Novel hybrids of 1,2,3-triazole-benzoxazole: design, synthesis, and assessment of DprE1 enzyme inhibitors using fluorometric assay and computational analysis.

Decaprenylphosphoryl-ß-D-ribose-oxidase (DprE1), a subunit of the essential decaprenylphosphoribose-2'-epimerase, plays a crucial role in the synthesis of cell wall arabinan components in mycobacteria, including the pathogen responsible for tuberculosis, Mycobacterium tuberculosis. In this study, we designed, synthesised, and evaluated 15 (BOK-1-BOK-10 and BOP-1-BOP-5) potential inhibitors of DprE1 from a series of 1,2,3-triazole ligands using a validated DprE1 inhibition assay. Two compounds, BOK-2 and BOK-3, demonstrated significant inhibition with IC50 values of 2.2 ± 0.1 and 3.0 ± 0.6 µM, respectively, whereas the standard drug (TCA-1) showed inhibition at 3.0 ± 0.2 µM. Through molecular modelling and dynamic simulations, we explored the structural relationships between selected 1,2,3-triazole compounds and DprE1, revealing key features for effective drug-target interactions. This study introduces a novel approach for designing ligands against DprE1, offering a potential therapeutic strategy for tuberculosis treatment.

Identification of 15 (BOK-1­BOK-10 and BOP-1­BOP-5) potent inhibitors of DprE1 enzyme from 1,2,3-triazole ligands.BOK-2 and BOK-3 exhibited significant DprE1 inhibition with IC₅₀ values of 2.2 ± 0.1 and 3.0 ± 0.6 µM, respectively.Molecular modelling and dynamic simulations elucidated key structural features for effective drug­target interactions.Novel approach introduced for designing DprE1 ligands, potentially aiding tuberculosis treatment.Findings offer promising candidates for future tuberculosis research.

A case of pleural Mycobacterium tuberculosis infection with reversion of Quantiferon Gold Plus results from positive to negative.

Introduction. Mycobacterium tuberculosis (MTB) infections continue to have a high mortality and morbidity burden globally. Interferon-gamma release assays such as Quantiferon Gold Plus (QFG-Plus) aid in diagnosis of latent TB but diagnosis of pleural TB remains challenging. We present a case of active pleural MTB infection with reversion from positive to negative of IGRA result as well as negative Xpert MTB/RIF Ultra PCR result from tissues obtained from pleural biopsy. Case summary. A 52-year-old otherwise healthy male presented in August 2022 with a 2 week history of pleuritic chest pain associated with modest elevation in inflammatory markers. The patient had had a positive QFG-Plus result in 2018, however QFG-Plus during this admission was negative. Computed-tomography pulmonary angiogram and needle thoracocentesis showed an exudative left pleural effusion with predominant lymphocytes. The patient's symptoms failed to resolve with empiric antimicrobial therapy for community-acquired pneumonia. Broncho-alveolar lavage as well as biopsies of pleural tissues via video-assisted thoracoscopic surgery from the left lower lobe yielded negative results on routine microbiological culture as well as Xpert Ultra PCR. Growth of acid-fast bacilli was noted from mycobacterial cultures of pleural tissues which was identified as MTB. Conclusion. Despite significant technological advances, microbiological diagnosis of MTB infections remains challenging. We document QFG-Plus reversion during development from latent to active pleural TB. Decline in the ability of CD4+ and CD8+ T cells to produce interferon gamma in response to TB antigens (ESAT-6 and CFP-10) was likely associated with loss of host control of latent MTB. This case serves as a reminder that despite exhaustive testing with state-of-art diagnostic platforms, MTB infections can still elude discovery.

Revisiting the role of the spindle assembly checkpoint in the formation of gross chromosomal rearrangements in Saccharomyces cerevisiae.

