Visible-Light-Mediated Synthesis of Thioesters Using Thiocarboxylic Acid as the Dual Reagent.

We have developed a visible-light-driven method for thioester synthesis that relies on the unique dual role of thiobenzoic acids as one-electron reducing agents and reactants leading to the formation of sulfur radical species. This synthetic process offers a wide scope, accommodating various thioacid and thiol substrates without the need for a photocatalyst.

The von Hippel-Lindau protein forms fibrillar amyloid assemblies that are mitigated by the anti-amyloid molecule Purpurin.

The von Hippel-Lindau protein (pVHL) is a tumor suppressor involved in oxygen regulation via dynamic nucleocytoplasmic shuttling. It plays a crucial role in cell survival by degrading hypoxia-inducible factors (HIFs). Mutations in the VHL gene cause angiogenic tumors, characterized as VHL syndrome. However, aggressive tumors involving wild-type pVHL have also been described but the underlying mechanism remains to be revealed. We have previously shown that pVHL possesses several short amyloid-forming motifs, making it aggregation-prone. In this study, using a series of biophysical assays, we demonstrated that a pVHL-derived fragment (pVHL104-140) that harbors the nuclear export motif and HIF binding site, forms amyloid-like fibrillar structures in vitro by following secondary-nucleation-based kinetics. The peptide also formed amyloids at acidic pH that mimics the tumor microenvironment. We, subsequently, validated the amyloid formation by pVHL in vitro. Using the Curli-dependent amyloid generator (C-DAG) expression system, we confirmed the amyloidogenesis of pVHL in bacterial cells. The pVHL amyloids are an attractive target for therapeutics of the VHL syndrome. Accordingly, we demonstrated in vitro that Purpurin is a potent inhibitor of pVHL fibrillation. The amyloidogenic behavior of wild-type pVHL and its inhibition provide novel insights into the molecular underpinning of the VHL syndrome and its possible treatment.

Cobalt-Centered Supramolecular Nanoensemble for Regulated Aerobic Oxidation of Alcohols and "One-Pot" Synthesis of Quinazolin-4(3H)-ones.

The supramolecular assemblies of the donor-acceptor (D-A) system Im-Tpy, having phenanthro[9,10-d]imidazole as the donor and terpyridyl group as the acceptor unit, have been developed, which serve as supramolecular host to stabilize Co(II) in its nanoform. The as-prepared supramolecular nanoensemble Im-Tpy@Co in DMSO:water (7:3) shows high thermal stability and photostability. Even in the case of solvent mismatch, i.e., on dilution with cosolvent THF/DMSO, insignificant changes were observed in the size/morphology of the nanoensemble. The as-prepared Im-Tpy@Co nanoensemble in low catalytic loading (0.1 mol % of Co) catalyzes the oxidation of a wide variety of alcohols to aromatic aldehydes/ketones using visible light radiations as the source of energy without the need of any additive at room temperature. In comparison to already reported systems, the Im-Tpy@Co nanoensemble exhibits high turnover numbers (TONs) and turnover frequencies (TOFs). The practical application of the catalytic system has also been demonstrated in the gram-scale synthesis of 4-chlorobenzaldehyde. The Im-Tpy@Co nanoensemble exhibits recyclability up to four catalytic cycles with insignificant leaching and morphological changes. The present study also demonstrates the catalytic activity of the Im-Tpy@Co nanoensemble in "one-pot" synthesis of quinazolin-4(3H)-ones from 2-aminobenzamide and primary alcohols with better efficiency in comparison to other transition-metal-based catalytic systems.

Exploring the Divergent Reactivity of Vinyl Radicals Emanating from Alkynes and Thiols via Photoredox Catalysis.

Organic chemistry has seen a surge in visible-light-driven transformations, which offer unique reaction pathways and access to new synthetic possibilities. We aim to provide a comprehensive understanding of state-of-the-art photo-mediated alkyne functionalization, with a focus on the reactive behavior of vinyl radicals. This review outlines our contributions to the field, including developing new methods for forming carbon-carbon and carbon-heteroatom bonds.

Histidine-Containing Amphiphilic Peptide-Based Non-Cytotoxic Hydrogelator with Antibacterial Activity and Sustainable Drug Release.

