IL-17RA-signaling in Lgr5+ intestinal stem cells induces expression of transcription factor ATOH1 to promote secretory cell lineage commitment.

The Th17 cell-lineage-defining cytokine IL-17A contributes to host defense and inflammatory disease by coordinating multicellular immune responses. The IL-17 receptor (IL-17RA) is expressed by diverse intestinal cell types, and therapies targeting IL-17A induce adverse intestinal events, suggesting additional tissue-specific functions. Here, we used multiple conditional deletion models to identify a role for IL-17A in secretory epithelial cell differentiation in the gut. Paneth, tuft, goblet, and enteroendocrine cell numbers were dependent on IL-17A-mediated induction of the transcription factor ATOH1 in Lgr5+ intestinal epithelial stem cells. Although dispensable at steady state, IL-17RA signaling in ATOH1+ cells was required to regenerate secretory cells following injury. Finally, IL-17A stimulation of human-derived intestinal organoids that were locked into a cystic immature state induced ATOH1 expression and rescued secretory cell differentiation. Our data suggest that the cross talk between immune cells and stem cells regulates secretory cell lineage commitment and the integrity of the mucosa.

Signaling by Fyn-ADAP via the Carma1-Bcl-10-MAP3K7 signalosome exclusively regulates inflammatory cytokine production in NK cells.

Inflammation is a critical component of the immune response. However, acute or chronic inflammation can be highly destructive. Uncontrolled inflammation forms the basis for allergy, asthma and various autoimmune disorders. Here we identified a signaling pathway that was exclusively responsible for the production of inflammatory cytokines but not for cytotoxicity. Recognition of tumor cells expressing the NK cell-activatory ligands H60 or CD137L by mouse natural killer (NK) cells led to efficient cytotoxicity and the production of inflammatory cytokines. Both of those effector functions required the kinases Lck, Fyn and PI(3)K (subunits p85α and p110δ) and the signaling protein PLC-γ2. However, a complex of Fyn and the adaptor ADAP exclusively regulated the production of inflammatory cytokines but not cytotoxicity in NK cells. That unique function of ADAP required a Carma1-Bcl-10-MAP3K7 signaling axis. Our results have identified molecules that can be targeted to regulate inflammation without compromising NK cell cytotoxicity.

Intestinal Interleukin-17 Receptor Signaling Mediates Reciprocal Control of the Gut Microbiota and Autoimmune Inflammation.

Interleukin-17 (IL-17) and IL-17 receptor (IL-17R) signaling are essential for regulating mucosal host defense against many invading pathogens. Commensal bacteria, especially segmented filamentous bacteria (SFB), are a crucial factor that drives T helper 17 (Th17) cell development in the gastrointestinal tract. In this study, we demonstrate that Th17 cells controlled SFB burden. Disruption of IL-17R signaling in the enteric epithelium resulted in SFB dysbiosis due to reduced expression of α-defensins, Pigr, and Nox1. When subjected to experimental autoimmune encephalomyelitis, IL-17R-signaling-deficient mice demonstrated earlier disease onset and worsened severity that was associated with increased intestinal Csf2 expression and elevated systemic GM-CSF cytokine concentrations. Conditional deletion of IL-17R in the enteric epithelium demonstrated that there was a reciprocal relationship between the gut microbiota and enteric IL-17R signaling that controlled dysbiosis, constrained Th17 cell development, and regulated the susceptibility to autoimmune inflammation.

Partial Thermal Condensation Mediated Synthesis of High-Density Nickel Single Atom Sites on Carbon Nitride for Selective Photooxidation of Methane into Methanol.

Direct selective transformation of greenhouse methane (CH4) to liquid oxygenates (methanol) can substitute energy-intensive two-step (reforming/Fischer-Tropsch) synthesis while creating environmental benefits. The development of inexpensive, selective, and robust catalysts that enable room temperature conversion will decide the future of this technology. Single-atom catalysts (SACs) with isolated active centers embedded in support have displayed significant promises in catalysis to drive challenging reactions. Herein, high-density Ni single atoms are developed and stabilized on carbon nitride (NiCN) via thermal condensation of preorganized Ni-coordinated melem units. The physicochemical characterization of NiCN with various analytical techniques including HAADF-STEM and X-ray absorption fine structure (XAFS) validate the successful formation of Ni single atoms coordinated to the heptazine-constituted CN network. The presence of uniform catalytic sites improved visible absorption and carrier separation in densely populated NiCN SAC resulting in 100% selective photoconversion of (CH4) to methanol using H2O2 as an oxidant. The superior catalytic activity can be attributed to the generation of high oxidation (NiIII═O) sites and selective C─H bond cleavage to generate •CH3 radicals on Ni centers, which can combine with •OH radicals to generate CH3OH.

