deepGraphh: AI-driven web service for graph-based quantitative structure-activity relationship analysis.

Artificial intelligence (AI)-based computational techniques allow rapid exploration of the chemical space. However, representation of the compounds into computational-compatible and detailed features is one of the crucial steps for quantitative structure-activity relationship (QSAR) analysis. Recently, graph-based methods are emerging as a powerful alternative to chemistry-restricted fingerprints or descriptors for modeling. Although graph-based modeling offers multiple advantages, its implementation demands in-depth domain knowledge and programming skills. Here we introduce deepGraphh, an end-to-end web service featuring a conglomerate of established graph-based methods for model generation for classification or regression tasks. The graphical user interface of deepGraphh supports highly configurable parameter support for model parameter tuning, model generation, cross-validation and testing of the user-supplied query molecules. deepGraphh supports four widely adopted methods for QSAR analysis, namely, graph convolution network, graph attention network, directed acyclic graph and Attentive FP. Comparative analysis revealed that deepGraphh supported methods are comparable to the descriptors-based machine learning techniques. Finally, we used deepGraphh models to predict the blood-brain barrier permeability of human and microbiome-generated metabolites. In summary, deepGraphh offers a one-stop web service for graph-based methods for chemoinformatics.

Artificial intelligence uncovers carcinogenic human metabolites.

The genome of a eukaryotic cell is often vulnerable to both intrinsic and extrinsic threats owing to its constant exposure to a myriad of heterogeneous compounds. Despite the availability of innate DNA damage responses, some genomic lesions trigger malignant transformation of cells. Accurate prediction of carcinogens is an ever-challenging task owing to the limited information about bona fide (non-)carcinogens. We developed Metabokiller, an ensemble classifier that accurately recognizes carcinogens by quantitatively assessing their electrophilicity, their potential to induce proliferation, oxidative stress, genomic instability, epigenome alterations, and anti-apoptotic response. Concomitant with the carcinogenicity prediction, Metabokiller is fully interpretable and outperforms existing best-practice methods for carcinogenicity prediction. Metabokiller unraveled potential carcinogenic human metabolites. To cross-validate Metabokiller predictions, we performed multiple functional assays using Saccharomyces cerevisiae and human cells with two Metabokiller-flagged human metabolites, namely 4-nitrocatechol and 3,4-dihydroxyphenylacetic acid, and observed high synergy between Metabokiller predictions and experimental validations.

Adamantoid Scaffolds for Multiple Cargo Loading and Cellular Delivery as ß-Cyclodextrin Inclusion Complexes.

There is huge demand for developing guests that bind ß-CD and can conjugate multiple cargos for cellular delivery. We synthesized trioxaadamantane derivatives, which can conjugate up to three cargos per guest. 1 H NMR titration and isothermal titration calorimetry revealed these guests form 1 : 1 inclusion complexes with ß-CD with association constants in the order of 103  M-1 . Co-crystallization of ß-CD with guests yielded crystals of their 1 : 1 inclusion complexes as determined by single-crystal X-ray diffraction. In all cases, trioxaadamantane core is buried within the hydrophobic cavity of ß-CD and three hydroxyl groups are exposed outside. We established biocompatibility using representative candidate G4 and its inclusion complex with ß-CD (ß-CD⊂G4), by MTT assay using HeLa cells. We incubated HeLa cells with rhodamine-conjugated G4 and established cellular cargo delivery using confocal laser scanning microscopy (CLSM) and fluorescence-activated cell sorting (FACS) analysis. For functional assay, we incubated HeLa cells with ß-CD-inclusion complexes of G4-derived prodrugs G6 and G7, containing one and three units of the antitumor drug (S)-(+)-camptothecin, respectively. Cells incubated with ß-CD⊂G7 displayed the highest internalization and uniform distribution of camptothecin. ß-CD⊂G7 showed higher cytotoxicity than G7, camptothecin, G6 and ß-CD⊂G6, affirming the efficiency of adamantoid derivatives in high-density loading and cargo delivery.

OdoriFy: A conglomerate of artificial intelligence-driven prediction engines for olfactory decoding.