Multiple pathways are known to suppress the formation of gross chromosomal rearrangements (GCRs), which can cause human diseases including cancer. In contrast, much less is known about pathways that promote their formation. The spindle assembly checkpoint (SAC), which ensures the proper separation of chromosomes during mitosis, has been reported to promote GCR, possibly by delaying mitosis to allow GCR-inducing DNA repair to occur. Here we show that this conclusion is the result of an experimental artifact arising from the synthetic lethality caused by disruption of the SAC and loss of the CIN8 gene, which is often lost in the genetic assay used to select for GCRs. After correcting for this artifact, we find no role of the SAC in promoting GCR.

Low-Cost Ni-W Catalysts Supported on Glucose/Carbon Nanotube Hybrid Carbons for Sustainable Ethylene Glycol Synthesis.

The production of ethylene glycol (EG) from cellulose has garnered significant attention in recent years as an attractive alternative to fossil fuels due to the potential of cellulose as a renewable and sustainable feedstock. In this work, to the best of our knowledge, a series of low-cost Ni-W bimetallic catalysts supported on glucose/carbon nanotube hybrid carbons were synthesised for the first time and employed to transform cellulose into EG. Two different strategies were combined for the preparation of the carbons: the activation and addition of carbon nanotubes (CNTs) to obtain a hybrid material (AG-CNT). The catalytic conversion process proceeded through cellulose hydrolysis to glucose, followed by glucose retro-aldol condensation to glycolaldehyde and its subsequent hydrogenation to EG. Through the optimisation of the catalyst's properties, particularly the metals' content, a good synergistic effect of C-C bond cleavage and hydrogenation capabilities was assured, resulting in the highly selective production of EG. The balance between Ni and W active sites was confirmed to be a crucial parameter. Thus, total cellulose conversion (100%) was achieved with EG yields of 60-62%, which are amongst the best yields ever reported for the catalytic conversion of cellulose into EG via carbon-supported catalysts.

Cellulose from bacteria as a delivery system for improved treatment of infectious diseases: A review of updates and prospects.

Cellulose from bacteria is a high-purity biomaterial naturally produced by bacteria as part of their metabolic process. Although it inherently lacks antimicrobial activity, its modification with bioactive substances can significantly enhance its efficacy beyond that of the original compounds. This biomaterial features a unique ability to retain substantial quantities of liquids within its three-dimensional network, making it a prime candidate for biomedical applications. Versatile in its properties, it can be utilized across various industries. Previous research has highlighted its capacity to exhibit antimicrobial properties and to encapsulate nanostructured materials, thereby augmenting its antibacterial effectiveness. This review focuses on the use of cellulose from bacteria as a carrier for active compounds, specifically targeting antibacterial activity against drug-resistant strains. We explore its role in innovative bacterial cellulose-based systems, which present a promising solution for tackling bacterial resistance. This review aims to showcase the potential of bacterial cellulose in developing new devices and treatment strategies that address critical concerns in global health.

Impact of antiparasitic used in livestock: effects of ivermectin spiked sediment in Prochilodus lineatus, an inland fishery species of South America.

Ivermectin (IVM) is a widely used antiparasitic. Concerns have been raised about its environmental effects in the wetlands of Río de la Plata basin where cattle have been treated with IVM for years. This study investigated the sublethal effects of environmentally relevant IVM concentrations in sediments on the Neotropical fish Prochilodus lineatus. Juvenile P. lineatus were exposed to IVM-spiked sediments (2 and 20 µg/Kg) for 14 days, alongside a control sediment treatment without IVM. Biochemical and oxidative stress responses were assessed in brain, gills, and liver tissues, including lipid damage, glutathione levels, enzyme activities, and antioxidant competence. Muscle and brain acetylcholinesterase activity (AChE) and stable isotopes of 13C and 15N in muscle were also measured. The lowest IVM treatment resulted in an increase in brain lipid peroxidation, as measured by thiobarbituric acid reactive substances (TBARs), decreased levels of reduced glutathione (GSH) in gills and liver, increased catalase activity (CAT) in the liver, and decreased antioxidant capacity against peroxyl radicals (ACAP) in gills and liver. The highest IVM treatment significantly reduced GSH in the liver. Muscle (AChE) was decreased in both treatments. Multivariate analysis showed significant overall effects in the liver tissue, followed by gills and brain. These findings demonstrate the sublethal effects of IVM in P. lineatus, emphasizing the importance of considering sediment contamination and trophic habits in realistic exposure scenarios.