Flavonols affect the interrelated glucosinolate and camalexin biosynthetic pathways in Arabidopsis thaliana.

Flavonols are structurally and functionally diverse biomolecules involved in plant biotic and abiotic stress tolerance, pollen development, and inhibition of auxin transport. However, their effects on global gene expression and signaling pathways are unclear. To explore the roles of flavonol metabolites in signaling, we performed comparative transcriptome and targeted metabolite profiling of seedlings from the flavonol-deficient Arabidopsis loss-of-function mutant flavonol synthase1 (fls1) with and without exogenous supplementation of flavonol derivatives (kaempferol, quercetin, and rutin). RNA-seq results indicated that flavonols modulate various biological and metabolic pathways, with significant alterations in camalexin and aliphatic glucosinolate synthesis. Flavonols negatively regulated camalexin biosynthesis but appeared to promote the accumulation of aliphatic glucosinolates via transcription factor-mediated up-regulation of biosynthesis genes. Interestingly, upstream amino acid biosynthesis genes involved in methionine and tryptophan synthesis were altered under flavonol deficiency and exogenous supplementation. Quercetin treatment significantly up-regulated aliphatic glucosinolate biosynthesis genes compared with kaempferol and rutin. In addition, expression and metabolite analysis of the transparent testa7 mutant, which lacks hydroxylated flavonol derivatives, clarified the role of quercetin in the glucosinolate biosynthesis pathway. This study elucidates the molecular mechanisms by which flavonols interfere with signaling pathways, their molecular targets, and the multiple biological activities of flavonols in plants.

Predictive Performance of 1 H-NMR Metabolomics-Derived Biomarkers of Bacterial Vaginosis.

ABSTRACT: 1 H-NMR metabolomics-derived biomarkers maltose, acetate, formate, and lactate have excellent potential as predictive biomarkers for bacterial vaginosis with an area under curve of 0.97 (95% confidence interval, 0.88-1.00), sensitivity of 0.90, and specificity of 0.95.

Energy Dissipation during Wenzel Wetting via Roughness Scale Interface Dynamics.

A numerical method is proposed to simulate the roughness scale interface dynamics of a slow-moving fluid interface as it advances over a chemically homogeneous rough surface. Analysis of the governing augmented Navier-Stokes and Young's boundary condition equations shows how the local interface behavior can be represented via a series of incrementally advanced equilibrium interfacial morphologies. Combined with a roughness scale mechanical energy balance [Harvie, D. J. E. Contact-angle hysteresis on rough surfaces: mechanical energy balance framework. J. Fluid Mech. 2024, 986, A17], the simulations are used to calculate the energy dissipation associated with a surface decorated with a periodic array of round-edge square pillars. This dissipation is used to predict static contact angle hysteresis (CAH) from knowledge of just the surface roughness topography and equilibrium contact angle. We show that the energy dissipated varies approximately as ϕln ϕ (with ϕ being the area fraction), becoming zero as ϕ → 0. The CAH predicted by our method is in good agreement with the experimental results of Forsberg et al. [Forsberg, P. S.; Priest, C.; Brinkmann, M.; Sedev, R.; Ralston, J. Contact line pinning on microstructured surfaces for liquids in the Wenzel state. Langmuir 2010, 26, 860-865], thereby demonstrating that our numerical method of simulating interfacial dynamics adequately captures the real interface motion, as well as illustrating how far-field contact angle and energy dissipation approaches are consistent for this surface. We also compute CAH for an interface moving at 45° to the surface periodicity direction to show that the experimental measurements are bracketed by the 0° and 45° advance direction results. The proposed method opens up the field to quantitative analysis, surface functionalization, and design for different specific applications.

