ABSTRACT
Application of an aqueous Zn-ion battery is plagued by a water-induced hydrogen evolution reaction (HER), resulting in local pH variations and an unstable electrode-electrolyte interface (EEI) with uncontrolled Zn plating and side reactions. Here, 4-methyl pyridine N-oxide (PNO) is introduced as a redox non-innocent additive that comprises a hydrophilic bipolar N+-O- ion pair as a coordinating ligand for Zn and a hydrophobic âCH3 group at the para position of the pyridine ring that reduces water activity at the EEI, thereby enhancing stability. The N+-O- moiety of PNO possesses the unique functionality of an efficient push electron donor and pull electron acceptor, thus maintaining the desired pH during charging/discharging. Intriguingly, replacing âCH3 (electron pushing +I effect) by âCF3 group (electron pulling âI effect), however, does not improve the reversibility; instead, it degrades the cell performance. The electrolyte with 2 m ZnSO4 + 15 mm PNO enables symmetric cell Zn plating/stripping for a remarkable > 10 000 h at 0.5 mA cm-2 and exhibits coulombic efficiency (CE) ≈99.61% at 0.8 mA cm-2 in Zn/Cu asymmetric cell. This work showcases the immense interplay of the electron push-pull of the additives on the cycling.
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A transition metal-free, atom-economical, and highly stereospecific synthetic approach to Friedel-Crafts-type alkylation of arenes/heteroarenes has been developed. The protocol involves the catalytic aminium radical-cation salt (Magic Blue)-initiated SN2-type nucleophilic ring opening of activated aziridines with arenes/heteroarenes to give the corresponding 2,2-diarylethylamines up to 99% yield and 85% ee (for nonracemic aziridines) in a very short reaction time. Moreover, on reaction with 1,3-dimethylindole and benzofuran, aziridines undergo domino-ring-opening cyclization (DROC) to give the various biologically significant heterocyclic scaffolds in moderate to good yields.
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A simple one-pot, two-step strategy for the synthesis of tetrahydro-1H-azepino[4,3,2-cd]indoles via Lewis acid-catalyzed SN2-type ring opening of activated azetidines with 4-bromoindole, followed by a Pd-catalyzed intramolecular C-N cyclization reaction, with good to excellent yields is described. Utilizing this protocol, the vasopressin V2 receptor antagonist precursor has been synthesized easily. Enantioenriched tetrahydro-1H-azepino[4,3,2-cd]indoles were obtained by starting from enantiopure azetidine.
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BACKGROUND: The epidemiological characterization of endometriosis, particularly with regard to its incidence, has been inadequate to date both in Germany and other countries. The goal of this study was to determine trends in the incidence of diagnosed endometriosis and changes in age structure at the time of first diagnosis over the period 2014-2022. METHODS: Nationwide claims data from physicians in private practice, obtained according to relevant German law (§ 295 SGB V), were used to identify the population at risk for a first assured diagnosis of endometriosis (ICD-10-GM: N80) during each year of the study period, consisting of women and girls aged 10-52 who were insured by the statutory health insurance system and for whom at least two years of prior observation were possible. Patients were defined as incident if they were documented as having received a first confirmed diagnosis of endometriosis, according to the case definition, during the study year. The case definition comprised multiple options for validating the diagnosis. RESULTS: The incidence of diagnosed endometriosis rose over the period of the study from 2.8 per 1000 persons at risk in 2014 to 4.1 per 1000 in 2022, corresponding to a 44% relative increase. There was also a marked shift in age-specific incidence toward higher values at younger ages: the median age at diagnosis fell from 37 years (2014) to 34 (2022). CONCLUSION: This is the first study providing nationwide population-based data on the incidence of endometriosis in Germany. The observed rise in newly diagnosed cases is presumably mainly due to an increased awareness of endometriosis and to the growing recognition of the disease.