The molecular mechanisms of olfaction, or the sense of smell, are relatively underexplored compared with other sensory systems, primarily because of its underlying molecular complexity and the limited availability of dedicated predictive computational tools. Odorant receptors (ORs) allow the detection and discrimination of a myriad of odorant molecules and therefore mediate the first step of the olfactory signaling cascade. To date, odorant (or agonist) information for the majority of these receptors is still unknown, limiting our understanding of their functional relevance in odor-induced behavioral responses. In this study, we introduce OdoriFy, a Web server featuring powerful deep neural network-based prediction engines. OdoriFy enables (1) identification of odorant molecules for wildtype or mutant human ORs (Odor Finder); (2) classification of user-provided chemicals as odorants/nonodorants (Odorant Predictor); (3) identification of responsive ORs for a query odorant (OR Finder); and (4) interaction validation using Odorant-OR Pair Analysis. In addition, OdoriFy provides the rationale behind every prediction it makes by leveraging explainable artificial intelligence. This module highlights the basis of the prediction of odorants/nonodorants at atomic resolution and for the ORs at amino acid levels. A key distinguishing feature of OdoriFy is that it is built on a comprehensive repertoire of manually curated information of human ORs with their known agonists and nonagonists, making it a highly interactive and resource-enriched Web server. Moreover, comparative analysis of OdoriFy predictions with an alternative structure-based ligand interaction method revealed comparable results. OdoriFy is available freely as a web service at https://odorify.ahujalab.iiitd.edu.in/olfy/.

TCT-mediated click chemistry for the synthesis of nitrogen-containing functionalities: conversion of carboxylic acids to carbamides, carbamates, carbamothioates, amides and amines.

Here, we report a s-trichlorotriazine (TCT, also known as cyanuric chloride) mediated one-pot general method for the conversion of carboxylic acids into ubiquitous functionalities such as carbamides, carbamates, carbamothioates, amides, and amines. The TCT-mediated activation of acids followed by azidation and heating led to the isocyanate formation via Curtius rearrangement which involves click chemistry in the presence of nucleophiles and provided the coupled product. The TCT was employed at ≤40 mol% with respect to the starting materials; however, its bulk availability and low cost provide a unique opportunity towards its applicability in the synthesis of functional molecules. The optimized conditions have also been successfully demonstrated for gram scale synthesis and late-stage functionalization of natural products and drugs such as podophyllotoxin, eugenol, diosgenin, geraniol and fluvoxamine.

The ubiquitin ligase FBXW7 targets the centriolar assembly protein HsSAS-6 for degradation and thereby regulates centriole duplication.

Formation of a single new centriole from a pre-existing centriole is strictly controlled to maintain correct centrosome number and spindle polarity in cells. However, the mechanisms that govern this process are incompletely understood. Here, using several human cell lines, immunofluorescence and structured illumination microscopy methods, and ubiquitination assays, we show that the E3 ubiquitin ligase F-box and WD repeat domain-containing 7 (FBXW7), a subunit of the SCF ubiquitin ligase, down-regulates spindle assembly 6 homolog (HsSAS-6), a key protein required for procentriole cartwheel assembly, and thereby regulates centriole duplication. We found that FBXW7 abrogation stabilizes HsSAS-6 and increases its recruitment to the mother centriole at multiple sites, leading to supernumerary centrioles. Ultrastructural analyses revealed that FBXW7 is broadly localized on the mother centriole and that its presence is reduced at the site where the HsSAS-6-containing procentriole is formed. This observation suggested that FBXW7 restricts procentriole assembly to a specific site to generate a single new centriole. In contrast, during HsSAS-6 overexpression, FBXW7 strongly associated with HsSAS-6 at the centriole. We also found that SCFFBXW7 interacts with HsSAS-6 and targets it for ubiquitin-mediated degradation. Further, we identified putative phosphodegron sites in HsSAS-6, whose substitutions rendered it insensitive to FBXW7-mediated degradation and control of centriole number. In summary, SCFFBXW7 targets HsSAS-6 for degradation and thereby controls centriole biogenesis by restraining HsSAS-6 recruitment to the mother centriole, a molecular mechanism that controls supernumerary centrioles/centrosomes and the maintenance of bipolar spindles.

Guggulsterone ameliorates ethidium bromide-induced experimental model of multiple sclerosis via restoration of behavioral, molecular, neurochemical and morphological alterations in rat brain.