Non-conductive silicon-containing materials improve methane production by pure cultures of methanogens.

Conductive materials (CM) enhance methanogenesis, but there is no clear correlation between conductivity and faster methane production (MP) rates. We investigated if MP by pure cultures of methanogens (Methanobacterium formicicum, Methanospirillum hungatei, Methanothrix harundinacea and Methanosarcina barkeri) is affected by CM (activated carbon (AC), magnetite), and other sustainable alternatives (sand and glass beads, without conductivity, and zeolites (Zeo)). The significant impact of the materials was on M. formicicum as MP was significantly accelerated by non-CM (e.g., sand reduced the lag phase (LP) duration by 48 %), Zeo and AC (LP reduction in 71% and 75 %, respectively). Conductivity was not correlated with LP reduction. Instead, silicon content in the materials was inversely correlated with the time required for complete MP, and silicon per se stimulated M. formicicum's activity. These findings highlight the potential of using non-CM silicon-containing materials in anaerobic digesters to accelerate methanogenesis.

Simulation-Based Training Program for Peripherally Inserted Central Catheter Placement: Randomized Comparative Study of in-Person Training With Synchronous Feedback Versus Distance Training With Asynchronous Feedback.

INTRODUCTION: Simulation training that includes deliberate practice is effective for procedural skill training. Delivering feedback remotely and asynchronously has been examined for more cost-efficient training. This prospective randomized study aimed to compare 2 feedback techniques for simulation training: synchronous direct feedback versus asynchronous distance feedback (ASYNC). METHODS: Forty anesthesia and internal medicine residents were recruited after study approval by the institutional ethics committee. Residents reviewed instructional material on an online platform and performed a pretraining assessment (PRE) for peripherally inserted central catheter (PICC) placement. Each resident was then randomly assigned to 1 of 2 training types, practice with synchronous direct feedback (SYNC) or practice with ASYNC. Training consisted of four, 1-hour practice sessions; each was conducted once per week. Both groups underwent posttraining evaluation (POST). The PRE and POST assessments were videotaped and evaluated by 2 independent, blinded reviewers using a global rating scale. RESULTS: Thirty-five residents completed the training program and both evaluations. Both groups had significantly improved global rating scale scores after 4 sessions. The SYNC group improved from 28 to 45 points (P < 0.01); the ASYNC group improved from 26.5 to 46 points (P < 0.01). We found no significant between-group differences for the PRE (P = 0.42) or POST assessments (P = 0.13). CONCLUSION: This simulation-based training program significantly improved residents' peripherally inserted central venous catheter placement skills using either modality. With these results, we are unable to demonstrate the superiority of synchronous feedback over ASYNC. Asynchronous feedback training modality represents a new, innovative approach for health care procedural skills training.

Homo- and Heterogeneous Benzyl Alcohol Catalytic Oxidation Promoted by Mononuclear Copper(II) Complexes: The Influence of the Ligand upon Product Conversion.

