IκBζ is a dual-use coactivator of NF-κB and POU transcription factors.

OCA-B, OCA-T1, and OCA-T2 belong to a family of coactivators that bind to POU transcription factors (TFs) to regulate gene expression in immune cells. Here, we identify IκBζ (encoded by the NFKBIZ gene) as an additional coactivator of POU TFs. Although originally discovered as an inducible regulator of NF-κB, we show here that IκBζ shares a microhomology with OCA proteins and uses this segment to bind to POU TFs and octamer-motif-containing DNA. Our functional experiments suggest that IκBζ requires its interaction with POU TFs to coactivate immune-related genes. This finding is reinforced by epigenomic analysis of MYD88L265P-mutant lymphoma cells, which revealed colocalization of IκBζ with the POU TF OCT2 and NF-κB:p50 at hundreds of DNA elements harboring octamer and κB motifs. These results suggest that IκBζ is a transcriptional coactivator that can amplify and integrate the output of NF-κB and POU TFs at inducible genes in immune cells.

Structure, mechanism, and inhibition of Hedgehog acyltransferase.

The Sonic Hedgehog (SHH) morphogen pathway is fundamental for embryonic development and stem cell maintenance and is implicated in various cancers. A key step in signaling is transfer of a palmitate group to the SHH N terminus, catalyzed by the multi-pass transmembrane enzyme Hedgehog acyltransferase (HHAT). We present the high-resolution cryo-EM structure of HHAT bound to substrate analog palmityl-coenzyme A and a SHH-mimetic megabody, revealing a heme group bound to HHAT that is essential for HHAT function. A structure of HHAT bound to potent small-molecule inhibitor IMP-1575 revealed conformational changes in the active site that occlude substrate binding. Our multidisciplinary analysis provides a detailed view of the mechanism by which HHAT adapts the membrane environment to transfer an acyl chain across the endoplasmic reticulum membrane. This structure of a membrane-bound O-acyltransferase (MBOAT) superfamily member provides a blueprint for other protein-substrate MBOATs and a template for future drug discovery.

Li Salt Assisted Highly Flexible Carbonaceous Ni3N@polyimide Electrode for an Efficient Asymmetric Supercapacitor.

This work used a highly flexible, sustainable polyimide tape as a substrate to deposit ductile-natured carbonaceous Ni3N (C/Ni3N@polyimide) material for supercapacitor application. C/Ni3N was prepared using a co-sputtering technique, and this method also provided better adhesion of the electrode material over the substrate, which is helpful in improving bending performance. The ductile behavior of the sputter-grown electrode and the high flexibility of the polyimide tape provide ultimate flexibility to the C/Ni3N@polyimide-based supercapacitor. To achieve optimum electrochemical performance, a series of electrochemical tests were done in the presence of various electrolytes. Further, a flexible asymmetric supercapacitor (NC-FSC) (C/Ni3N//carbon@polyimide) was assembled by using C/Ni3N as a cathode and a carbon thin film as an anode, separated by a GF/C-glass microfiber soaked in optimized 1 M Li2SO4 aqueous electrolyte. The NC-FSC offers a capacitance of 324 mF cm-2 with a high areal energy density of 115.26 µWh cm-2 and a power density of 811 µW cm-2, with ideal bending performance.

Photocatalytic Decarboxylative Fluorination by Quinone-Based Isoreticular Covalent Organic Frameworks.