A histidine-based amphiphilic peptide (P) has been found to form an injectable transparent hydrogel in phosphate buffer solution over a pH range from 7.0 to 8.5 with an inherent antibacterial property. It also formed a hydrogel in water at pH = 6.7. The peptide self-assembles into a nanofibrillar network structure which is characterized by high-resolution transmission electron microscopy, field-emission scanning electron microscopy, atomic force microscopy, small-angle X-ray scattering, Fourier-transform infrared spectroscopy, and wide-angle powder X-ray diffraction. The hydrogel exhibits efficient antibacterial activity against both Gram-positive bacteria Staphylococcus aureus (S. aureus) and Gram-negative bacteria Escherichia coli (E. coli). The minimum inhibitory concentration of the hydrogel ranges from 20 to 100 µg/mL. The hydrogel is capable of encapsulation of the drugs naproxen (a non-steroidal anti-inflammatory drug), amoxicillin (an antibiotic), and doxorubicin, (an anticancer drug), but, selectively and sustainably, the gel releases naproxen, 84% being released in 84 h and amoxicillin was released more or less in same manner with that of the naproxen. The hydrogel is biocompatible with HEK 293T cells as well as NIH (mouse fibroblast cell line) cells and thus has potential as a potent antibacterial and drug releasing agent. Another remarkable feature of this hydrogel is its magnification property like a convex lens.

Modulatory role of copper on hIAPP aggregation and toxicity in presence of insulin.

Aggregation of the human islets amyloid polypeptide, or hIAPP, is linked to ß-cell death in type II diabetes mellitus (T2DM). Different pancreatic ß-cell environmental variables such as pH, insulin and metal ions play a key role in controlling the hIAPP aggregation. Since insulin and hIAPP are co-secreted, it is known from numerous studies that insulin suppresses hIAPP fibrillation by preventing the initial dimerization process. On the other hand, zinc and copper each have an inhibitory impact on hIAPP fibrillation, but copper promotes the production of toxic oligomers. Interestingly, the insulin oligomeric equilibrium is controlled by the concentration of zinc ions when the effect of insulin and zinc has been tested together. Lower zinc concentrations cause the equilibrium to shift towards the monomer and dimer states of insulin, which bind to monomeric hIAPP and stop it from developing into a fibril. On the other hand, the combined effects of copper and insulin have not yet been studied. In this study, we have demonstrated how the presence of copper affects hIAPP aggregation and the toxicity of the resultant conformers with or without insulin. For this purpose, we have used a set of biophysical techniques, including NMR, fluorescence, CD etc., in combination with AFM and cell cytotoxicity assay. In the presence and/or absence of insulin, copper induces hIAPP to form structurally distinct stable toxic oligomers, deterring the fibrillation process. More specifically, the oligomers generated in the presence of insulin have slightly higher toxicity than those formed in the absence of insulin. This research will increase our understanding of the combined modulatory effect of two ß-cell environmental factors on hIAPP aggregation.

Collaborative Privacy-preserving Approaches for Distributed Deep Learning Using Multi-Institutional Data.

Deep learning (DL) algorithms have shown remarkable potential in automating various tasks in medical imaging and radiologic reporting. However, models trained on low quantities of data or only using data from a single institution often are not generalizable to other institutions, which may have different patient demographics or data acquisition characteristics. Therefore, training DL algorithms using data from multiple institutions is crucial to improving the robustness and generalizability of clinically useful DL models. In the context of medical data, simply pooling data from each institution to a central location to train a model poses several issues such as increased risk to patient privacy, increased costs for data storage and transfer, and regulatory challenges. These challenges of centrally hosting data have motivated the development of distributed machine learning techniques and frameworks for collaborative learning that facilitate the training of DL models without the need to explicitly share private medical data. The authors describe several popular methods for collaborative training and review the main considerations for deploying these models. They also highlight publicly available software frameworks for federated learning and showcase several real-world examples of collaborative learning. The authors conclude by discussing some key challenges and future research directions for distributed DL. They aim to introduce clinicians to the benefits, limitations, and risks of using distributed DL for the development of medical artificial intelligence algorithms. ©RSNA, 2023 Quiz questions for this article are available in the supplemental material.

Isolation, characterization, and utilization of wheat bran protein fraction for food application.

