Serum Resistin as a Potential Mortality Predictor in Neonatal Sepsis.

Aim The aim of this study was to investigate the utility of serum resistin levels as a prognostic indicator for mortality in neonates diagnosed with sepsis. Methodology This one-year prospective study at Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences (PGIMS), Rohtak, India, included 151 neonates categorized into two groups based on blood culture results: group 1 (n=86) included those with culture-negative, probable sepsis and group 2 (n=65) included those with culture-positive, proven sepsis. Blood samples obtained pre-treatment underwent comprehensive analysis, including complete blood count, C-reactive protein assessment, micro-erythrocyte sedimentation rate, and resistin level measurement via enzyme-linked immunosorbent assay. The comparison between groups was conducted using either the Student t-test or the Mann-Whitney U test, while correlations were assessed using the Spearman correlation. These analyses were employed to identify the optimal resistin cut-off for distinguishing patients with sepsis. A p-value of <0.05 was considered statistically significant. Results This study with 151 neonates diagnosed with sepsis found a significant association (p < 0.05) between elevated serum resistin levels and increased mortality risk. Multivariate analysis confirmed an independent predictive role of resistin. Elevated resistin levels correlate with higher chances of requiring mechanical ventilation and prolonged hospital stays. These findings highlight serum resistin's potential as a prognostic tool for the early identification of high-risk neonatal sepsis patients. Conclusion This study highlights the link between elevated serum resistin levels and increased mortality risk in neonatal sepsis, supported by strong multivariate analysis, indicating an independent predictive role. Additionally, resistin correlates with higher chances of mechanical ventilation and prolonged hospitalization, suggesting its potential as a prognostic marker for early identification of high-risk neonatal sepsis cases.

Trifluoromethyl-ß-dicarbonyls as Versatile Synthons in Synthesis of Heterocycles.

Trifluoromethyl group relishes a privileged position in the realm of medicinal chemistry because its incorporation into organic molecules often enhances the bioactivity by altering pharmacological profile of molecule. Trifluoromethyl-ß-dicarbonyls have emerged as pivotal building blocks in synthetic organic chemistry due to their facile accessibility, stability and remarkable versatility. Owing to presence of nucleophilic and electrophilic sites, they offer multifunctional sites for the reaction. This review covers a meticulous exploration of their multifaceted role, encompassing an in-depth analysis of mechanism, extensive scope, limitations and wide-ranging applications in diverse organic synthesis, covering the literature from the 21st century. This comprehensive review encapsulates the applications of trifluoromethyl-ß-dicarbonyls and their synthetic equivalents as precursors of complex and diverse heterocyclic scaffolds, fused heterocycles and spirocyclic compounds having medicinal and material importance. Their potent synthetic utility in cyclocondensation reactions with binucleophiles, cycloaddition reactions, C-C bond formations, asymmetric multicomponent reactions using classical/solvent-free/catalytic synthesis have been presented. Influence of unsymmetrical trifluoromethyl-ß-diketones on regioselectivity of transformation is also reviewed. This review will benefit the synthetic and pharmaceutical communities to explore trifluoromethyl-ß-dicarbonyls as trifluoromethyl building blocks for fabrication of heterocyclic scaffolds having implementation into drug discovery programs in the imminent future.

Uncommon presentation of granulomatosis with polyangiitis: Prostate involvement.

Granulomatosis with polyangiitis (GPA) is an autoimmune granulomatous disease of unknown etiology; frequently associated with anti-proteinase 3 antineutrophil cytoplasmic antibody (PR3-ANCA). Although any organ can be involved, prostatic involvement in GPA is very rare. We present a male patient with GPA, 26 years old, with pulmonary manifestations and prostatic involvement who underwent exhaustive evaluation. The patient's laboratory tests and imaging scans showed evidence of lesions in multiple areas, including the prostate. Histopathological testing confirmed that the lesions were consistent with granulomatosis with polyangiitis. The patient was treated with oral steroids and rituximab and showed significant improvement. He was later maintained on azathioprine without any relapse.