The catalytic properties of three copper complexes, [Cu(en)2](ClO4)2 (1), [Cu(amp)2](ClO4)2, (2) and [Cu(bpy)2](ClO4)2 (3) (where en = ethylenediamine, amp = 2-aminomethylpyridine and bpy = 2,2'-bipyridine), were explored upon the oxidation of benzyl alcohol (BnOH). Maximized conversions of the substrates to their respective products were obtained using a multivariate analysis approach, a powerful tool that allowed multiple variables to be optimized simultaneously, thus creating a more economical, fast and effective technique. Considering the studies in a fluid solution (homogeneous), all complexes strongly depended on the amount of the oxidizing agent (H2O2), followed by the catalyst load. In contrast, time seemed to be statistically less relevant for complexes 1 and 3 and not relevant for 2. All complexes showed high selectivity in their optimized conditions, and only benzaldehyde (BA) was obtained as a viable product. Quantitatively, the catalytic activity observed was 3 > 2 > 1, which is related to the π-acceptor character of the ligands employed in the study. Density functional theory (DFT) studies could corroborate this feature by correlating the geometric index for square pyramid Cu(II)-OOH species, which should be generated in the solution during the catalytic process. Complex 3 was successfully immobilized in silica-coated magnetic nanoparticles (Fe3O4@SiO2), and its oxidative activity was evaluated through heterogenous catalysis assays. Substrate conversion promoted by 3-Fe3O4@SiO2 generated only BA as a viable product, and the supported catalyst's recyclability was proven. Reduced catalytic conversions in the presence of the radical scavenger (2,2,6,6-tetrametil-piperidi-1-nil)oxil (TEMPO) indicate that radical and non-radical mechanisms are involved.

Long-term climate and hydrologic regimes shape stream invertebrate community responses to a hurricane disturbance.

Disturbances can produce a spectrum of short- and long-term ecological consequences that depend on complex interactions of the characteristics of the event, antecedent environmental conditions, and the intrinsic properties of resistance and resilience of the affected biological system. We used Hurricane Harvey's impact on coastal rivers of Texas to examine the roles of storm-related changes in hydrology and long-term precipitation regime on the response of stream invertebrate communities to hurricane disturbance. We detected declines in richness, diversity and total abundance following the storm, but responses were strongly tied to direct and indirect effects of long-term aridity and short-term changes in stream hydrology. The amount of rainfall a site received drove both flood duration and flood magnitude across sites, but lower annual rainfall amounts (i.e. aridity) increased flood magnitude and decreased flood duration. Across all sites, flood duration was positively related to the time it took for invertebrate communities to return to a long-term baseline and flood magnitude drove larger invertebrate community responses (i.e. changes in diversity and total abundance). However, invertebrate response per unit flood magnitude was lower in sub-humid sites, potentially because of differences in refuge availability or ecological-evolutionary interactions. Interestingly, sub-humid streams had temporary large peaks in invertebrate total abundance and diversity following recovery period that may be indicative of the larger organic matter pulses expected in these systems because of their comparatively well-developed riparian vegetation. Our findings show that hydrology and long-term precipitation regime predictably affected invertebrate community responses and, thus, our work underscores the important influence of local climate to ecosystem sensitivity to disturbances.

Neural processing in the primary auditory cortex following cholinergic lesions of the basal forebrain in ferrets.

Cortical acetylcholine (ACh) release has been linked to various cognitive functions, including perceptual learning. We have previously shown that cortical cholinergic innervation is necessary for accurate sound localization in ferrets, as well as for their ability to adapt with training to altered spatial cues. To explore whether these behavioral deficits are associated with changes in the response properties of cortical neurons, we recorded neural activity in the primary auditory cortex (A1) of anesthetized ferrets in which cholinergic inputs had been reduced by making bilateral injections of the immunotoxin ME20.4-SAP in the nucleus basalis (NB) prior to training the animals. The pattern of spontaneous activity of A1 units recorded in the ferrets with cholinergic lesions (NB ACh-) was similar to that in controls, although the proportion of burst-type units was significantly lower. Depletion of ACh also resulted in more synchronous activity in A1. No changes in thresholds, frequency tuning or in the distribution of characteristic frequencies were found in these animals. When tested with normal acoustic inputs, the spatial sensitivity of A1 neurons in the NB ACh- ferrets and the distribution of their preferred interaural level differences also closely resembled those found in control animals, indicating that these properties had not been altered by sound localization training with one ear occluded. Simulating the animals' previous experience with a virtual earplug in one ear reduced the contralateral preference of A1 units in both groups, but caused azimuth sensitivity to change in slightly different ways, which may reflect the modest adaptation observed in the NB ACh- group. These results show that while ACh is required for behavioral adaptation to altered spatial cues, it is not required for maintenance of the spectral and spatial response properties of A1 neurons.

