivotal functional rotation of the TM protein, inducing conformational changes in each protomer and propelling drugs toward the outer membrane domain. Surprisingly, inhibitors binding to the TM domain display a preference for L protomers over T protomers. Metadynamics simulations elucidate that Lys940 in the TM domain of AcrB can adopt two conformations in L protomers, whereas the energy barrier for such transitions is higher in T protomers. This phenomenon results in stable inhibitor binding in l protomers. Upon a detailed analysis of unbinding pathways using random accelerated molecular dynamics and umbrella sampling, we have identified three distinct routes for ligand exit from the allosteric site, specifically involving regions within the TM domains─TM4, TM5, and TM10. To explore allosteric crosstalk, we focused on the following key residues: Val452 from the TM domain and Ala831 from the porter domain. Surprisingly, our findings reveal that inhibitor binding disrupts this communication. The shortest path connecting Val452 and Ala831 increases upon inhibitor binding, suggesting sabotage of the natural interdomain communication dynamics. This result highlights the intricate interplay between inhibitor binding and allosteric signaling within our studied system.