ABSTRACT
Dicarboxylate metallosurfactants (AASM), synthesized by mixing N-dodecyl aminomalonate, -aspartate and -glutamate with CaCl2, MnCl2 and CdCl2, were characterized by XRD, FTIR, and NMR spectroscopy. Layered structures, formed by metallosurfactants, were evidenced from differential scanning calorimetry and thermogravimetric analyses. Solvent-spread monolayer of AASM in combination with soyphosphatidylcholine (SPC) and cholesterol (CHOL) were studied using Langmuir surface balance. With increasing mole fraction of AASM mean molecular area increased and passed through maxima at ~60 mol% of AASMs, indicating molecular packing reorganization. Systems with 20 and 60 mol% AASM exhibited positive deviations from ideal behavior signifying repulsive interaction between the AASM and SPC, while synergistic interactions were established from the negative deviation at other combinations. Dynamic surface elasticity increased with increasing surface pressure signifying formation of rigid monolayer. Transition of monolayer from gaseous to liquid expanded to liquid condensed state was established by Brewster angle microscopic studies. Stability of the hybrid vesicles, formed by AASM+SPC+CHOL, was established by monitoring their size, zeta potential and polydispersity index values over 100 days. Size and spherical morphology of hybrid vesicles were confirmed by transmission electron microscopic studies. Biocompatibility of the hybrid vesicles were established by cytotoxicity studies revealing their possible applications in drug delivery and imaging.
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The effects of two ionic liquids (ILs), 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF4) and 1-butyl-1-methyl pyrrolidinium tetrafluoroborate ([bmp]BF4), on a mixture of phospholipids (PLs) 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), and 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol (DPPG) (6:3:1, M/M/M, 70% PL) in combination with 30 mol % cholesterol (CHOL) were investigated in the form of a solvent-spread monolayer and bilayer (vesicle). Surface pressure (π)-area (A) isotherm studies, using a Langmuir surface balance, revealed the formation of an expanded monolayer, while the cationic moiety of the IL molecules could electrostatically and hydrophobically bind to the PLs on the palisade layer. Turbidity, dynamic light scattering (size, ζ-potential, and polydispersity index), electron microscopy, small-angle X-ray/neutron scattering, fluorescence spectroscopy, and differential scanning calorimetric studies were carried out to evaluate the effects of IL on the structural organization of bilayer in the vesicles. The ILs could induce vesicle aggregation by acting as a "glue" at lower concentrations (<1.5 mM), while at higher concentrations, the ILs disrupt the bilayer structure. Besides, ILs could result in the thinning of the bilayer, evidenced from the scattering studies. Steady-state fluorescence anisotropy and lifetime studies suggest asymmetric insertion of ILs into the lipid bilayer. MTT assay using human blood lymphocytes indicates the safe application of vesicles in the presence of ILs, with a minimal toxicity of up to 2.5 mM IL in the dispersion. These results are proposed to have applications in the field of drug delivery systems with benign environmental impact.
Subject(s)
Ionic Liquids , Ionic Liquids/chemistry , Imidazoles/chemistry , Phospholipids/chemistry , Cholesterol/chemistry , Lipid Bilayers/chemistry , Surface Properties , 1,2-Dipalmitoylphosphatidylcholine/chemistryABSTRACT
Natural products as starting templates have shown historically major contribution to development of drugs. Inspired by the structure-function of an anticancer natural alkaloid Rutaecarpine, the Scaffold-hopped Acyclic Analogues of Rutaecarpine (SAAR) with 'N'-atom switch (1°-hop) and ring-opening (2°-hop) were investigated. A new synthetic route was developed for an effective access to the analogues, i.e. 2-indolyl-pyrido[1,2-a]pyrimidinones, which involved preparation of N-Boc-N'-phthaloyltryptamine/mexamine-bromides and pyridopyrmidinon-2-yl triflate, a nickel/palladium-catalysed Ullmann cross-coupling of these bromides and triflate, deprotection of phthalimide followed by N-aroylation, and Boc-deprotection. Fourteen novel SAAR-compounds were prepared, and they showed characteristic antiproliferative activity against various cancer cells. Three most active compounds (11a, 11b, and 11c) exhibited good antiproliferative activity, IC50 7.7-15.8 µM against human breast adenocarcinoma cells (MCF-7), lung cancer cells (A549), and colon cancer cells (HCT-116). The antiproliferative property was also observed in the colony formation assay. The SAAR compound 11b was found to have superior potency than original natural product Rutaecarpine and an anticancer drug 5-FU in antiproliferative activities with relatively lower cytotoxicity towards normal breast epithelial cells (MCF10A) and significantly higher inhibitory effect on cancer cells' migration. The compound 11b was found to possess favourable in silico physicochemical characteristics (lipophilicity-MLOGP, TPSA, and water solubility-ESOL, and others), bioavailability score, and pharmacokinetic properties (GI absorption, BBB non-permeant, P-gp, and CYP2D6). Interestingly, the compound 11b did not show any medicinal chemistry structural alert of PAINS and Brenk filter. The study represents for the first time the successful discovery of new potent anticancer chemotypes using Rutaecarpine natural alkaloid as starting template and reaffirms the significance of natural product-inspired scaffold-hopping technique in drug discovery research.
