Nonenzymatic dual glucose sensing on boronic acid modified zeolitic imidazolate framework-67 nanoparticles for diabetes management.

For early diabetes identification and management, the progression of an uncomplicated and exceedingly responsive glucose testing technology is crucial. In this study, we present a new sensor incorporating a composite of metal organic framework (MOF) based on cobalt, coated with boronic acid to facilitate selective glucose binding. Additionally, we successfully employed a highly sensitive electro-optical immunosensor for the detection of subtle changes in concentration of the diabetes biomarker glycated haemoglobin (HbA1c), using zeolitic imidazolate framework-67 (ZIF-67) coated with polydopamine which further modified with boronic acid. Utilizing the polymerization characteristics of dopamine and the NH2 groups, a bonding structure is formed between ZIF-67 and 4-carboxyphenylboronic acid. ZIF-67 composite served as an effective substrate for immobilising 4-carboxyphenylboronic acid binding agent, ensuring precise and highly selective glucose identification. The sensing response was evaluated through both electrochemical and optical methods, confirming its efficacy. Under optimized experimental condition, the ZIF-67 based sensor demonstrated a broad detection range of 50-500 mg dL-1, a low limit of detection (LOD) of 9.87 mg dL-1 and a high correlation coefficient of 0.98. Furthermore, the 4-carboxyphenylboronic acid-conjugated ZIF-67-based sensor platform exhibited remarkable sensitivity and selectivity in optical-based detection for glycated haemoglobin within the clinical range of 4.7-11.3%, achieving a LOD of 3.7%. These findings highlight the potential of the 4-carboxyphenylboronic acid-conjugated ZIF-67-based electro-optical sensor as a highly sensitive platform for diabetes detection.

Sub-operon promoter arrangement of disA facilitates c-di-AMP homeostasis and selective stress responses in Mycobacterium smegmatis.

Bacterial second messenger signaling often plays an important role in cellular physiology. In this study, we have attempted to understand how c-di-AMP synthesis and degradation are transcriptionally regulated in Mycobacterium smegmatis. We found that although a c-di-AMP synthesis gene, disA, exists in a multi-gene operon, a sub-operon promoter arrangement facilitates disA gene expression under normal conditions to maintain intracellular c-di-AMP concentration and is induced further during certain stress adaptations. Individual gene-specific promoters also play a key role under various genotoxic stress conditions to shut down c-di-AMP synthesis, which could otherwise be detrimental for cells. Further, we learned that a high c-di-AMP concentration plays a role in the autoregulation of the disA promoter to limit intracellular c-di-AMP concentration. This study was helpful to understand how c-di-AMP synthesis is regulated under normal and stress conditions linked to its physiological relevance in M. smegmatis.

Novel markers of COVID-19 mortality-A comparative study with patients of acute coronary syndrome.

Background: COVID-19 can cause severe pneumonia that can progress to multiple organ failure. It is believed that dysregulation of inflammation and cytokine storm, contributes to severe COVID-19. As inflammatory mediators play an important role in the pathogenesis of the severe disease, inflammatory markers like fever, leucocytosis, and C-reactive protein are known to predict severe disease. Various other biomarkers have been known to have prognostic value in patients with COVID-19 infection. Inflammation, both local and systemic plays an important role in the pathogenesis of acute coronary syndrome (ACS). Thus in this study, we aimed to compare and describe the various biomarkers, and mortality between patients admitted with COVID-19 infection and ACS patients without COVID-19 infection. Methods: In a retrospective observational case-control study, a total of 108 patients admitted to our hospital during the month of May 2021 with COVID-19 were enrolled. Patients of the acute coronary syndrome (tested negative for COVID-19 infection) admitted during the same month were enrolled (including both the intensive care unit and ward) as controls. Results: The median age of patients with COVID was significantly lower than that of patients with acute coronary syndrome [49 years (IQR, 36-62 years) and 60 years (IQR, 52-66 years)]. Left ventricular ejection fraction was significantly higher among patients with COVID infection (58.5 ± 6.3% versus 36.9 ± 9.3%). The total leukocyte count was significantly higher among patients with COVID-19 compared to those with acute coronary syndrome [13200 per microliter (8625-17500) vs 9800 per microliter (8150-12150), P < 0.001]. The blood urea level was significantly higher among patients with COVID infection [52.5 (IQR, 34.7-81.5) versus 20 (IQR, 16-31)]. Levels of C-reactive protein were significantly higher among patients with COVID [39 (IQR, 7.7-100) versus 2 (1.4-3.5)]. The mortality of patients hospitalized with COVID was 4 times higher than those with acute coronary syndrome [25.9% (28) versus 6.1% (6)]. Survivors of COVID-19 had higher hemoglobin levels than those who did not [12.5 g/dLvs 11.5 g/dL, P = 0.03]. Conclusions: Elevated total leukocyte counts reflect underlying secondary bacterial infection among patients with COVID-19 and help initiate appropriate antibiotics. Depletion of intravascular volume reflected by an increased urea/creatinine ratio increases the risk of mortality and warrants aggressive measures of rehydration and albumin infusion.