Wheat bran (WB), a low-cost industrial by-product, is a vital source of high-quality proteins, minerals, vitamins, and several bioactive compounds. The present study encompasses the identification of appropriate bran streams of a commercial roller flour mill (CRFM) essentially based on hector liter weight, (HLW), optimization of WB protein isolation process, amino acid characterization, rendering more emphasis on simple water-soluble albumins, having higher commercial viability, and its application in food formulation. Total WB protein was 16.18% protein, the sum of the extracted proteins viz. albumin (2.43%), a prolamin (2.47%), glutelin (5.25%), globulin (1.92%), and insoluble proteins (4.09%) was 12.08%. Following albumin extraction, residual WB was subjected to ultra-sonication which further increased albumin protein yield from 2.43 to 3.07%. The extracted WB albumin isolate (WBAI) was utilized to develop high protein bread having significantly high volume and protein content, compared to control bread. The structural and sensorial attributes of the developed bread were superior compared to control bread. Thus, WBAI has a tremendous scope as a natural, affordable potential inexpensive food improver/fortificant to address protein-energy malnutrition (PEM). The process has the great advantage of being eco-friendly, besides, residual bran can still be used as cattle feed, enhancing profitability and viability.

One-year continuous abstinence rate for smoking cessation via telephonic counselling: The Indian scenario.

Tobacco control methods differ by country, with telephonic counseling being one of them. The effectiveness of telephone counseling in smoking cessation has been discussed on several occasions. India's tobacco problem is more complex than that of any other country in the world. To begin with, tobacco is consumed in a variety of ways, and India is a large multilingual country with remarkable cultural diversity. In India, the National Tobacco Quitline Service (NTQLS) is a government-run program. Its data from May 2016 to May 2021 were analyzed retrospectively in this cross-sectional study to determine the prevalence and pattern of tobacco use in India, as well as the abstinence rate for smoking cessation. A total of 4,611,866 calls were received by the Interactive Voice Response system (IVR). The number of calls increased from 600 to 5400 per day after the toll-free number was printed on all tobacco products. Smokeless tobacco use was discovered to be more prevalent, with males significantly more likely to use both smoking and smokeless tobacco. At one month and one year after quitting, 33.42% and 21.9%, respectively, remained tobacco-free. The study emphasizes the efficacy of behavioral counseling in increasing abstinence rates. The printing of a toll-free number on tobacco products is an effective strategy for expanding the operation of quit lines. Despite the challenges of cultural diversity and complex tobacco use, India's quit line service has been able to provide counseling to callers with prolonged abstinence and quit rates comparable to the various quit lines around the world.

Mechanistic insight into functionally different human islet polypeptide (hIAPP) amyloid: the intrinsic role of the C-terminal structural motifs.

Targeting amyloidosis requires high-resolution insight into the underlying mechanisms of amyloid aggregation. The sequence-specific intrinsic properties of a peptide or protein largely govern the amyloidogenic propensity. Thus, it is essential to delineate the structural motifs that define the subsequent downstream amyloidogenic cascade of events. Additionally, it is important to understand the role played by extrinsic factors, such as temperature or sample agitation, in modulating the overall energy barrier that prompts divergent nucleation events. Consequently, these changes can affect the fibrillation kinetics, resulting in structurally and functionally distinct amyloidogenic conformers associated with disease pathogenesis. Here, we have focused on human Islet Polypeptide (hIAPP) amyloidogenesis for the full-length peptide along with its N- and C-terminal fragments, under different temperatures and sample agitation conditions. This helped us to gain a comprehensive understanding of the intrinsic role of specific functional epitopes in the primary structure of the peptide that regulates amyloidogenesis and subsequent cytotoxicity. Intriguingly, our study involving an array of biophysical experiments and ex vivo data suggests a direct influence of external changes on the C-terminal fibrillating sequence. Furthermore, the observations indicate a possible collaborative role of this segment in nucleating hIAPP amyloidogenesis in a physiological scenario, thus making it a potential target for future therapeutic interventions.

Towards More Efficient Data Valuation in Healthcare Federated Learning using Ensembling.