Multiple Sclerosis (MS) is a progressive neurodegenerative disease with clinical signs of neuroinflammation and the central nervous system's demyelination. Numerous studies have identified the role of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) overexpression and the low level of peroxisome proliferator-activated receptor-gamma (PPAR-γ) in MS pathogenesis. Guggulsterone (GST), an active component derived from 'Commiphora Mukul,' has been used to treat various diseases. Traditional uses indicate that GST is a suitable agent for anti-inflammatory action. Therefore, we assessed the therapeutic potential of GST (30 and 60 mg/kg) in ethidium bromide (EB) induced demyelination in experimental rats and investigated the molecular mechanism by modulating the JAK/STAT and PPAR-γ receptor signaling. Wistar rats were randomly divided into six groups (n = 6). EB (0.1%/10 µl) was injected selectively in the intracerebropeduncle (ICP) region for seven days to cause MS-like manifestations. The present study reveals that long-term administration of GST for 28 days has a neuroprotective effect by improving behavioral deficits (spatial cognition memory, grip, and motor coordination) associated with lower STAT-3 levels. While elevating PPAR-γ and myelin basic protein levels in rat brains are consistent with the functioning of both signaling pathways. Also, GST modulates the neurotransmitter level by increasing Ach, dopamine, serotonin and by reducing glutamate. Moreover, GST ameliorates inflammatory cytokines (TNF, IL-1ß), and oxidative stress markers (AchE, SOD, catalase, MDA, GSH, nitrite). In addition, GST prevented apoptosis, as demonstrated by the reduction of caspase-3 and Bax. Simultaneously, Bcl-2 elevation and the restoration of gross morphology alterations are also recovered by long-term GST treatment. Therefore, it can be concluded that GST may be a potential alternative drug candidate for MS-related motor neuron dysfunctions.

An Integrated Guide for Designing Video Abstracts Using Freeware and Their Emerging Role in Academic Research Advancement.

Video abstracts (VAs) are a motion picture equivalent of written abstracts. With greater use of social media platforms for post publication promotions of research articles, VAs have gained increasing popularity among researchers in recent years. Widespread lockdowns and social distancing protocols in the pandemic period furthered the use of VAs as a tool for efficient learning. Moreover, these may be the preferred medium for communicating certain types of information, such as diagnostic or therapeutic procedures, qualitative research, perspectives, and techniques. In this article, the authors discuss the role of VAs in the advancement of academic research, plausible designs, freeware for making videos, and specific considerations for crafting good VAs.

A comprehensive review on singlet oxygen generation in nanomaterials and conjugated polymers for photodynamic therapy in the treatment of cancer.

A key role in lessening humanity's continuous fight against cancer could be played by photodynamic therapy (PDT), a minimally invasive treatment employed in the medical care of a range of benign disorders and malignancies. Cancerous tissue can be effectively removed by using a light source-excited photosensitizer. Singlet oxygen and reactive oxygen species are produced via the photosensitizer as a result of this excitation. In the recent past, researchers have put in tremendous efforts towards developing photosensitizer molecules for photodynamic treatment (PDT) to treat cancer. Conjugated polymers, characterized by their efficient fluorescence, exceptional photostability, and strong light absorption, are currently under scrutiny for their potential applications in cancer detection and treatment through photodynamic and photothermal therapy. Researchers are exploring the versatility of these polymers, utilizing sophisticated chemical synthesis and adaptable polymer structures to create new variants with enhanced capabilities for generating singlet oxygen in photodynamic treatment (PDT). The incorporation of photosensitizers into conjugated polymer nanoparticles has proved to be beneficial, as it improves singlet oxygen formation through effective energy transfer. The evolution of nanotechnology has emerged as an alternative avenue for enhancing the performance of current photosensitizers and overcoming significant challenges in cancer PDT. Various materials, including biocompatible metals, polymers, carbon, silicon, and semiconductor-based nanomaterials, have undergone thorough investigation as potential photosensitizers for cancer PDT. This paper outlines the recent advances in singlet oxygen generation by investigators using an array of materials, including graphene quantum dots (GQDs), gold nanoparticles (Au NPs), silver nanoparticles (Ag NPs), titanium dioxide (TiO2), ytterbium (Yb) and thulium (Tm) co-doped upconversion nanoparticle cores (Yb/Tm-co-doped UCNP cores), bismuth oxychloride nanoplates and nanosheets (BiOCl nanoplates and nanosheets), and others. It also stresses the synthesis and application of systems such as amphiphilic block copolymer functionalized with folic acid (FA), polyethylene glycol (PEG), poly(ß-benzyl-L-aspartate) (PBLA10) (FA-PEG-PBLA10) functionalized with folic acid, tetra(4-hydroxyphenyl)porphyrin (THPP-(PNIPAM-b-PMAGA)4), pyrazoline-fused axial silicon phthalocyanine (HY-SiPc), phthalocyanines (HY-ZnPcp, HY-ZnPcnp, and HY-SiPc), silver nanoparticles coated with polyaniline (Ag@PANI), doxorubicin (DOX) and infrared (IR)-responsive poly(2-ethyl-2-oxazoline) (PEtOx) (DOX/PEtOx-IR NPs), particularly in NIR imaging-guided photodynamic therapy (fluorescent and photoacoustic). The study puts forward a comprehensive summary and a convincing justification for the usage of the above-mentioned materials in cancer PDT.