The strategic incorporation of fluorine atoms into molecules has become a cornerstone of modern pharmaceuticals, agrochemicals, and materials science. Herein, we have developed a covalent organic framework (COF)-based, robust photocatalyst that enables the photofluorodecarboxylation reaction of diverse carboxylic acids, producing alkyl fluorides with remarkable efficiency. The catalytic activity of an anthraquinone-based COF catalyst TpAQ outperforms other structurally analogous ß-ketoenamine COFs. Through comprehensive control experiments, photoluminescence, and electrochemical studies, we have elucidated the unique features of the material and the mechanistic pathway. This in-depth understanding has paved the way for optimizing the reaction conditions and achieving high yields of alkyl fluorides. The versatility of this protocol extends to a broad range of aliphatic acids with diverse functional groups and heterocycles. It also enabled the late-stage diversification of anti-inflammatory drugs and steroid derivatives. This opens up exciting possibilities for synthesizing novel pharmaceuticals and functionalized molecules. The methodology was also generalized to other light-mediated decarboxylative halogenation reactions. Furthermore, our method demonstrates scalability under both batch and continuous flow conditions, offering a promising approach for large-scale production. Additionally, the TpAQ catalyst exhibits exceptional durability and can be reused multiple times without significant activity loss (>80% yield after the eighth cycle), making it a sustainable and cost-effective solution. This work lays the foundation for developing efficient and sustainable light-driven synthesis methods using COFs as photocatalysts with potential applications beyond alkyl halide synthesis.

Atezolizumab plus bevacizumab as a downstaging therapy for liver transplantation in hepatocellular carcinoma with portal vein thrombosis: The first report.

Atezolizumab plus bevacizumab is the preferred first-line treatment regimen for patients with advanced hepatocellular carcinoma. Limited data have shown promising results with the use of immune checkpoint inhibitors like nivolumab to downstage these patients for liver transplantation (LT). Here, we describe the first case of successful downstaging with atezolizumab plus bevacizumab in a patient with multifocal hepatocellular carcinoma and main portal vein tumoral thrombosis, followed by ABO-incompatible live donor LT. This illustrated case highlights that atezolizumab plus bevacizumab therapy may be a potential bridging tool for curative LT.

Conserved LBL1-ta-siRNA and miR165/166-RLD1/2 modules regulate root development in maize.

Root system architecture and anatomy of monocotyledonous maize is significantly different from dicotyledonous model Arabidopsis The molecular role of non-coding RNA (ncRNA) is poorly understood in maize root development. Here, we address the role of LEAFBLADELESS1 (LBL1), a component of maize trans-acting short-interfering RNA (ta-siRNA), in maize root development. We report that root growth, anatomical patterning, and the number of lateral roots (LRs), monocot-specific crown roots (CRs) and seminal roots (SRs) are significantly affected in lbl1-rgd1 mutant, which is defective in production of ta-siRNA, including tasiR-ARF that targets AUXIN RESPONSE FACTOR3 (ARF3) in maize. Altered accumulation and distribution of auxin, due to differential expression of auxin biosynthesis and transporter genes, created an imbalance in auxin signalling. Altered expression of microRNA165/166 (miR165/166) and its targets, ROLLED1 and ROLLED2 (RLD1/2), contributed to the changes in lbl1-rgd1 root growth and vascular patterning, as was evident by the altered root phenotype of Rld1-O semi-dominant mutant. Thus, LBL1/ta-siRNA module regulates root development, possibly by affecting auxin distribution and signalling, in crosstalk with miR165/166-RLD1/2 module. We further show that ZmLBL1 and its Arabidopsis homologue AtSGS3 proteins are functionally conserved.

Integrative approaches to improve litchi (Litchi chinensis Sonn.) plant health using bio-transformations and entomopathogenic fungi.