Subject(s)
Antineoplastic Agents , Cell Proliferation , Drug Screening Assays, Antitumor , Indole Alkaloids , Quinazolines , Humans , Quinazolines/chemistry , Quinazolines/pharmacology , Quinazolines/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Indole Alkaloids/chemistry , Indole Alkaloids/pharmacology , Indole Alkaloids/chemical synthesis , Cell Proliferation/drug effects , Structure-Activity Relationship , Molecular Structure , Cell Line, Tumor , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Pyrimidinones/chemical synthesis , Indoles/chemistry , Indoles/pharmacology , Indoles/chemical synthesis , Dose-Response Relationship, Drug , QuinazolinonesABSTRACT
Introduction: Routine immunization programs have focused on increasing vaccination coverage, which is equally important for decreasing vaccine-preventable diseases (VPDs), particularly in low- and lower-middle-income countries (LMICs). We estimated the trends and projections of age-appropriate vaccination coverage at the regional and national levels, as well as place of residence and wealth index in LMICs. Methods: In total, 174 nationally representative household surveys from 2000 to 2020 from 41 LMICs were included in this study. Bayesian hierarchical regression models were used to estimate trends and projections of age-appropriate vaccination. Results: The trend in coverage of age-appropriate Bacillus Calmette-Guérin (BCG), third dose of diphtheria, tetanus, and pertussis (DTP3), third dose of polio (polio3), and measles-containing vaccine (MCV) increased rapidly from 2000 to 2020 in LMICs. Findings indicate substantial increases at the regional and national levels, and by area of residence and socioeconomic status between 2000 and 2030. The largest rise was observed in East Africa, followed by South and Southeast Asia. However, out of the 41 countries, only 10 countries are estimated to achieve 90% coverage of the BCG vaccine by 2030, five of DTP3, three of polio3, and none of MCV. Additionally, by 2030, wider pro-urban and -rich inequalities are expected in several African countries. Conclusion: Significant progress in age-appropriate vaccination coverage has been made in LMICs from 2000 to 2020. Despite this, projections show many countries will not meet the 2030 coverage goals, with persistent urban-rural and socioeconomic disparities. Therefore, LMICs must prioritize underperforming areas and reduce inequalities through stronger health systems and increased community engagement to ensure high coverage and equitable vaccine access.
Subject(s)
Developing Countries , Immunization Programs , Vaccination Coverage , Humans , Vaccination Coverage/statistics & numerical data , Vaccination Coverage/trends , Developing Countries/statistics & numerical data , Asia , Africa South of the Sahara , Immunization Programs/statistics & numerical data , Immunization Programs/trends , Infant , Child, Preschool , Bayes Theorem , Vaccination/statistics & numerical data , Vaccination/trendsABSTRACT
A variety of complications and associated clinical presentations may be seen in patients with cirrhotic and non-cirrhotic portal hypertension. We present one such case of Upper GI hemorrhage from ectopic duodenal varices in a case of pre-hepatic portal hypertension due to Extrahepatic Portal Venous Obstruction (EHPVO). The case was managed successfully with endovascular Portal Vein Recanalization (PVR) and metallic stent deployment. With adequate technical success, improved symptoms, and laboratory parameters, the patient was discharged on long-term anticoagulation and interval follow-up.