Elucidating the role of c-di-AMP in Mycobacterium smegmatis: Phenotypic characterization and functional analysis.

Cyclic-di-AMP (c-di-AMP) is an important secondary messenger molecule that plays a critical role in monitoring several important cellular processes, especially in several Gram-positive bacteria. In this study, we seek to unravel the physiological significance of the molecule c-di-AMP in Mycobacterium smegmatis under different conditions, using strains with altered c-di-AMP levels: c-di-AMP null mutant (ΔdisA) and a c-di-AMP over-expression mutant (Δpde). Our thorough analysis of the mutants revealed that the intracellular concentration of c-di-AMP could determine many basic phenotypes such as colony architecture, cell shape, cell size, membrane permeability etc. Additionally, it was shown to play a significant role in multiple stress adaptation pathways in the case of different DNA and membrane stresses. Our study also revealed how the biofilm phenotypes of M. smegmatis cells are altered with high intracellular c-di-AMP concentration. Next, we checked how c-di-AMP contributes to antibiotic resistance or susceptibility characteristics of M. smegmatis, which was followed by a detailed transcriptome profile analysis to reveal key genes and pathways such as translation, arginine biosynthesis, cell wall and plasma membrane are regulated by c-di-AMP in mycobacteria.

Synthesis of Polyfunctionalized Pyrroles via a Tandem Reaction of Michael Addition and Intramolecular Cyanide-Mediated Nitrile-to-Nitrile Condensation.

A new approach for the synthesis of tetrasubstituted/functionalized NH-pyrroles from gem-diactivated acrylonitriles and TMSCN has been developed. The strategy utilizes the generation of vic-dinitrile via Michael addition and cyanide-mediated nitrile-to-nitrile cyclocondensation, which proceed in tandem guided by manifold roles of "CN". An extended application to the production of fused pyrrole has also been realized.

A nitrile-stabilized ammonium ylide as a masked C-C[double bond, length as m-dash]N synthon in heterocyclization with amidine-imine: 3-component assembly to fused pyrimidine scaffolds.

A unique reactivity of a nitrile-stabilized quaternary ammonium ylide as a masked C-C[double bond, length as m-dash]N synthon in contrast to its usual sigmatropic rearrangement has been demonstrated. Its reaction with 2-aminopyridine-derived aldimine undergoes electronically-assisted nucleophilic additions and Hofmann elimination, and provides a new method to access fused pyrimidines.

Neonatal Hypoxic-ischemic Encephalopathy: A Radiological Review.

Neonatal hypoxic-ischemic encephalopathy (HIE) is a devastating condition that may result in death or severe neurologic deficits in children. Neuroimaging with cranial ultrasound (US), computed tomography and magnetic resonance imaging are valuable tools in the workup of patients with HIE. The pattern of brain injury depends on the severity and duration of hypoxia and degree of brain maturation. Mild to moderate HI injury results in periventricular leukomalacia and germinal matrix bleed in preterm neonates, and parasagittal watershed infarcts in full-term neonates. Severe HI injury involves deep gray matter in both term and preterm infants. Treatment of HIE is largely supportive. The current article reviews the etiopathophysiology and clinical manifestations of HIE, role of imaging in the evaluation of the condition, patterns of brain injury in term and preterm neonates, the treatment and the prognosis.

Central Nervous System Tuberculosis: An Imaging Perspective.

The increasing prevalence of tuberculosis in both immunocompetent and immunocompromised individuals in recent years makes the disease a topic of universal concern. It has insidious onset and can affect virtually any organ system in the body, including the central nervous system (CNS). CNS tuberculosis (TB) is becoming more and more complex and atypical with onset of multidrug-resistant TB. Routine diagnostic techniques using serology and body tissue are time consuming and may delay the definitive management. Hence, it is important to be familiar with various radiologic features of CNS TB to ensure early and accurate diagnosis, thereby reducing high morbidity and mortality associated with the disease. The newer imaging techniques further help to improve the characterization and diagnosis of atypical CNS TB. The authors review the imaging characteristics of different forms of CNS tuberculosis involving the brain and spine and discuss the role of advanced imaging modalities in differentiating CNS TB from other disease process.

The diabetic pregnancy: An ultrasonographic perspective.

The incidence of congenital foetal anomalies and perinatal mortality in diabetic pregnancy is much higher than that in the normal pregnancy. The purpose of this review is to evaluate the role of ultrasound in the management of pregnancy complicated by diabetes. The ultrasound has been found to be very useful for foetal surveillance, assessment of diabetes related foetal complications, image guided interventions and in the obstetric management of the pregnancies complicated by diabetes.

Identification of leads for antiproliferative activity on MDA-MB-435 human breast cancer cells through pharmacophore and CYP1A1-mediated metabolism.