Bio-transformations refer to the chemical modifications made by an organism on a chemical compound that often involves the interaction of plants with microbes to alter the chemical composition of soil or plant. Integrating bio-transformations and entomopathogenic fungi into litchi cultivation can enhance symbiotic relationships, microbial enzymatic activity in rhizosphere, disease suppression and promote overall plant health. The integration of biological formulations and entomopathogenic fungi can significantly influence growth, nutrient dynamics, physiology, and rhizosphere microbiome of air-layered litchi (Litchi chinensis Sonn.) saplings. Biological modifications included, K-mobilizers, AM fungi, Pseudomonas florescence and Azotobacter chroococcum along with Metarhizium, entomopathogenic fungi have been used. The treatments included, T1-Litchi orchard soil + sand (1:1); T2-Sand + AM fungi + Azotobacter chroococcum (1:2:1); T3-Sand + Pseudomonas florecence + K-mobilizer (1:1:1); T4- AM fungi + K-mobilizers (1:1); T5, P. Florecence + A. chroococcum + K-mobilizer (1:1:1); T6-Sand + P. florecence (1:2) and T7-Uninoculated control for field performance. Treatments T4-T6 were further uniformly amended with drenching of Metarrhizium in rhizosphere. T2 application significantly increased resident microbe survival, total chlorophyll content and root soil ratio in seedlings. A. chroococcum, Pseudomonas, K-mobilizers and AM fungi increased in microbial biomass of 2.59, 3.39, 2.42 and 2.77 times, respectively. Acidic phosphatases, dehydrogenases and alkaline phosphatases were increased in rhizosphere. Leaf nutrients reflected through DOP were considerably altered by T2 treatment. Based on Eigen value, PCA-induced changes at biological modifications showed maximum total variance. The study inferred that the bio-transformations through microbial inoculants and entomopathogenic fungi could be an encouraging strategy to enhance the growth of plants, health and productivity. Such practices align well with the goals of sustainable agriculture through biological means by reducing dependency on chemical inputs. By delving into these aspects, the research gaps including microbial processes, competitive and symbiotic relationships, resistance in microbes and how complex interactions among bio-transformations, entomopathogenic fungi and microbes can significantly impact the health and productivity of litchi. Understanding and harnessing these interactions can lead to more effective and sustainable farming practices.

Nanotechnology Applications in Breast Cancer Immunotherapy.

Next-generation cancer treatments are expected not only to target cancer cells but also to simultaneously train immune cells to combat cancer while modulating the immune-suppressive environment of tumors and hosts to ensure a robust and lasting response. Achieving this requires carriers that can codeliver multiple therapeutics to the right cancer and/or immune cells while ensuring patient safety. Nanotechnology holds great potential for addressing these challenges. This article highlights the recent advances in nanoimmunotherapeutic development, with a focus on breast cancer. While immune checkpoint inhibitors (ICIs) have achieved remarkable success and lead to cures in some cancers, their response rate in breast cancer is low. The poor response rate in solid tumors is often associated with the low infiltration of anti-cancer T cells and an immunosuppressive tumor microenvironment (TME). To enhance anti-cancer T-cell responses, nanoparticles are employed to deliver ICIs, bispecific antibodies, cytokines, and agents that induce immunogenic cancer cell death (ICD). Additionally, nanoparticles are used to manipulate various components of the TME, such as immunosuppressive myeloid cells, macrophages, dendritic cells, and fibroblasts to improve T-cell activities. Finally, this article discusses the outlook, challenges, and future directions of nanoimmunotherapeutics.

Formation to Transportation: En-Route Fission-Facilitated Formation of Spheres in a Phosphorus-Based Porous Organic Polymer for Transportation of Iodine.

Despite its potential as a clean power source to meet rising electricity demands, nuclear energy generates radioactive waste, including isotopes of iodine, that pose significant environmental and health risks. There is a growing demand to capture radioactive iodine and repurpose it effectively. However, achieving this dual functionality with a single material remains a significant challenge. This study explores phosphorus-based porous organic polymers (P-POPs) as probes for these dual functionalities. By employing 4-formyl(triphenyl)phosphine (BB1) and phenyl-1,4-diacetonitrile (BB2) under the Knoevenagel polycondensation method, P-POPs (PKPOPs) have been synthesized that exhibit a smooth spherical morphology, which efficiently captures and release iodine under ambient conditions, facilitating efficient transportation of molecular iodine. This novel approach aims to potentially transform nuclear waste into valuable organic feedstock via an iodination reaction. The innovative application of PKPOP has also been demonstrated for iodination reactions using ball mills and under continuous flow conditions, showcasing its potential for safer waste management and utilization.

Divergent Synthesis of Pyrazoles via Manganese Pincer Complex Catalyzed Acceptorless Dehydrogenative Coupling Reactions.