Federated Learning (FL) wherein multiple institutions collaboratively train a machine learning model without sharing data is becoming popular. Participating institutions might not contribute equally - some contribute more data, some better quality data or some more diverse data. To fairly rank the contribution of different institutions, Shapley value (SV) has emerged as the method of choice. Exact SV computation is impossibly expensive, especially when there are hundreds of contributors. Existing SV computation techniques use approximations. However, in healthcare where the number of contributing institutions are likely not of a colossal scale, computing exact SVs is still exorbitantly expensive, but not impossible. For such settings, we propose an efficient SV computation technique called SaFE (Shapley Value for Federated Learning using Ensembling). We empirically show that SaFE computes values that are close to exact SVs, and that it performs better than current SV approximations. This is particularly relevant in medical imaging setting where widespread heterogeneity across institutions is rampant and fast accurate data valuation is required to determine the contribution of each participant in multi-institutional collaborative learning.

Pyrazine Based Type-I Sensitizing Assemblies for Photoreduction of Cu(II) in 'One-Pot Three-Component' CuAAC Reaction Under Aerial Conditions.

Photosensitizing assemblies of pyrazine derivative PDA have been developed which exhibit a high photostability, 'lighted' excited state, balanced redox potential, high transportation potential and activate oxygen via type-I pathway only. These PDA assemblies in combination with Cu(II) ions catalyze the CuAAC reaction via in situ reduction of Cu(II) ions without any reducing or stabilizing agent. The present protocol has wide substrate scope with recyclability of the catalytic system up to six catalytic cycles and is applicable to gram-scale synthesis.

Effect of PEGylation on Host Defense Peptide Complexation with Bacterial Lipopolysaccharide.

Conjugation with poly(ethylene glycol) ("PEGylation") is a widely used approach for improving the therapeutic propensities of peptide and protein drugs through prolonging bloodstream circulation, reducing toxicity and immunogenicity, and improving proteolytic stability. In the present study, we investigate how PEGylation affects the interaction of host defense peptides (HDPs) with bacterial lipopolysaccharide (LPS) as well as HDP suppression of LPS-induced cell activation. In particular, we investigate the effects of PEGylation site for KYE28 (KYEITTIHNLFRKLTHRLFRRNFGYTLR), a peptide displaying potent anti-inflammatory effects, primarily provided by its N-terminal part. PEGylation was performed either in the N-terminus, the C-terminus, or in both termini, keeping the total number of ethylene groups (n = 48) constant. Ellipsometry showed KYE28 to exhibit pronounced affinity to both LPS and its hydrophobic lipid A moiety. The PEGylated peptide variants displayed lower, but comparable, affinity for both LPS and lipid A, irrespective of the PEGylation site. Furthermore, both KYE28 and its PEGylated variants triggered LPS aggregate disruption. To investigate the peptide structure in such LPS complexes, a battery of nuclear magnetic resonance (NMR) methods was employed. From this, it was found that KYE28 formed a well-folded structure after LPS binding, stabilized by hydrophobic domains involving aromatic amino acids as well as by electrostatic interactions. In contrast, the PEGylated peptide variants displayed a less well-defined secondary structure, suggesting weaker LPS interactions in line with the ellipsometry findings. Nevertheless, the N-terminal part of KYE28 retained helix formation after PEGylation, irrespective of the conjugation site. For THP1-Xblue-CD14 reporter cells, KYE28 displayed potent suppression of LPS activation at simultaneously low cell toxicity. Interestingly, the PEGylated KYE28 variants displayed similar or improved suppression of LPS-induced cell activation, implying the underlying key role of the largely retained helical structure close to the N-terminus, irrespective of PEGylation site. Taken together, the results show that PEGylation of HDPs can be done insensitively to the conjugation site without losing anti-inflammatory effects, even for peptides inducing such effects through one of its termini.

Solvent Relaxation NMR: A Tool for Real-Time Monitoring Water Dynamics in Protein Aggregation Landscape.

Solvent dynamics strongly induce the fibrillation of an amyloidogenic system. Probing the solvation mechanism is crucial as it enables us to predict different proteins' functionalities, such as the aggregation propensity, structural flexibility, and toxicity. This work shows that a straightforward NMR method in conjunction with phenomenological models gives a global and qualitative picture of water dynamics at different concentrations and temperatures. Here, we study amyloid system Aß40 and its fragment AV20 (A21-V40) and G37L (mutation at Gly37 → Leu of AV20), having different aggregation and toxic properties. The independent validation of this method is elucidated using all-atom classical MD simulation. These two state-of-the-art techniques are pivotal in linking the effect of solvent environment in the near hydration-shell to their aggregation nature. The time-dependent modulation in solvent dynamics probed with the NMR solvent relaxation method can be further adopted to gain insight into amyloidogenesis and link with their toxicity profiles.