CYP1A1 is a potential target for anticancer drug development due to its overexpression in certain cancer cells and role in cancer progression. To identify new leads for CYP1A1 mediated anticancer action, we attempted ligand based pharmacophore mapping, virtual screening of databases, molecular docking, MetaSite based filtering, and molecular dynamics simulations. Initial computational and in vitro screening identified 11 compounds from which we identified two lead compounds, ZINC33468944 and ZINC32101539, showed potential antitumor activity on MDA-MB-435 cell lines (GI50 < 0.1 µM) and CYP1A1 inhibition of 0.13 and 0.3 µM, respectively. Furthermore, the lead compounds were evaluated for CYP1A1 mediated metabolism, showing N-hydroxylated metabolites, which have potential of DNA adduct formation and cause cancerous cell death. Analysis of molecular dynamics simulations provided important guidelines for the further modification of the lead compounds. Hence, we claim the lead molecules for further development in anticancer drug discovery.

Novel Combretastatin-2-aminoimidazole Analogues as Potent Tubulin Assembly Inhibitors: Exploration of Unique Pharmacophoric Impact of Bridging Skeleton and Aryl Moiety.

Combretastatin A-4 (CA-4) in phosphate and serine pro-drug forms is under phase II clinical trials. With our interest of discovering CA-4 inspired new chemical entities, a novel series of 4,5-diaryl-2-aminoimidazole analogues of the compound was designed and synthesized by an efficient and diversity feasible route involving atom economical arene C-H bond arylation. Interestingly, four compounds showed potent cell-based antiproliferative activities in nanomolar concentrations. Among the compounds, compound 12 inhibited the proliferation of several types of cancer cells much more efficiently than CA-4. It depolymerized microtubules, induced spindle defects, and stalled mitosis in cells. Compound 12 bound to tubulin and inhibited the polymerization of tubulin in vitro. In addition, podophyllotoxin and CA-4 inhibited the binding of compound 12 to tubulin. The distinctive pharmacophoric features of the bridging motif as well as quinoline nucleus were explored. We noted also a valuable quality of compound 12 as a potential probe in characterizing new CA-4 analogues.

Oxidative Dearomatization of Indoles via Pd-Catalyzed C-H Oxygenation: An Entry to C2-Quaternary Indolin-3-ones.

An oxidative dearomatization chemistry of 2-arylindole via a unique pathway involving Pd-catalyzed C-H peroxygenation is documented. Coupled with cascade transformation, it provides a new route to access indolin-3-ones bearing a C2-quaternary functionality, including a chiral center (indoxyls), a motif prevalent in indole alkaloids but synthetically underexplored. The method is chemo- and regioselective and compatible with versatile substrates. A mechanism has been outlined on the basis of results of control experiments, isolation/use of intermediates, and spectroscopic studies.

Switch in Site of Inhibition: A Strategy for Structure-Based Discovery of Human Topoisomerase IIα Catalytic Inhibitors.

A study of structure-based modulation of known ligands of hTopoIIα, an important enzyme involved in DNA processes, coupled with synthesis and in vitro assays led to the establishment of a strategy of rational switch in mode of inhibition of the enzyme's catalytic cycle. 6-Arylated derivatives of known imidazopyridine ligands were found to be selective inhibitors of hTopoIIα, while not showing TopoI inhibition and DNA binding. Interestingly, while the parent imidazopyridines acted as ATP-competitive inhibitors, arylated derivatives inhibited DNA cleavage similar to merbarone, indicating a switch in mode of inhibition from ATP-hydrolysis to the DNA-cleavage stage of catalytic cycle of the enzyme. The 6-aryl-imidazopyridines were relatively more cytotoxic than etoposide in cancer cells and less toxic to normal cells. Such unprecedented strategy will encourage research on "choice-based change" in target-specific mode of action for rapid drug discovery.

Radiology and diabetes mellitus.

Diabetes mellitus (DM) is a major health concern globally, affecting almost every organ of the body. A major issue with DM is that a relatively large proportion of patients remain undiagnosed till the development of complications, many of which may cause permanent impairment. Therefore, early recognition of the radiological manifestations (of DM) is of utmost importance, so that the disease may be diagnosed and managed well in time. Some common and important radiological features encountered in practice are compiled in this article.

Radiography in primary care diabetes.

Diabetes mellitus is a relatively common disease, and a variety of plain radiographic changes are frequently encountered in diabetic patients. Primary care physicians should be able to recognize these common x-ray findings so that early treatment may be started, thereby preventing disease progression and decreasing patient morbidity.

Efficiency of hysteroscopic visualization of bubaline uterus.

Abattoir derived buffalo genitalia (n=98) were evaluated for uterine pathology employing palpable, ultrasonographic and hysteroscopic visualization. A high proportion (45.92%) of genitalia evidenced uterine pathology including endometritis (14.29%), pyometra (7.14%), hemorrhages in the endometrium (14.29%) and mucometra (6.12%). The sensitivity and specificity of hysteroscopy was 100% for endometritis and hemorrhages whereas for same conditions ultrasonography and palpation had low sensitivity and specificity. For pyometra and mucometra the sensitivity and specificity of ultrasonography and hysteroscopy was similar. It was concluded that for the diagnosis of minor pathological changes in the uterus such as endometritis and hemorrhages which can hamper fertility hysteroscopy is more efficient technique.