This report detailed the synthesis of multi-substituted pyrazoles through the acceptorless dehydrogenative coupling (ADC) reaction catalyzed by a well-defined manganese(I)-pincer complex. Symmetrically substituted pyrazoles were synthesized by reacting 1,3-diols with hydrazines. Unsymmetrically substituted pyrazoles were selectively made via the ADC of primary alcohols with methyl hydrazones. Water and hydrogen are liberated as the green byproducts. The endurance of these methodologies has been presented by producing 30 substrates with varied functionalities. Model reactions were scaled up to demonstrate practicability. The reaction rate and order were measured to transparent the involvement of the reagents during catalysis. Control experiments elucidated the plausible reaction mechanisms.

Effect of an external/internal magnetic field on the photocurrent in Py-topological insulator heterojunction Ni80Fe20/TI (Bi2Te3/Bi2Se3/Bi2Te2Se)/p-Si devices.

This study demonstrates the fabrication and study of a permalloy (Py)/topological insulator heterojunction, i.e., the Ni80Fe20/TI(Bi2Te3/Bi2Se3/Bi2Te2Se)/p-Si heterojunction, for spintronic device applications at room temperature. In this work, the forward current values, under the absence of a magnetic field, for Ni80Fe20/Bi2Te2Se/p-Si, Ni80Fe20/Bi2Se3/p-Si, and Ni80Fe20/Bi2Te3/p-Si heterojunctions were 12.7 µA, 8.7 µA, and 6.85 µA, respectively; while in the presence of a magnetic field, the corresponding values were 10.8 µA, 7.6 µA, and 4.47 µA, respectively. Such reductions in current were attributed to an increase in the resistance of the p-n junction diode due to Lorentz force and a magnetoresistance effect, which was also verified using magneto-transport measurements. This resulted in a modification of the space charge shape and an increase in the potential barrier. Along with this, the magnetic field also affected the diffusion length, leading to a reduction in the current. Such a phenomenon enables the development of durable devices with improved reliability and longevity under harsh environments. The special features of topological edge states in the presence of a magnetic field can be used for sophisticated sensing applications. The future applications will likely lead to the emergence of other novel applications across disciplines such as computing, health, materials science, and energy harvesting.

Multipronged regulation of autophagy and apoptosis: emerging role of TRIM proteins.

TRIM proteins are characterized by their conserved N-terminal RING, B-box, and coiled-coil domains. These proteins are efficient regulators of autophagy, apoptosis, and innate immune responses and confer immunity against viruses and bacteria. TRIMs function as receptors or scaffold proteins that target substrates for autophagy-mediated degradation. Most TRIMs interact with the BECN1-ULK1 complex to form TRIMosomes, thereby efficiently targeting substrates to autophagosomes. They regulate the functions of ATG proteins through physical interactions or ubiquitination. TRIMs affect the lipidation of MAP1LC3B1 to form MAP1LC3B2, which is a prerequisite for phagophore and autophagosome formation. In addition, they regulate MTOR kinase and TFEB, thereby regulating the expression of ATG genes. TRIM proteins are efficient regulators of apoptosis and are crucial for regulating cell proliferation and tumor formation. Many TRIM proteins regulate intrinsic and extrinsic apoptosis via the cell surface receptors TGFBR2, TNFRSF1A, and FAS. Mitochondria modulate the anti- and proapoptotic functions of BCL2, BAX, BAK1, and CYCS. These proteins use a multipronged approach to regulate the intrinsic and extrinsic apoptotic pathways, culminating in coordinated activation or inhibition of the initiator and executor CASPs. Furthermore, TRIMs can have a dual effect in determining cell fate and are therefore crucial for cellular homeostasis. In this review, we discuss mechanistic insights into the role of TRIM proteins in regulating autophagy and apoptosis, which can be used to better understand cellular physiology. These findings can be used to develop therapeutic interventions to prevent or treat multiple genetic and infectious diseases.

Structure and function at the lipid-protein interface of a pentameric ligand-gated ion channel.