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Background: The burden of hepatitis C virus (HCV) in India is alarming, with a major share of this virus being witnessed in patients with end-stage renal disease (ESRD). A pan-genotypic combination of sofosbuvir and velpatasvir is found to be safe, effective, and economical in resource-constraint countries such as ours. However, there are scanty data on the efficacy and safety of sofosbuvir and velpatasvir combination in patients with ESRD. Hence, we performed this study to evaluate the safety and efficacy of the combination of sofosbuvir and velpatasvir in patients of chronic hepatitis C (CHC) with ESRD. Methods: This is an observational study comprising of 40 CHC patients with ESRD on maintenance hemodialysis. All patients were treated with a fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks in case of non-cirrhotic or compensated cirrhosis and 24 weeks in case of decompensated cirrhosis. The efficacy was assessed by sustained virological response defined by negative HCV RNA at 12 weeks (sustained virological response [SVR] 12) post treatment, and safety was assessed by recording any side-effects of all patients. Results: Out of the 40 patients enrolled in our study, majority were non-cirrhotic (77%), and all were treatment-naive. The mean age was 49.87 ± 12.13 years, and 80% patients were male. The mean baseline HCV RNA was 2.61 ± 7.83 × 106 IU/ml. All the 40 patients (100%) achieved undetectable HCV RNA at the end of treatment; however, 39 patients (97.5%) achieved SVR 12. There was no significant deterioration of estimated glomerular filtration rate (eGFR) after completion of antiviral therapy as compared to the baseline eGFR (13.27 ± 10.32 vs13.54 ± 11.38, P = 0.54). None of the patients reported any serious adverse effects during treatment. Conclusion: The fixed-dose combination of sofosbuvir and velpatasvir is effective and has showed excellent safety profile in patients of CHC with ESRD.
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ABSTRACT: Alpha-fetoprotein-producing gastric cancer is a rare variant of gastric adenocarcinoma. This tumor is likely to be misdiagnosed, particularly in patients with liver metastasis. This rare subgroup of gastric carcinoma may show divergent differentiation on histology and may pose a diagnostic challenge to the pathologist. They have an aggressive course with a dismal prognosis.
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OBJECTIVES: Cardiac surgery for coronary artery disease was dramatically reduced during the first wave of the COVID-19 pandemic. Many patients with disease ordinarily treated with coronary artery bypass grafting (CABG) instead underwent percutaneous coronary intervention (PCI). We sought to describe 12-month outcomes following PCI in patients who would typically have undergone CABG. METHODS: Between March 1 and July 31, 2020, patients who received revascularization with PCI when CABG would have been the primary choice of revascularization were enrolled in the prospective, multicenter UK-ReVasc Registry. We evaluated the following major adverse cardiovascular events at 12 months: all-cause mortality, myocardial infarction, repeat revascularization, stroke, major bleeding, and stent thrombosis. RESULTS: A total of 215 patients were enrolled across 45 PCI centers in the United Kingdom. Twelve-month follow up data were obtained for 97% of the cases. There were 9 deaths (4.3%), 5 myocardial infarctions (2.4%), 12 repeat revascularizations (5.7%), 1 stroke (0.5%), 3 major bleeds (1.4%), and no cases of stent thrombosis. No difference in the primary endpoint was observed between patients who received complete vs incomplete revascularization (residual SYNTAX score £ 8 vs > 8) (P = .22). CONCLUSIONS: In patients with patterns of coronary disease in whom CABG would have been the primary therapeutic choice outside of the pandemic, PCI was associated with acceptable outcomes at 12 months of follow-up. Contemporary randomized trials that compare PCI to CABG in such patient cohorts may be warranted.