Formulation, development and evaluation of high fibre-high protein chapati (Indian flat bread) from composite flour using common industrial by-products.

Triple ground whole-wheat flour with 18.45% damaged starch was partially substituted by double sifted full-fat stabilised rice bran (SRB) and undamaged-stabilised-debitterised-wheat germ (USDWG) flour to produce high TDF (total dietary fibre), high protein flour for chapati. Five formulations, F1-5 with up to 15% SRB and 20% USDWG incorporations on weight basis were used for baking chapatis. The most sensorially and functionally acceptable formulation (F4), had 10% SRB and 15% USDWG, showed significant (P < 0.05) improvement in desired parameters viz. TDF increased 16.83 ± 0.06% to 18.59 ± 0.03%, crude protein from 14.43 ± 0.06 to 19.52 ± 0.10% and in vitro starch digestibility decreased 8.30 ± 0.10% to 7.55 ± 0.01% when compared to control chapati. Texture profiling and sensory analysis indicated F4 formulation had overall acceptable qualities than chapati made from control, commercial and target flours. Water was completely replaced by liquid whey during chapati making, which showed promising results; Formulation F5 (15% SRB and 20% USDWG) scored 20.2% TDF and 22.7% protein. The above findings are useful for developing TDF and protein dense, low GI functional food, utilizing common industrial by-products at 20% lesser cost.

Protective efficacy of Tinospora sinensis against streptozotocin induced pancreatic islet cell injuries of diabetic rats and its correlation to its phytochemical profiles.

ETHNOPHARMACOLOGICAL RELEVANCE: Tinospora sinensis Lour. (Merr.) belongs to the family Menispermaceae and its stem extract have been used traditionally in broad aspects of therapeutic remedies including debility, dyspepsia, fever, jaundice, ulcer, bronchitis, urinary disease, skin disease, liver disease and diabetes. AIM OF THE STUDY: The aim of the study was to evaluate the protective effects of methanol extract of stem of Tinospora sinensis (METS) on streptozotocin induced pancreatic islet cell injuries of diabetic rats and its correlation to its phytochemical profiles. MATERIALS AND METHODS: A high-performance liquid chromatography technique (HPLC) was used to identify and quantify the major phytochemicals present in the METS. Diabetic rats were administered with METS at a dose of (100, 200 and 400 mg/kg respectively orally) and standard drug Metformin (300 mg/kg) was given orally to group serving positive control. Effect of the METS on glucose homeostasis, oxidative stress, antioxidant status, histopathology of pancreas and also on intracellular reactive oxygen species (ROS), mitochondrial membrane potential, apoptosis, cell cycle of pancreatic islet cells were studied in diabetic rats. RESULTS: The major phytochemicals identified and quantified by HPLC in the extract were berberine, caffeic acid, myricetin and ferulic acid. This result showed that methanol extract exhibited good antioxidant effect. The methanol extract of the plant prevented the diabetogenic effect of STZ and significantly lowered the fasting blood glucose level, glycated haemoglobin and increased insulin and C-peptide level in treated rats. METS reduced apoptosis of STZ treated islet cells by significantly decreasing pro-inflammatory cytokines (TNFα, IL6), intracellular ROS generation, lipid peroxidation, nitric oxide (NO) production and increasing mitochondrial membrane potential and sub-G0 peak area, enzymatic and nonenzymatic antioxidants. CONCLUSION: The results revealed that the methanol extract of the stem of the plant possesses protective effects against diabetes and associated complications.

An explicitly designed paratope of amyloid-ß prevents neuronal apoptosis in vitro and hippocampal damage in rat brain.