Although it has long been proposed that membrane proteins may contain tightly bound lipids, their identity, the structure of their binding sites, and their functional and structural relevance have remained elusive. To some extent, this is because tightly bound lipids are often located at the periphery of proteins, where the quality of density maps is usually poorer, and because they may be outcompeted by detergent molecules used during standard purification procedures. As a step toward characterizing natively bound lipids in the superfamily of pentameric ligand-gated ion channels (pLGICs), we applied single-particle cryogenic electron microscopy to fragments of native membrane obtained in the complete absence of detergent-solubilization steps. Because of the heterogeneous lipid composition of membranes in the secretory pathway of eukaryotic cells, we chose to study a bacterial pLGIC (ELIC) expressed in Escherichia coli's inner membrane. We obtained a three-dimensional reconstruction of unliganded ELIC (2.5-Å resolution) that shows clear evidence for two types of tightly bound lipid at the protein-bulk-membrane interface. One of them was consistent with a "regular" diacylated phospholipid, in the cytoplasmic leaflet, whereas the other one was consistent with the tetra-acylated structure of cardiolipin, in the periplasmic leaflet. Upon reconstitution in E. coli polar-lipid bilayers, ELIC retained the functional properties characteristic of members of this superfamily, and thus, the fitted atomic model is expected to represent the (long-debated) unliganded-closed, "resting" conformation of this ion channel. Notably, the addition of cardiolipin to phosphatidylcholine membranes restored the ion-channel activity that is largely lost in phosphatidylcholine-only bilayers.

Predicting the miniaturization limit of vertical organic field effect transistor (VOFET) with perforated graphene as a source electrode.

Vertical organic field effect transistors (VOFETs) are of paramount importance due to their fast switching speed, low power consumption, and higher density on a chip compared to lateral OFETs. The low charge carrier mobility in organic semiconductors and longer channel lengths in lateral OFETs lead to higher operating voltages. The channel length in VOFETs can be less than 100 nm which reduces the size of the channel and hence the operating voltages. Another important factor in the operation of VOFETs is the thickness and width of the source electrode. The channel length, source electrode thickness and width sets the miniaturization limit of the VOFETs. The graphene monolayer can be exploited as a source electrode due to its thinness, high carrier mobility, and metallic behaviors. However, for better gate modulation, perforations in the source material are desired. Here, we simulate the VOFET having perforated graphene monolayer as a source electrode and n-type organic semiconductor N, N'-dioctyl-3,4,9,10-perylenedicarboximide (PTCDI-C8) as an active channel material, while aluminum as a drain electrode to predict the best-miniaturized device. The miniaturization limit of such a VOFET has a limit to the gate opening/perforation in which the minimum source width is 10 nm, as in the sub 10 nm range graphene starts behaving like a semiconductor. The subthreshold swing, deduced from the drain current (JD) versus gate voltage (VG) graph, advocates the limit of the organic semiconductor height/channel length to 50 nm, while 50 nm for the gate.

Host and viral non-coding RNAs in dengue pathogenesis.

Dengue virus (DENV) is a mosquito-borne flavivirus that causes frequent outbreaks in tropical countries. Due to the four different serotypes and ever-mutating RNA genome, it is challenging to develop efficient therapeutics. Early diagnosis is crucial to prevent the severe form of dengue, leading to mortality. In the past decade, rapid advancement in the high throughput sequencing technologies has shed light on the crucial regulating role of non-coding RNAs (ncRNAs), also known as the "dark matter" of the genome, in various pathological processes. In addition to the human host ncRNAs like microRNAs and circular RNAs, DENV also produces ncRNAs such as subgenomic flaviviral RNAs that can modulate the virus life cycle and regulate disease outcomes. This review outlines the advances in understanding the interplay between the human host and DENV ncRNAs, their regulation of the innate immune system of the host, and the prospects of the ncRNAs in clinical applications such as dengue diagnosis and promising therapeutics.

Unusual similarity of DNA solvation dynamics in high-salinity crowding with divalent cations of varying concentrations.