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Campylobacter jejuni is a human pathogen and a leading cause of food poisoning in North America and Europe. The exterior surface of the bacterial cell wall is attached to a polymeric coat of sugar molecules known as the capsular polysaccharide (CPS) that helps protect the organism from the host immune response. The CPS is composed of a repeating sequence of common and unusual sugar residues. In the HS:11 serotype of C. jejuni, we identified two enzymes in the gene cluster for CPS formation that are utilized for the biosynthesis of UDP-α-N-acetyl-d-mannosaminuronic acid (UDP-ManNAcA). In the first step, UDP-α-N-acetyl-d-glucosamine (UDP-GlcNAc) is epimerized at C2 to form UDP-α-N-acetyl-d-mannosamine (UDP-ManNAc). This product is then oxidized by a NAD+-dependent C6-dehydrogenase to form UDP-ManNAcA. In the HS:6 serotype (C. jejuni strain 81116), we identified three enzymes that are required for the biosynthesis of CMP-ß-N-acetyl-d-neuraminic acid (CMP-Neu5Ac). In the first step, UDP-GlcNAc is epimerized at C2 and subsequently hydrolyzed to form N-acetyl-d-mannosamine (ManNAc) with the release of UDP. This product is then condensed with PEP by N-acetyl-d-neuraminate synthase to form N-acetyl-d-neuraminic acid (Neu5Ac). In the final step, CMP-N-acetyl-d-neuraminic acid synthase utilizes CTP to convert this product into CMP-Neu5Ac. A bioinformatic analysis of these five enzymes from C. jejuni serotypes HS:11 and HS:6 identified other bacterial species that can produce UDP-ManNAcA or CMP-Neu5Ac for CPS formation.
Subject(s)
Campylobacter jejuni , Cytidine Monophosphate/analogs & derivatives , Sialic Acids , Uronic Acids , Humans , Polysaccharides , Neuraminic Acids , Sugars , Uridine DiphosphateABSTRACT
Campylobacter jejuni is a Gram-negative pathogenic bacterium commonly found in chickens and is the leading cause of human diarrheal disease worldwide. The various serotypes of C. jejuni produce structurally distinct capsular polysaccharides (CPSs) on the exterior surfaces of the cell wall. The capsular polysaccharide from C. jejuni serotype HS:5 is composed of a repeating sequence of d-glycero-d-manno-heptose and d-glucitol-6-phosphate. We previously defined the pathway for the production of d-glycero-d-manno-heptose in C. jejuni. Here, we elucidate the biosynthetic pathway for the assembly of cytidine diphosphate (CDP)-6-d-glucitol by the combined action of two previously uncharacterized enzymes. The first enzyme catalyzes the formation of CDP-6-d-fructose from cytidine triphosphate (CTP) and d-fructose-6-phosphate. The second enzyme reduces CDP-6-d-fructose with NADPH to generate CDP-6-d-glucitol. Using sequence similarity network (SSN) and genome neighborhood network (GNN) analyses, we predict that these pairs of proteins are responsible for the biosynthesis of CDP-6-d-glucitol and/or CDP-d-mannitol in the lipopolysaccharides (LPSs) and capsular polysaccharides in more than 200 other organisms. In addition, high resolution X-ray structures of the second enzyme are reported, which provide novel insight into the manner in which an open-chain nucleotide-linked sugar is harbored in an active site cleft.
Subject(s)
Campylobacter jejuni , Animals , Humans , Sorbitol/metabolism , Chickens/metabolism , Polysaccharides/metabolism , Cytidine Diphosphate/metabolism , Fructose/metabolism , Polysaccharides, Bacterial/metabolismABSTRACT
A simple and atom economic protocol for the construction of C-X/C-C bonds via catalytic aminium radical-cation salt (Magic Blue)-initiated SN2-type nucleophilic ring-opening transformations of racemic and nonracemic aziridines with different hetero and carbon nucleophiles to afford various amino ethers, thioethers, and amines in up to 99% yield, and with perfect enantiospecificity for some substrates but reduced ee with others (for nonracemic aziridines), is developed. This aminium radical-cation salt-initiated, SN2-type nucleophilic ring-opening strategy, along with various cyclization protocols, is employed to synthesize various biologically significant compounds.