Unraveling Dilemmas and Lacunae in the Escalating Drug Resistance of Mycobacterium tuberculosis to Bedaquiline, Delamanid, and Pretomanid.

Delamanid, bedaquiline, and pretomanid have been recently added in the anti-tuberculosis (anti-TB) treatment regimens and have emerged as potential solutions for combating drug-resistant TB. These drugs have proven to be effective in treating drug-resistant TB when used in combination. However, concerns have been raised about the eventual loss of these drugs due to evolving resistance mechanisms and certain adverse effects such as prolonged QT period, gastrointestinal problems, hepatotoxicity, and renal disorders. This Perspective emphasizes the properties of these first-in-class drugs, including their mechanism of action, pharmacokinetics/pharmacodynamics profiles, clinical studies, adverse events, and underlying resistance mechanisms. A brief coverage of efforts toward the generation of best-in-class leads in each class is also provided. The ongoing clinical trials of new combinations of these drugs are discussed, thus providing a better insight into the use of these drugs while designing an effective treatment regimen for resistant TB cases.

Interpenetrating polymer networks for desalination and water remediation: a comprehensive review of research trends and prospects.

Interpenetrating polymer network (IPN) architectures have gained a lot of interest in recent decades, mainly due to their wide range of applications including water treatment and environmental remediation. IPNs are composed of two or more crosslinked polymeric matrices that are physically entangled but not chemically connected. In polymer science, the interpenetrating network structure with its high polymer chain entanglement is commonly used to generate materials with many functional properties, such as mechanical robustness and adaptable structure. In order to remove a targeted pollutant from contaminated water, it is feasible to modify the network architectures to increase the selectivity by choosing the monomer appropriately. This review aims to give a critical overview of the recent design concepts of IPNs and their applications in desalination and water treatment and their future prospects. This article also discusses the inclusion of inorganic nanoparticles into traditional polymeric membrane networks and its advantages. In the first part, the current scenario for desalination, water pollution and conventional desalination technologies along with their challenges is discussed. Subsequently, the main strategies for the synthesis of semi-IPNs and full-IPNs, and their relevant properties in water remediation are presented based on the nature of the networks and mechanism, with an emphasis on the IPN membrane. This review article has thoroughly investigated and critically assessed published works that describe the latest study on developing IPN membranes, hydrogels and composite materials in water purification and desalination. The goal of this critical analysis is to elicit fresh perspectives regarding the application and advantages of IPNs in desalination and water treatment. This article will also provide a glimpse into future areas of research to address the challenges relating to advanced water treatment as well as its emerging sustainable approaches. The study has put forward a convincing justification and establishes the relevance of IPNs being one of the most intriguing and important areas for achieving a sustainable generation of advanced materials that could benefit mankind.

Going beyond Cellulose and Chitosan: Synthetic Biodegradable Membranes for Drinking Water, Wastewater, and Oil-Water Remediation.

Membrane technology is an efficient way to purify water, but it generates non-biodegradable biohazardous waste. This waste ends up in landfills, incinerators, or microplastics, threatening the environment. To address this, research is being conducted to develop compostable alternatives that are sustainable and ecofriendly. Bioplastics, which are expected to capture 40% of the market share by 2030, represent one such alternative. This review examines the feasibility of using synthetic biodegradable materials beyond cellulose and chitosan for water treatment, considering cost, carbon footprint, and stability in mechanical, thermal, and chemical environments. Although biodegradable membranes have the potential to close the recycling loop, challenges such as brittleness and water stability limit their use in membrane applications. The review suggests approaches to tackle these issues and highlights recent advances in the field of biodegradable membranes for water purification. The end-of-life perspective of these materials is also discussed, as their recyclability and compostability are critical factors in reducing the environmental impact of membrane technology. This review underscores the need to develop sustainable alternatives to conventional membrane materials and suggests that biodegradable membranes have great potential to address this challenge.