Double-stranded DNA bears the highest linear negative charge density (2e- per base-pair) among all biopolymers, leading to strong interactions with cations and dipolar water, resulting in the formation of a dense 'condensation layer' around DNA. Interactions involving proteins and ligands binding to DNA are primarily governed by strong electrostatic forces. Increased salt concentrations impede such electrostatic interactions - a situation that prevails in oceanic species due to their cytoplasm being enriched with salts. Nevertheless, how these interactions' dynamics are affected in crowded hypersaline environments remains largely unexplored. Here, we employ steady-state and time-resolved fluorescence Stokes shifts (TRFSS) of a DNA-bound ligand (DAPI) to investigate the static and dynamic solvation properties of DNA in the presence of two divalent cations, magnesium (Mg2+), and calcium (Ca2+) at varying high to very-high concentrations of 0.15 M, 1 M and 2 M. We compare the results to those obtained in physiological concentrations (0.15 M) of monovalent Na+ ions. Combining data from fluorescence femtosecond optical gating (FOG) and time-correlated single photon counting (TCSPC) techniques, dynamic fluorescence Stokes shifts in DNA are analysed over a broad range of time-scales, from 100 fs to 10 ns. We find that while divalent cation crowding strongly influences the DNA stability and ligand binding affinity to DNA, the dynamics of DNA solvation remain remarkably similar across a broad range of five decades in time, even in a high-salinity crowded environment with divalent cations, as compared to the physiological concentration of the Na+ ion. Steady-state and time-resolved data of the DNA-groove-bound ligand are seemingly unaffected by ion-crowding in hypersaline solution, possibly due to ions being mostly displaced by the DNA-bound ligand. Furthermore, the dynamic coupling of cations with nearby water may possibly contribute to a net-neutral effect on the overall collective solvation dynamics in DNA, owing to the strong anti-correlation of their electrostatic interaction energy fluctuations. Such dynamic scenarios may persist within the cellular environment of marine life and other biological cells that experience hypersaline conditions.

Bi2Te2Se and Sb2Te3 heterostructure based photodetectors with high responsivity and broadband photoresponse: experimental and theoretical analysis.

Topological insulators have emerged as one of the most promising candidates for the fabrication of novel electronic and optoelectronic devices due to the unique properties of nontrivial Dirac cones on the surface and a narrow bandgap in the bulk. In this work, the Sb2Te3 and Bi2Te2Se materials, and their heterostructure are fabricated by metal-organic chemical vapour deposition and evaporation techniques. Photodetection of these materials and their heterostructure shows that they detect light in a broadband range of 600 to 1100 nm with maximum photoresponse of Sb2Te3, Bi2Te2Se and Sb2Te3/Bi2Te2Se at 1100, 1000, and 1000 nm, respectively. The maximum responsivity values of Sb2Te3, Bi2Te2Se, and their heterostructure are 183, 341.8, and 245.9 A W-1 at 1000 nm, respectively. A computational study has also been done using density functional theory (DFT). Using the first-principles methods based on DFT, we have systematically investigated these topological insulators and their heterostructure's electronic and optical properties. The band structures of Sb2Te3 and Bi2Te2Se thin films (3 QL) and their heterostructure are calculated. The bandgaps of Sb2Te3 and Bi2Te2Se are 26.4 and 23 meV, respectively, while the Sb2Te3/Bi2Te2Se heterostructure shows metallic behaviour. For the optical properties, the dielectric function's real and imaginary parts are calculated using DFT and random phase approximation (RPA). It is observed that these topological materials and their heterostructure are light absorbers in a broadband range, with maximum absorption at 1.90, 2.40, and 3.21 eV.

Tenofovir-tethered gold nanoparticles as a novel multifunctional long-acting anti-HIV therapy to overcome deficient drug delivery-: an in vivo proof of concept.