Highlights in Interface of Wastewater Treatment by Utilizing Metal Organic Frameworks: Purification and Adsorption Kinetics.

Polluted water has become a concern for the scientific community as it causes many severe threats to living beings. Detection or removal of contaminants present in wastewater and attaining purity of water that can be used for various purposes are a primary responsibility. Different treatment methods have already been used for the purification of sewage. There is a need for low-cost, highly selective, and reusable materials that can efficiently remove pollutants or purify contaminated water. In this regard, MOFs have shown significant potential for applications such as supercapacitors, drug delivery, gas storage, pollutant adsorption, etc. The outstanding structural diversity, substantial surface areas, and adjustable pore sizes of MOFs make them superior candidates for wastewater treatment. This Review provides an overview of the interaction science and engineering (kinetic and thermodynamic aspects with interactions) underpinning MOFs for water purification. First, fundamental strategies for the synthesis methods of MOFs, different categories, and their applicability in wastewater treatment are summarized, followed by a detailed explanation of various interaction mechanisms. Finally, current challenges and future outlooks for research on MOF materials toward the adsorption of hazardous components are discussed. A new avenue for modifying their structural characteristics for the adsorption and separation of hazardous materials, which will undoubtedly direct future work, is also summarized.

Usual breast lump with unusual features.

The co-existence of granulomatous mastitis and collagenous spherulosis in a breast lump is an uncommon finding. The awareness of cytomorphological features can help corroborate a cytological diagnosis. A palpable breast lump in an elderly female warrants urgent attention and fine needle aspiration is a rapid, reliable method of evaluation. An elderly female with a firm breast lump mimicking malignancy was subjected to fine needle aspiration cytology (FNAC). Smears showed ill-formed granulomas, inflammatory cells and homogeneous hyaline stromal globular elements intermingled with the benign ductal epithelial and myoepithelial cells.

Preliminary investigation reveals novel pathological consequences of bluetongue virus-1 infection in the endocrine glands of pregnant Indian sheep.

Bluetongue virus (BTV), a major peril to the sheep industry, infects a wide range of the cells in the infected animals including mononuclear, dendritic and epithelial cells. However, little is known about its tropism for the secretory epithelial cells of endocrine glands and the pathogenesis it induces. The aim of the study was to assess the BTV load, antigen distribution in the tissue of the pituitary, thyroid as well as adrenal glands and associated histopathological consequences. BTV antigens were localized using immunohistochemistry in the thyroid's epithelial cells, zona fasciculata and zona reticularis cells and the anterior pituitary epithelial cells. The real-time PCR portrayed the high viral load in adrenals at 7th days postinoculation (DPI) and in thyroid and pituitary glands at 15th DPI. Serum examination revealed variation in the T-3 and T-4 of infected animals in comparison to the control group. Caspase-3 immunolocalization revealed BTV-1 induces apoptosis in the affected cells of endocrine gland of infected animals. Further, this study signifies the tropism of BTV in the novel sites (endocrine glands) of the host that might be one of the reasons for the poor performance of infected animals.

Multifunctional carbon nitride nanoarchitectures for catalysis.

Catalysis is at the heart of modern-day chemical and pharmaceutical industries, and there is an urgent demand to develop metal-free, high surface area, and efficient catalysts in a scalable, reproducible and economic manner. Amongst the ever-expanding two-dimensional materials family, carbon nitride (CN) has emerged as the most researched material for catalytic applications due to its unique molecular structure with tunable visible range band gap, surface defects, basic sites, and nitrogen functionalities. These properties also endow it with anchoring capability with a large number of catalytically active sites and provide opportunities for doping, hybridization, sensitization, etc. To make considerable progress in the use of CN as a highly effective catalyst for various applications, it is critical to have an in-depth understanding of its synthesis, structure and surface sites. The present review provides an overview of the recent advances in synthetic approaches of CN, its physicochemical properties, and band gap engineering, with a focus on its exclusive usage in a variety of catalytic reactions, including hydrogen evolution reactions, overall water splitting, water oxidation, CO2 reduction, nitrogen reduction reactions, pollutant degradation, and organocatalysis. While the structural design and band gap engineering of catalysts are elaborated, the surface chemistry is dealt with in detail to demonstrate efficient catalytic performances. Burning challenges in catalytic design and future outlook are elucidated.