Visible Light-Prompted Regioselective Synthesis of Novel 5-Aroyl/hetaroyl-2',4-dimethyl-2,4'-bithiazoles as DNA- and BSA-Targeting Agents.

Organic transformations mediated by visible light have gained popularity in recent years as they are green, renewable, inexpensive, and clean and yield excellent products. The present study describes cyclo-condensation of 2-methylthiazole-4-carbothioamide with differently substituted α-bromo-1,3-diketones achieved by utilizing a white light-emitting diode (LED) (9W) to accomplish the regioselective synthesis of novel 5-aroyl/hetaroyl-2',4-dimethyl-2,4'-bithiazole derivatives as DNA/bovine serum albumin (BSA)-targeting agents. The structure characterization of the exact regioisomer was achieved unequivocally by heteronuclear two-dimensional nuclear magnetic resonance (2D-NMR) spectroscopy [1H-13C] HMBC; [1H-13C] HMQC; and [1H-15N] HMBC. In silico toxicity studies indicated that the synthesized compounds exhibit low toxicity risks and adhere to the rules of oral bioavailability without any exception. Computational molecular modeling of the bithiazole derivatives with the dodecamer sequence of the DNA duplex and BSA identified 5-(4-chlorobenzoyl)-2',4-dimethyl-2,4'-bithiazole 7g as the most suitable derivative that can interact effectively with these biomolecules. Furthermore, theoretical results concurred with the ex vivo binding mode of the 7g with calf thymus DNA (ct-DNA) and BSA through a variety of spectroscopic techniques, viz., ultraviolet-visible (UV-visible), circular dichroism (CD), steady-state fluorescence, and competitive displacement assay, along with viscosity measurements.

Near-thermo-neutral electron recombination of titanium oxide ions.

While the dissociative recombination (DR) of ground-state molecular ions with low-energy free electrons is generally known to be exothermic, it has been predicted to be endothermic for a class of transition-metal oxide ions. To understand this unusual case, the electron recombination of titanium oxide ions (TiO+) with electrons has been experimentally investigated using the Cryogenic Storage Ring. In its low radiation field, the TiO+ ions relax internally to low rotational excitation (≲100 K). Under controlled collision energies down to ∼2 meV within the merged electron and ion beam configuration, fragment imaging has been applied to determine the kinetic energy released to Ti and O neutral reaction products. Detailed analysis of the fragment imaging data considering the reactant and product excitation channels reveals an endothermicity for the TiO+ dissociative electron recombination of (+4 ± 10) meV. This result improves the accuracy of the energy balance by a factor of 7 compared to that found indirectly from hitherto known molecular properties. Conversely, the present endothermicity yields improved dissociation energy values for D0(TiO) = (6.824 ± 0.010) eV and D0(TiO+) = (6.832 ± 0.010) eV. All thermochemistry values were compared to new coupled-cluster calculations and found to be in good agreement. Moreover, absolute rate coefficients for the electron recombination of rotationally relaxed ions have been measured, yielding an upper limit of 1 × 10-7 cm3 s-1 for typical conditions of cold astrophysical media. Strong variation of the DR rate with the TiO+ internal excitation is predicted. Furthermore, potential energy curves for TiO+ and TiO have been calculated using a multi-reference configuration interaction method to constrain quantum-dynamical paths driving the observed TiO+ electron recombination.

An Explicative Review on the Progress of Quinazoline Scaffold as Bioactive Agents in the Past Decade.

In the last decade, quinazoline has been one of the most explored scaffolds by researchers around the globe in medicinal chemistry. Its unique structural features provide a wide range of substitutions for nitrogen and carbonyl groups. In the current situation of COVID-19, hydroxychloroquine, an antimalarial drug of the quinoline category, was used for the treatment of severe infections. Various substitution patterns, hybrids, and conjugates of quinazoline have been developed and studied for various pharmacological activities like anticancer, anti-inflammatory, antimalarial, antitubercular, etc. The scaffold can be considered a potential molecule for various pharmacological activities, especially antimicrobial and anti-hypertensive. This review article aims to study the physicochemical properties, chemistry, and pharmacological profile of quinazoline.