A universal approach to 'host' carbon nanotubes on a charge triggered 'guest' interpenetrating polymer network for excellent 'green' electromagnetic interference shielding.

The widespread use of miniaturized electronic gadgets today faces stiff reliability obstacles from factors like stray electromagnetic signals. The challenge is to design lightweight shielding materials that combine small volume and high-frequency operations to reliably reduce/eliminate electromagnetic interference. Herein, in the first of its kind, a sequential interpenetrating polymeric network (IPN) membrane was used to host a CNT construct through a stimuli-responsive trigger. The proposed construct besides being robust, sustainable, and scalable is a universal approach to fabricate a CNT construct where conventional strategies are not amenable. This approach of self-assembling counter-charged CNTs also maximizes the number of CNTs in the final construct, thereby greatly enhancing the shielding performance dominated by 90% absorption in a wide frequency band of 8.2-26.5 GHz. The IPN-CNT construct achieves specific shielding effectiveness in the range of ca. 1607-5715 dB cm2 g-1 by tuning the thickness of the CNT construct with an endearing green index (gs ≈ 1.8). The performance of such an ultra-thin, light-weight IPN-CNT construct remained unchanged when subjected to 10 000 bending cycles and on exposure to different chemical environments, indicating outstanding mechanical/chemical stability.

Silver-mediated Room Temperature Reactions for the Synthesis of N-α-Ketoacyl Sulfoximines and N-α,ß-Unsaturated Acyl Sulfoximines.

Here, we report a silver-mediated coupling of acetylenes with sulfoximines to synthesize N-α-ketoacyl sulfoximines and N-α,ß-unsaturated acyl sulfoximines. The reactions are performed under an open atmosphere using the oxidant K2S2O8 and the ligand 2,2-bipyridyl. However, the fate of the product formation is controlled by the type of substrate used. The coupling between aryl acetylenes and sulfoximines afforded the N-α-ketoacylsulfoximines, while the alkyl acetylenes provided the N-α,ß-unsaturated acyl sulfoximines. Controlled experiments reveal the differential reactivity patterns of substrates. The labeling 18O experiments showed that water is the source of the incoming oxygen atom for the keto group of N-α-ketoacyl sulfoximines and N-α,ß-unsaturated acyl sulfoximines.

On the role of wall thickness in determining the plasmonic properties of silver-gold nanocages.

This work examines the roles played by wall thickness in determining the plasmonic properties of gold-silver (Ag-Au) nanocages. Ag-Au cages with different wall thicknesses, but the same void or outer size, shape, and elemental composition, were designed as a model platform. The experimental findings were understood with theoretical calculations. This study not only investigates the effect of wall thickness but also provides an effective knob to tailor the plasmonic properties of hollow nanostructures.

Assessment of quality and reliability of YouTube videos for patient and physician education on inflammatory myositis.

INTRODUCTION: YouTube is the second most popular search website worldwide to access health information online. This study was undertaken to assess the reliability and quality of information about myositis on YouTube and delineate attributes of useful videos using standard metrics. METHODS: We conducted a thorough search on YouTube using 9 search terms related to myositis. The inclusion criteria were content related to myositis, English language and acceptable audio-video quality. Duplicates and advertisements were excluded from the analysis. Videos were classified as useful, not very useful or misleading and patient narratives. Reliability was determined using the mDISCERN criteria, quality using the Global Quality Scale (GQS) and JAMA system, using appropriate cut-offs (mDISCERN > 4, GQS > 4, JAMA > 3). RESULTS: Out of a total of 900 videos, 453 were included for the analysis. Seventy-four per cent and 2% provided useful and not very useful information respectively, while 24% were patient narratives. Seventy-one per cent were intended specifically for patients while 69% were for healthcare providers and students. Noteworthily, useful and not very useful videos had similar total views though the number of likes and daily viewership were higher for useful videos (p = 0.024, p = 0.046). Nearly half (47%) of useful videos were by professional medical societies/patient support groups (PSGs) while not very useful ones were by nonmedical media (38%). Physician-predicted usefulness was discordant with score-based usefulness (κ = 0.129). However, GQS emerged as a significant (p = 0.008) predictor of video usefulness in multivariate analysis. CONCLUSION: A large majority of English YouTube videos on myositis provide useful information for patients. Physicians could signpost patients to high-quality useful videos as determined by GQS and sources like professional medical societies and PSGs. Key Points •This study highlights the importance of regulating health information posted online, accessed by millions of people, to gauge the quality of information and to identify and curb misinformation. •It also identifies recommendations for the future for uploading such content on the Internet. •The implications lie in our patients being better informed about their disease as they are important stakeholders in the healthcare decision-making process.