Declining Trend in Antimicrobial Sensitivity in Respiratory Tract Bacterial Pathogens against Commonly Used Drugs at a Tertiary Care Hospital.

OBJECTIVES: Antimicrobial resistance (AMR) is a major health issue. To determine trends in bacterial organisms in respiratory tract infections (RTIs) and their antibiotic sensitivity at a tertiary care center in India, we performed this study. METHODS: Successive samples received from January 2017 to December 2021 from the respiratory tract (sputum, endotracheal secretion, and bronchoalveolar lavage) from intensive care units and medical inpatients were processed for bacterial growth. The identification of isolates and antibiotic sensitivity patterns was performed using an automated VITEK-2 system. Descriptive statistics are reported. RESULTS: We received 7,204 respiratory samples. Significant bacterial growth was in 3,000 (41.6%), and 2,992 (41.5%) were gram-negative. Klebsiella pneumoniae was the most prevalent, followed by Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, and Enterobacter aerogenes. Increasing secular trends were observed for Klebsiella and Pseudomonas and declining trends for Acinetobacter and Escherichia (p < 0.05). Antimicrobial sensitivity patterns showed that Klebsiella, Pseudomonas, Acinetobacter, E. coli, and Enterobacter had a high sensitivity with colistin and polymyxin (99-100%). Moderate sensitivity was observed with carbapenems (Acinetobacter: 47.5%, Enterobacter: 62.0%, Escherichia: 76.5%, Klebsiella: 72.3%, Pseudomonas: 66.7%) and tigecycline (Acinetobacter: 50.4%, Enterobacter: 68.0%, Escherichia: 81.1%, Klebsiella: 66.6%, Pseudomonas: 0%). Aminoglycosides had <50% sensitivity for various organisms, and <25% sensitivity was observed with third-generation cephalosporins and quinolones. Trend analysis showed persistent sensitivity of various pathogenic bacteria to colistin and polymyxin and declining pharmacological sensitivity in Acinetobacter (carbapenems and tigecycline), Escherichia (carbapenems, quinolones, and tigecycline), Klebsiella (carbapenems, quinolones, aminoglycosides, and tigecycline), and Pseudomonas (carbapenems and aminoglycosides) species (p < 0.05). CONCLUSION: Common respiratory tract gram-negative bacterial pathogens at a tertiary care hospital are K. pneumoniae, P. aeruginosa, A. baumannii, and E. coli. All these bacteria demonstrate high sensitivity only with colistin and polymyxin. Significant AMR is observed to carbapenems, tigecycline, aminoglycosides, and third-generation cephalosporins. Secular trends show declining antimicrobial sensitivity among various bacterial pathogens.

Fenfuro®-mediated arrest in the formation of protein-methyl glyoxal adducts: a new dimension in the anti-hyperglycemic potential of a novel fenugreek seed extract.

The fenugreek plant (Trigonella foenum-graecum) is traditionally known for its anti-diabetic properties owing to its high content of furostanolic saponins, which can synergistically treat many human ailments. Non-enzymatic protein glycation leading to the formation of Advanced Glycation End products (AGE) is a common pathophysiology observed in diabetic or prediabetic individuals, which can initiate the development of neurodegenerative disorders. A potent cellular source of glycation is Methyl Glyoxal, a highly reactive dicarbonyl formed as a glycolytic byproduct. We demonstrate the in vitro glycation arresting potential of Fenfuro®, a novel patented formulation of Fenugreek seed extract with clinically proven anti-diabetic properties, in Methyl-Glyoxal (MGO) adducts of three abundant amyloidogenic cellular proteins, alpha-synuclein, Serum albumin, and Lysozyme. A 0.25% w/v Fenfuro® was able to effectively arrest glycation by more than 50% in all three proteins, as evidenced by AGE fluorescence. Glycation-induced amyloid formation was also arrested by more than 36%, 14% and 15% for BSA, Alpha-synuclein and Lysozyme respectively. An increase in MW by attachment of MGO was also partially prevented by Fenfuro® as confirmed by SDS-PAGE analysis. Glycation resulted in enhanced aggregation of the three proteins as revealed by Native PAGE and Dynamic Light Scattering. However, in the presence of Fenfuro®, aggregation was arrested substantially, and the normal size distribution was restored. The results cumulatively indicated the lesser explored potential of direct inhibition of glycation by fenugreek seed in addition to its proven role in alleviating insulin resistance. Fenfuro® boosts its therapeutic potential as an effective phytotherapeutic to arrest Type 2 diabetes.