Effectiveness of "Resuscitation Cover All" in Minimizing COVID-19 Transmission to Health-Care Workers during Cardiopulmonary Resuscitation.

Introduction: Coronavirus disease 2019 (COVID-19) is a highly contagious disease transmitted by contact, droplets, and aerosols. Front line health-care workers (HCWs), particularly emergency physicians and acute care providers, are vulnerable to being exposed while treating their sick patients. Despite appropriate personal protective equipment use, HCW gets infected, suggesting the need for multiple layers of protection such as barrier devices. Methods: We aimed to determine the effectiveness of our novel "Resuscitation Cover All"(RCA) in reducing the exposure of HCW to simulated respiratory particles and its feasibility during cardio pulmonary resuscitation (CPR). This was a pilot simulation-based study. Five CPR simulation sessions were performed in Standard and RCA protocols, individually. Exposures through contact, droplets, and aerosols were simulated using a standardized volume of liquid detergent. Under Wood's lamp illumination, exposures of participants were compared between the protocols. Rate and depth of chest compressions, time taken to intubate, interruptions in CPR, and first-pass success were analyzed. Results: Overall mean exposure in standard protocol was 4950.4 ± 1461.6 (95%confidence interval [CI]:3135.7-6765.2) sq.pixels and RCA protocol was 2203.6 ± 1499.0 (95%CI: 342.4-4064.9) sq.pixels (P = 0.019). In standard, chest compressor had the highest exposure of 3066.6 ± 1419.2 (95%CI: 2051.3-4081.9) sq.pixels followed by defibrillator assistant 1166.4 ± 767.4 (95%CI: 617.4-1715.4) sq.pixels. Chest compressor of RCA had reduced exposure compared to that of standard (P < 0.001). Hands were the most frequently exposed body part. Airway manager of RCA had no exposure over head and neck in any session. No significant difference in CPR performance metrics was observed. Conclusion: This pilot simulation-based study shows that the novel RCA device could minimize the exposure of HCW to simulated respiratory particles during CPR. Also, it might not alter the high-quality CPR performance metrics. We need more real-life evidence.

Visible-Light-Prompted Synthesis and Binding Studies of 5,6-Dihydroimidazo[2,1-b]thiazoles with BSA and DNA Using Biophysical and Computational Methods.

Fused heterocyclic systems containing a bridgehead nitrogen atom have emerged as imperative pharmacophores in the design and development of new drugs. Among these heterocyclic moieties, the imidazothiazole scaffold has long been used in medicinal chemistry for the treatment of various diseases. In this study, we have established a simplistic and environmentally safe regioselective protocol for the synthesis of 5,6-dihydroimidazo[2,1-b]thiazole derivatives from easily available reactants. The reaction proceeds through in situ formation of the α-bromodiketones ensuing trap with imidazolidine-2-thione to provide these versatile bicyclic heterocycles in excellent yields. The synthesized compounds were screened through the molecular docking approach for the most stable complex formation with bovine serum albumin (BSA) and calf thymus deoxyribonucleic acid (ctDNA). The selected compound was further studied using ex vivo binding studies, which revealed moderate interactions with BSA and ctDNA. The binding studies were performed using biophysical approaches including UV-visible spectroscopy, steady-state fluorescence, circular dichroism (CD), and viscosity parameters.

Visible-light driven regioselective synthesis, characterization and binding studies of 2-aroyl-3-methyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidines with DNA and BSA using biophysical and computational techniques.