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In this work, we report the first example of two crystal solvates of an anthracene-benzhydrazide based molecule (Ant) that display very distinct photo-responsive behaviour when 365 or 405â nm or visible light is illuminated. For the first time, the crystal hydrate that has water molecule in the lattice (hereafter named as Ant-H2O) display fascinating puffing behavior with large volume expansion upto 50 % accompanied with surface modulation when illuminated with 405â nm light, a phenomenon very much similar to the rice or popcorn puffing by thermal treatment. Utilizing the properties of photoconverted Ant-H2O crystals, we have demonstrated their application in photoinduced enhanced liquid absorption using various liquids/solutions. The other crystal solvate having DMF in the crystal lattice (hereafter named as Ant-DMF) responds to 405â nm light by bending, twisting, chopping, jumping or splitting etc. The chopping of Ant-DMF crystal was also observed under ambient/white light but at a slower rate compared to 405â nm light. Single crystal X-ray diffraction study reveals that the photoinduced puffing and photomechanical effects of these materials are rooted to the topochemical [4+4] cycloaddition reaction between the anthracene moieties that facilitate molecular packing change assisted by the reconfiguration of intermolecular non-covalent interactions involving lattice trapped solvent molecules.
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Apyrase (APY) enzymes are nucleoside triphosphate (NTP) diphosphohydrolases that can remove the terminal phosphate from NTPs and nucleoside diphosphates but not from nucleoside monophosphates. They have conserved structures and functions in yeast, plants, and animals. Among the most studied APYs in plants are those in Arabidopsis (Arabidopsis thaliana; AtAPYs) and pea (Pisum sativum; PsAPYs), both of which have been shown to play major roles in regulating plant growth and development. Valuable insights on their functional roles have been gained by transgenically altering their transcript abundance, either by constitutively expressing or suppressing APY genes. This review focuses on recent studies that have provided insights on the mechanisms by which APY activity promotes growth in different organisms. Most of these studies have used transgenic lines that constitutively expressed APY in multiple different plants and in yeast. As APY enzymatic activity can also be changed post-translationally by chemical blockage, this review also briefly covers studies that used inhibitors to suppress APY activity in plants and fungi. It concludes by summarizing some of the main unanswered questions about how APYs regulate plant growth and proposes approaches to answering them.
Subject(s)
Arabidopsis , Saccharomyces cerevisiae , Animals , Apyrase/genetics , Nucleosides , Arabidopsis/genetics , Nucleotides , Pisum sativumABSTRACT
Hepatocellular carcinoma (HCC) presents significant treatment challenges despite considerable advancements in its management. The Indian National Association for the Study of the Liver (INASL) first published its guidelines to aid healthcare professionals in the diagnosis and treatment of HCC in 2014. These guidelines were subsequently updated in 2019. However, INASL has recognized the need to revise its guidelines in 2023 due to recent rapid advancements in the diagnosis and management of HCC, particularly for intermediate and advanced stages. The aim is to provide healthcare professionals with evidence-based recommendations tailored to the Indian context. To accomplish this, a task force was formed, and a two-day round table discussion was held in Puri, Odisha. During this event, experts in their respective fields deliberated and finalized consensus statements to develop these updated guidelines. The 2023 INASL guidelines offer a comprehensive framework for the diagnosis, staging, and management of intermediate and advanced HCC in India. They represent a significant step forward in standardizing clinical practices nationwide, with the primary objective of ensuring that patients with HCC receive the best possible care based on the latest evidence. The guidelines cover various topics related to intermediate and advanced HCC, including biomarkers of aggressive behavior, staging, treatment options, and follow-up care.