Fenfuro^® is a novel patented formulation of Fenugreek seed extract with more than 45% furostanolic saponins and anti-diabetic property free from any side effect as established through clinical study.In the present study, the role of Fenfuro® in arresting in vitro AGE formation and glycation-induced amyloid formation has been demonstrated with the help of three amyloidogenic proteins, namely Human Lysozyme, Human alpha-synuclein and Bovine Serum Albumin using Methyl Glyoxal as the glycating agent.A 0.25% (w/v) ethanolic solution of Fenfuro® resulted in more than 50% arrest in glycation with simultaneous prevention of aggregation as demonstrated by native PAGE, DLS and inhibition of development of Thio-T positive amyloid like entities.The studies collectively aim toward the development of a safe therapeutic method for arresting protein glycation through direct physical intervention.

Comparison of efficacy of daily and alternate day maintenance treatment of GERD with Vonoprazan 10-mg using Gastroesophageal Reflux Disease Symptom Assessment Scale.

Objectives: To compare efficacy of 10-mg of vonoprazan daily & on alternate days by Gastroesophageal Reflux Disease Symptom Assessment Scale (GSAS). Method: This prospective interventional cohort was done at Department of Medicine/Gastroenterology Dow Medical College, Karachi, Pakistan during the period August 2022 & January 2023. Potential participants fulfilling inclusion and exclusion criteria were asked to fill out GSAS questionnaires after their written consent. Patients were allocated in to two groups using random tables. Group-A was given Tab Vonoprazan 10-mg daily for two weeks. Group-B was given Tab Vonoprazan 10-mg on alternate day. GSAS was scored by totaling scores across symptoms and then they are divided by the total number of non-missing symptom scores. Both groups were assessed week-0 & week-2. Results: Only 90 proformas that were completely filled were included, Group-A had 30 males and 15 females while Group-B had 29 males and 16 females. No significant difference in score was found in GSAS score at week-0 except that in item 'gurgling' while at week two there was no significant difference between any of the items. Total GSAS score were significantly lower at Week-2 than at week-0 (p = <.001). Conclusions: Vonoprazan of 10-mg on alternate day is equally effective as 10-mg daily in maintenance of GERD patients at two weeks.

High-Density Cobalt Single-Atom Catalysts for Enhanced Oxygen Evolution Reaction.

Single atom catalysts (SACs) possess unique catalytic properties due to low-coordination and unsaturated active sites. However, the demonstrated performance of SACs is limited by low SAC loading, poor metal-support interactions, and nonstable performance. Herein, we report a macromolecule-assisted SAC synthesis approach that enabled us to demonstrate high-density Co single atoms (10.6 wt % Co SAC) in a pyridinic N-rich graphenic network. The highly porous carbon network (surface area of ∼186 m2 g-1) with increased conjugation and vicinal Co site decoration in Co SACs significantly enhanced the electrocatalytic oxygen evolution reaction (OER) in 1 M KOH (η10 at 351 mV; mass activity of 2209 mA mgCo-1 at 1.65 V) with more than 300 h stability. Operando X-ray absorption near-edge structure demonstrates the formation of electron-deficient Co-O coordination intermediates, accelerating OER kinetics. Density functional theory (DFT) calculations reveal the facile electron transfer from cobalt to oxygen species-accelerated OER.

Targeted editing of multiple homologues of GTR1 and GTR2 genes provides the ideal low-seed, high-leaf glucosinolate oilseed mustard with uncompromised defence and yield.