BACKGROUND: The adoption of Antiretroviral Therapy (ART) substantially extends the life expectancy and quality of HIV-infected patients. Yet, eliminating the latent reservoirs of HIV to achieve a cure remains an unmet need. The advent of nanomedicine has revolutionized the treatment of HIV/AIDS. The present study explores a unique combination of Tenofovir (TNF) with gold nanoparticles (AuNPs) as a potential therapeutic approach to overcome several limitations of the current ART. RESULTS: TNF-tethered AuNPs were successfully synthesized. Cell viability, genotoxicity, haemolysis, and histopathological studies confirmed the complete safety of the preparation. Most importantly, its anti-HIV1 reverse transcriptase activity was ~ 15 folds higher than the native TNF. In addition, it exhibited potent anti-HIV1 protease activity, a much sought-after target in anti-HIV1 therapeutics. Finally, the in vivo biodistribution studies validated that the AuNPs could reach many tissues/organs, serving as a secure nest for HIV and overcoming the problem of deficient drug delivery to HIV reservoirs. CONCLUSIONS: We show that the combination of TNF and AuNPs exhibits multifunctional activity, viz. anti-HIV1 and anti-HIV1 protease. These findings are being reported for the first time and highlight the prospects of developing AuNP-TNF as a novel next-generation platform to treat HIV/AIDS.

Vitamin D deficiency in patients with diabetes and its correlation with water fluoride levels.

Chronic exposure to fluoride through drinking water has been linked to insulin resistance and resulting type 2 diabetes mellitus (T2DM). Here, we aim to study the impact of water fluoride levels on blood glucose and vitamin D levels. A hospital-based study was conducted on diabetic patients (n = 303) at All India Institute of Medical Sciences (AIIMS), Raebareli outstation patient department (OPD). The relationship between vitamin D or fasting blood glucose levels (BGLs) with water fluoride levels was estimated through Spearman's rank correlation. We found a significant negative correlation between water fluoride and vitamin D levels [rs = -0.777, p-value < 0.001] and a positive correlation between water fluoride and fasting BGLs [rs = 0.178, p-value <0.05]. The participants residing in fluoride-endemic areas (F > 1.5 mg/L) had higher odds of severe vitamin D deficiency (odds ratio: 5.07, 95% CI: 1.9-13.2, p-value = 0.0009). The results demonstrate that vitamin D deficiency and fasting BGLs are significantly associated with water fluoride levels. This study signifies the role of fluoride toxicity in poor glycemic control and derived vitamin D deficiency. Vitamin D supplementation and the application of standard household water purification devices are recommended to tackle vitamin D deficiency in fluoride-endemic areas.

Cryo-EM structures of a lipid-sensitive pentameric ligand-gated ion channel embedded in a phosphatidylcholine-only bilayer.

The lipid dependence of the nicotinic acetylcholine receptor from the Torpedo electric organ has long been recognized, and one of the most consistent experimental observations is that, when reconstituted in membranes formed by zwitterionic phospholipids alone, exposure to agonist fails to elicit ion-flux activity. More recently, it has been suggested that the bacterial homolog ELIC (Erwinia chrysanthemi ligand-gated ion channel) has a similar lipid sensitivity. As a first step toward the elucidation of the structural basis of this phenomenon, we solved the structures of ELIC embedded in palmitoyl-oleoyl-phosphatidylcholine- (POPC-) only nanodiscs in both the unliganded (4.1-Å resolution) and agonist-bound (3.3 Å) states using single-particle cryoelectron microscopy. Comparison of the two structural models revealed that the largest differences occur at the level of loop C-at the agonist-binding sites-and the loops at the interface between the extracellular and transmembrane domains (ECD and TMD, respectively). On the other hand, the transmembrane pore is occluded in a remarkably similar manner in both structures. A straightforward interpretation of these findings is that POPC-only membranes frustrate the ECD-TMD coupling in such a way that the "conformational wave" of liganded-receptor gating takes place in the ECD and the interfacial M2-M3 linker but fails to penetrate the membrane and propagate into the TMD. Furthermore, analysis of the structural models and molecular simulations suggested that the higher affinity for agonists characteristic of the open- and desensitized-channel conformations results, at least in part, from the tighter confinement of the ligand to its binding site; this limits the ligand's fluctuations, and thus delays its escape into bulk solvent.