Synthetic antibodies hold great promise in combating diseases, diagnosis, and a wide range of biomedical applications. However, designing a therapeutically amenable, synthetic antibody that can arrest the aggregation of amyloid-ß (Aß) remains challenging. Here, we report a flexible, hairpin-like synthetic paratope (SP1, ∼2 kDa), which prevents the aggregation of Aß monomers and reverses the preformed amyloid fibril to a non-toxic species. Structural and biophysical studies further allowed dissecting the mode and affinity of molecular recognition events between SP1 and Aß. Subsequently, SP1 reduces Aß-induced neurotoxicity, neuronal apoptosis, and ROS-mediated oxidative damage in human neuroblastoma cells (SH-SY5Y). The non-toxic nature of SP1 and its ability to ameliorate hippocampal neurodegeneration in a rat model of AD demonstrate its therapeutic potential. This paratope engineering module could readily implement discoveries of cost-effective molecular probes to nurture the basic principles of protein misfolding, thus combating related diseases.

Independent Geometrical Control of Spin and Charge Resistances in Curved Spintronics.

Spintronic devices operating with pure spin currents represent a new paradigm in nanoelectronics, with a higher energy efficiency and lower dissipation as compared to charge currents. This technology, however, will be viable only if the amount of spin current diffusing in a nanochannel can be tuned on demand while guaranteeing electrical compatibility with other device elements, to which it should be integrated in high-density three-dimensional architectures. Here, we address these two crucial milestones and demonstrate that pure spin currents can effectively propagate in metallic nanochannels with a three-dimensional curved geometry. Remarkably, the geometric design of the nanochannels can be used to reach an independent tuning of spin transport and charge transport characteristics. These results laid the foundation for the design of efficient pure spin current-based electronics, which can be integrated in complex three-dimensional architectures.

Bio-mimetic self-assembled computationally designed catalysts of Mo and W for hydrogenation of CO2/dehydrogenation of HCOOH inspired by the active site of formate dehydrogenase.

Density functional theory modelling has been used to design Mo and W-based catalysts MoIII(tBu)(CO) and WIII(tBu)(CO) for CO2 hydrogenation and HCOOH dehydrogenation, which are bio-mimics of the active site of formate dehydrogenase. Based on DFT calculations, the molybdenum and tungsten based complexes are good catalysts in the +3 oxidation state for CO2 hydrogenation with free energies of 24.03 and 21.31 kcal mol-1, respectively. Such a low barrier indicates that our newly designed Mo and W-based complexes are very efficient for CO2 hydrogenation or HCOOH dehydrogenation catalysis. Overall, our computational results provide in depth insights that can serve as a great tool for the design and development of new and efficient molybdenum and tungsten based catalysts for CO2 hydrogenation or HCOOH dehydrogenation.

A Synthetic Pro-Drug Peptide Reverses Amyloid-ß-Induced Toxicity in the Rat Model of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD), the most prevalent neurodegenerative disorder, involves the formation of the extracellular amyloid-ß (Aß) plaques and intracellular neurofibrillary tangles. The current therapies against AD are symptomatic with limited benefits but associated with major side effects. Inhibition of self-aggregation of Aß peptides into higher order cross-ß structure is one of the potential therapeutic approach which may counter oligomerization of Aß peptide. OBJECTIVE: The present study aimed to evaluate the neuroprotective and anti-inflammatory potential of a synthetic Pro-Drug type peptide (PDp) against Aß-induced toxicity in rat model of AD. METHODS: Intra-hippocampal microinjection of toxic Aß40 (IHAß40) by stereotaxic surgery was performed in the male Sprague-Dawley rats to generate an Aß-induced AD model. Sub-chronic toxicity of synthetic PDp using hematological, biochemical, and histopathological parameters was investigated. Evaluation of PDp on Aß-induced neurodegeneration and neuroinflammation was performed. RESULTS: PDp inhibits plaque formation with increase in Nissl granule staining in the rat hippocampus. Aß-induced toxicity associated imbalance in reactive oxygen species and antioxidant enzymes activity such as superoxide dismutase and catalase in the rat brain was overcome by PDp treatment. Tau protein hyperphosphorylation was normalized with PDp treatment. Also, the neuroinflammatory response was suppressed with PDp treatment. CONCLUSION: The present study depicts the potential neuroprotective role of PDp against Aß-induced toxicity in rat. PDp inhibits plaque formation thereby normalizing oxidative stress, inhibiting tau protein hyperphosphorylation, and suppressing neuroinflammatory responses. Future studies done in this direction will pave way for new therapeutic strategies.