Glucosinolate content in the two major oilseed Brassica crops-rapeseed and mustard has been reduced to the globally accepted Canola quality level (<30 µmoles/g of seed dry weight, DW), making the protein-rich seed meal useful as animal feed. However, the overall lower glucosinolate content in seeds as well as in the other parts of such plants renders them vulnerable to biotic challenges. We report CRISPR/Cas9-based editing of glucosinolate transporter (GTR) family genes in mustard (Brassica juncea) to develop ideal lines with the desired low seed glucosinolate content (SGC) while maintaining high glucosinolate levels in the other plant parts for uncompromised plant defence. Use of three gRNAs provided highly efficient and precise editing of four BjuGTR1 and six BjuGTR2 homologues leading to a reduction of SGC from 146.09 µmoles/g DW to as low as 6.21 µmoles/g DW. Detailed analysis of the GTR-edited lines showed higher accumulation and distributional changes of glucosinolates in the foliar parts. However, the changes did not affect the plant defence and yield parameters. When tested against the pathogen Sclerotinia sclerotiorum and generalist pest Spodoptera litura, the GTR-edited lines displayed a defence response at par or better than that of the wild-type line. The GTR-edited lines were equivalent to the wild-type line for various seed yield and seed quality traits. Our results demonstrate that simultaneous editing of multiple GTR1 and GTR2 homologues in mustard can provide the desired low-seed, high-leaf glucosinolate lines with an uncompromised defence and yield.

Defense versus growth trade-offs: Insights from glucosinolates and their catabolites.

Specialized metabolites are a structurally diverse group of naturally occurring compounds that facilitate plant-environment interactions. Their synthesis and maintenance in plants is overall a resource-demanding process that occurs at the expense of growth and reproduction and typically incurs several costs. Evidence emerging on different specialized compounds suggests that they serve multiple auxiliary functions to influence and moderate primary metabolism in plants. These new functionalities enable them to mediate trade-offs from defenses to growth and also to offset their production and maintenance costs in plants. Recent research on glucosinolates (GSLs), which are specialized metabolites of Brassicales, demonstrates their emerging multifunctionalities to fine-tune plant growth and development under variable environments. Herein, we present findings from the septennium on individual GSLs and their catabolites (GHPs) per se, that work as mobile signals within plants to mediate precise regulations of their primary physiological functions. Both GSLs and GHPs calibrate growth-defense trade-off interactions either synergistically or directly when they function as storage compounds, abiotic stress alleviators, and one-to-one regulators of growth pathways in plants. We finally summarize the overall lessons learned from GSLs and GHPs as a model and raise the most pressing questions to address the molecular-genetic intricacies of specialized metabolite-based trade-offs in plants.

From Balloon to Crystalline Structure in the Calcium Phosphate Flow-Driven Chemical Garden.

We have studied the calcium phosphate precipitation reaction by producing chemical gardens in a controlled manner using a three-dimensional flow-driven technique. The injection of the phosphate containing solution into the calcium ion reservoir has resulted in structures varying from membranes to crystals. Dynamical phase diagrams are constructed by varying chemical composition and flow rates from which three different growth mechanisms have been revealed. The microstructural analysis by scanning electron microscopy and powder X-ray diffraction confirmed the morphological transition from membrane tubes to crystalline branches upon decreasing pH.

Self-assembly to synchrony of active gels.

Self-assembly functionalizes active constituents to perform rhythmic activities. Here, our results show that the capillary-Marangoni interaction of irregularly moving gel beads develops complex patterns at the air-liquid interface. The collective behavior of the self-assembled structures exhibits breathing dynamics, polygonal oscillating rings, and cluster synchrony of chains. Interestingly, the trapping of soft particles generates relay synchronization of a rotor. Swarming of clusters is found to form rhythmic shrinking and expanding multiple-ring patterns. The development of self-organized spatiotemporal patterns of our active gel system provides a new way of creating collective oscillations.

Self-propulsion of a calcium alginate surfer.

A droplet of sodium alginate dripped into calcium chloride solution results in plate or boat shaped hydrogels. Both exhibit several minute-long self-propelled motion on the liquid surface without any extra fuel added, offering a new method to making active materials. By changing the initial concentrations, we are able to tune the transient dynamic activities from translational to rotational or stop-and-run motion. Dynamics are governed by osmotic pressure induced Marangoni effect, depending on the density difference and initial concentrations.