In recent times, fused azaheterocycles emerged as impressive therapeutic agents. Binding studies of such azaheterocycles with biomolecules is an important subject for pharmaceutical and biochemical studies aiming at the design and development of new drugs. Fused heterocyclic scaffolds, such as thiazolopyrmidines have long been used in the pharmaceutical industry for the treatment of various diseases. In this study, we have accomplished a regioselective synthesis of 2-aroyl-3-methyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidines by the reaction of tetrahydropyrimidine-2(H)-thione with α-bromo-1,3-diketones, generated in situ from 1,3-diketones and NBS, using visible light as an inexpensive, green and renewable energy source under mild reaction conditions with wide-ranging substrate scope. The regioisomer was characterized unambiguously by 2D-NMR [1H-13C] HMBC and [1H-13C] HMQC spectroscopy. In silico toxicity data analysis showed the low toxicity risks of the synthesized compounds. Computational molecular docking studies were carried out to examine the interaction of thiazolo[3,2-a]pyrimidines with calf-thymus DNA (ct-DNA) and Bovine Serum Albumin (BSA). Moreover, different spectroscopic approaches viz. steady-state fluorescence, competitive displacement assay, UV-visible and circular dichroism (CD) along with viscosity measurements were employed to investigate the binding mechanisms of thiazolo[3,2-a]pyrimidines with DNA and BSA. The results thus obtained revealed that thiazolo[3,2-a]pyrimidines offer groove bindings with DNA and showed moderate bindings with BSA.

Noncanonical secondary structures arising from non-B DNA motifs are determinants of mutagenesis.

Somatic mutations show variation in density across cancer genomes. Previous studies have shown that chromatin organization and replication time domains are correlated with, and thus predictive of, this variation. Here, we analyze 1809 whole-genome sequences from 10 cancer types to show that a subset of repetitive DNA sequences, called non-B motifs that predict noncanonical secondary structure formation can independently account for variation in mutation density. Combined with epigenetic factors and replication timing, the variance explained can be improved to 43%-76%. Approximately twofold mutation enrichment is observed directly within non-B motifs, is focused on exposed structural components, and is dependent on physical properties that are optimal for secondary structure formation. Therefore, there is mounting evidence that secondary structures arising from non-B motifs are not simply associated with increased mutation density-they are possibly causally implicated. Our results suggest that they are determinants of mutagenesis and increase the likelihood of recurrent mutations in the genome. This analysis calls for caution in the interpretation of recurrent mutations and highlights the importance of taking non-B motifs that can simply be inferred from the reference sequence into consideration in background models of mutability henceforth.

MPRAnator: a web-based tool for the design of massively parallel reporter assay experiments.

MOTIVATION: With the rapid advances in DNA synthesis and sequencing technologies and the continuing decline in the associated costs, high-throughput experiments can be performed to investigate the regulatory role of thousands of oligonucleotide sequences simultaneously. Nevertheless, designing high-throughput reporter assay experiments such as massively parallel reporter assays (MPRAs) and similar methods remains challenging. RESULTS: We introduce MPRAnator, a set of tools that facilitate rapid design of MPRA experiments. With MPRA Motif design, a set of variables provides fine control of how motifs are placed into sequences, thereby allowing the investigation of the rules that govern transcription factor (TF) occupancy. MPRA single-nucleotide polymorphism design can be used to systematically examine the functional effects of single or combinations of single-nucleotide polymorphisms at regulatory sequences. Finally, the Transmutation tool allows for the design of negative controls by permitting scrambling, reversing, complementing or introducing multiple random mutations in the input sequences or motifs. AVAILABILITY AND IMPLEMENTATION: MPRAnator tool set is implemented in Python, Perl and Javascript and is freely available at www.genomegeek.com and www.sanger.ac.uk/science/tools/mpranator The source code is available on www.github.com/hemberg-lab/MPRAnator/ under the MIT license. The REST API allows programmatic access to MPRAnator using simple URLs. CONTACT: igs@sanger.ac.uk or mh26@sanger.ac.ukSupplementary information: Supplementary data are available at Bioinformatics online.