Polyoxometalate-immobilized carbon nanotube constructs triggered by host-guest assembly result in excellent electromagnetic interference shielding.

In the era of fifth-generation networks and the Internet of Things, new classes of lightweight, ultrathin, and multifunctional electromagnetic interference (EMI) shielding materials have become inevitable prerequisites for the protection of electronics from stray electromagnetic signals. In the present study, for the first time, we have designed a unique nanohybrid composed of a copper-based polyoxometalate (Cu-POM)-immobilized carbon nanotube construct, having a micron (∼100 µm)-level thickness, through a facile vacuum-assisted filtration technique. In this course of study, a total of four Cu-POMs, two from each category of Keggin and Anderson bearing opposite charges, i.e., positive and negative, have been rationally selected to investigate the effects of the host-guest electrostatic interaction between CNT and POMs in the EMI shielding performance. This approach of the host-guest electrostatic assembly between Cu-based polyanionic oxo clusters and counter-charged CNTs in the construct synergistically enhances the EMI shielding performance compared to the individual components dominated by 90% absorption in the X-band (8.2-12.4 GHz) frequency regime. Further, mutable EMI SE can be achieved by tuning the concentration of POMs and CNTs with different weight ratios. Such Cu-POM-immobilized CNT constructs demonstrating excellent shielding (∼45 dB) are not amenable via any other conventional routes, including flakes and dispersion.

Transcriptional Profiling and Consensus Molecular Subtype Assignment to Understand Response and Resistance to Anti-Epidermal Growth Factor Receptor Therapy in Colorectal Cancer.

PURPOSE: Activating mutations in KRAS, NRAS, and BRAF are known to cause resistance to anti-epidermal growth factor receptor (EGFR) therapy; however, only approximately 40% of patients with colorectal cancer (CRC) with RASWT tumors respond to anti-EGFR treatment. We sought to discover novel biomarkers to predict response to anti-EGFR antibody treatment in CRC and to understand mechanisms of resistance to anti-EGFR therapy. MATERIALS AND METHODS: Transcriptomic profiles from three clinical and two preclinical cohorts treated with cetuximab were used to assign consensus molecular subtypes (CMS) to each sample and correlated with outcomes. RESULTS: Restricting to RASWT patients, we observed that CMS2 tumors (canonical subtype) had significantly higher response rates relative to other CMS when treated with cetuximab combination with doublet chemotherapy (Okita et al cohort: 92% disease control rate (DCR) for CMS2, chi-square P = .04; CALGB/SWOG 80405 cohort: 90% objective response rate (ORR) for CMS2, chi-square P < .001) and with single-agent cetuximab (68%, chi-square P = .01). CMS2 tumors showed best response among right-sided (ORR = 80%) and left-sided (ORR = 92%) tumors in the CALGB/SWOG 80405 cohort. CMS2 cells lines were most likely to be sensitive to cetuximab (60%) and CMS2 patient-derived xenograft had the highest DCR (84%). We found Myc, E2F, and mammalian target of rapamycin pathways were consistently upregulated in resistant samples (enrichment score >1, false discovery rate <0.25). Inhibitors of these pathways in resistant cell lines exhibited additive effects with cetuximab. CONCLUSION: These data suggest that CRC transcriptional profiles, when used to assign CMS, provide additional ability to predict response to anti-EGFR therapy relative to using tumor sidedness alone. Notably both right-sided and left-sided CMS2 tumors had excellent response, suggesting that anti-EGFR therapy be included as a treatment option for right-sided CMS2 tumors.

Fundamental Understanding of Ultrathin, Highly Stable Self-Assembled Liquid Crystalline Graphene Oxide Membranes Leading to Precise Molecular Sieving through Non-equilibrium Molecular Dynamics.

Self-assembled graphene oxide lyotropic liquid crystal (GO LLC) structures are mostly formed in aqueous medium; however, most GO derivatives are water insoluble, so processing GO LLCs in water poses a practical limitation. The use of polar aprotic solvent (like dimethyl sulfoxide) for the formation of GO LLC structures would be interesting, because it would allow incorporating additives, like photoinitiators or cross-linkers, or blending with polymers that are insoluble in water, which hence would expand its scope. The well-balanced electrostatic interaction between DMSO and GO can promote and stabilize the GO nanosheets' alignment even at lower concentrations. With this in mind, herein we report mechanically robust, chlorine-tolerant, self-assembled nanostructured GO membranes for precise molecular sieving. Small-angle X-ray scattering and polarized optical microscopy confirmed the alignment of the modified GO nanosheets in polar aprotic solvent, and the LLC structure was effectively preserved even after cross-linking under UV light. We found that the modified GO membranes exhibited considerably improved salt rejection for monovalent ions (99%) and water flux (120 LMH) as compared to the shear-aligned GO membrane, which is well supported by forward osmosis simulation studies. Additionally, our simulation studies indicated that water molecules traveled a longer path while permeating through the GO membrane compared to the GO LLC membrane. Consequently, salt ions permeate slowly across the GO LLC membrane, yielding higher salt rejection than the GO membrane. This begins to suggest strong electrostatic repulsion with the salt ions, causing higher salt rejection in the GO LLC membrane. We foresee that the ordered cross-linked GO sheets contributed to excellent mechanical stability under a high-pressure, cross-flow, chlorine environment. Overall, these membranes are easily scalable, exhibit good mechanical stability, and represent a breakthrough for the potential use of polymerized GO LLC membranes in practical water remediation applications.

Role of Sonic Hedgehog Signaling Activation in the Prevention of Neurological Abnormalities Associated with Obsessive-Compulsive Disorder.

The smoothened sonic hedgehog (Smo-Shh) pathway is one mechanism that influences neurogenesis, including brain cell differentiation and development during childhood. Shh signaling dysregulation leads to decreased target gene transcription, which contributes to increased neuronal excitation, apoptosis, and neurodegeneration, eventually leading to neurological deficits. Neuropsychiatric disorders such as OCD and related neurological dysfunctions are characterized by neurotransmitter imbalance, neuroinflammation, oxidative stress, and impaired neurogenesis, disturbing the cortico-striato-thalamo-cortical (CSTC) link neuronal network. Despite the availability of several treatments, such as selective serotonin reuptake inhibitors, some individuals may not benefit much from them. Several trials on the use of antipsychotics in the treatment of OCD have also produced inadequate findings. This evidence-based review focuses on a potential pharmacological approach to alleviating OCD and associated neuronal deficits by preventing neurochemical alterations, in which sonic hedgehog activators are neuroprotective, lowering neuronal damage while increasing neuronal maintenance and survival. As a result, stimulating SMO-Shh via its potential activators may have neuroprotective effects on neurological impairment associated with OCD. This review investigates the link between SMO-Shh signaling and the neurochemical abnormalities associated with the progression of OCD and associated neurological dysfunctions. Role of Smo-Shh signaling in serotonergic neurogenesis and in maintaining their neuronal identity. The Shh ligand activates two main transcriptional factors known as Foxa2 and Nkx2.2, which again activates another transcriptional factor, GATA (GATA2 and GATA3), in post mitotic precursor cells of serotonergic neurons-following increased expression of Pet-1 and Lmx1b after GATA regulates the expression of many serotonergic enzymes such as TPH2, SERT, VMAT, slc6a4, Htr1a, Htr1b (Serotonin receptor enzymes), and MAO that regulate and control the release of serotonin and maintain their neuronal identity after their maturation. Abbreviation: Foxa2: Forkhead box; GATA: Globin transcription factor; Lmx1b: LIM homeobox transcription factor 1 beta; TPH2: Tryptophan hydroxylase 2; Htr1a: Serotonin receptor 1a; Htr1b: Serotonin receptor 1b; SERT: Serotonin transporter; VMAT: Vesicular monoamine transporter; MAO: Monoamine oxidase.