Improving access to cancer clinical research in Brazil: recent advances and new opportunities. Expert opinions from the 4th CURA meeting, São Paulo, 2023.

Clinical research is the cornerstone of improvements in cancer care. However, it has been conducted predominantly in high-income countries with few clinical trials available in Brazil and other low-and-middle-income countries (LMIC). Of note, less than one-third of registered clinical trials addressing some of the most commonly diagnosed cancers (breast, lung and cervical) recruited patients from LMIC in the last years. The Institute Project CURA promoted the fourth CURA meeting, discussing barriers to cancer clinical research and proposing potential solutions. A meeting was held in São Paulo, Brazil, in June 2023 with representatives from different sectors: Brazilian Health Regulatory Agency (Anvisa), National Commission of Ethics in Research (CONEP), non-governmental organisations, such as the Latin American Cooperative Oncology Group, the Brazilian Society of Clinical Oncology (SBOC), Contract Research Organisations, pharmaceutical companies and investigators. A total of 16 experts pointed out achievements as shortening the time of regulatory processes involving Anvisa and CONEP, development of staff training programs, maintenance of the National Program of Oncological Attention (PRONON), and the foundation of qualified centres in North and Northeast Brazilian regions. Participants also highlighted the need to be more competitive in the field, which requires optimising ongoing policies and implementing new strategies as decentralisation of clinical research centres, public awareness campaigns, community-centered approaches, collaborations and partnerships, expansion of physicians-directed policies, exploring the role of the steering committee. Active and consistent reporting of the initiatives might help to propagate ongoing advances, increasing Brazilian participation in clinical cancer research. Engagement of all players is crucial to maintain continuous progress with further improvements in critical points including regulatory timelines and increments in qualified human resources which aligned with new educational initiatives focused on physicians and the general population will expand access to cancer clinical trials in Brazil.

High sodium, rather than high blood pressure, induces immune cell activation and renal infiltration in ovariectomized adult Wistar rats.

We used an animal model of salt-sensitive hypertension (SSH) in which ovariectomized (oVx) rats developed hypertension with high salt (HS) intake. Hypertension is accompanied by changes in the percentage of CD4+ T lymphocytes, immune CD45+ cell infiltration into renal tissue, and changes in Na+, K+- ATPase (NKA) expression in both renal tissue and peripheral blood mononuclear cells (PBMCs). To determine whether the observed changes resulted from HS intake, high blood pressure, or both, hydralazine (HDZ) was used to lower blood pressure. The oVx HS rats received two HDZ schedules either to prevent or to treat hypertension. NKA was overexpressed in the kidneys of all oVx groups and in PBMCs of oVx HS rats. This pattern was not altered with HDZ treatment. Changes in CD4+ T lymphocytes and renal infiltration of CD45+ cells were not reversed either. High salt, but not high blood pressure, induces immune cell activation and renal infiltration. Overexpressed NKA is the primary event, and HS is the perturbation to the system in this model of SSH, which resembles the postmenopausal state.

International cooperation in radiology training: A multipronged approach.

INTRODUCTION: Medical imaging has undergone significant technical advancements in recent years, posing a considerable challenge for radiologists to stay up-to-date with emerging modalities and their applications in daily practice. This challenge is even more daunting in developing countries with limited resources compared to the US and other developed nations with greater economic assets. The collaboration between the United States and other advanced nations with radiological institutions in Latin America has been a significant achievement in the pursuit of new opportunities for continuous medical education. The aim of this study was to evaluate the effectiveness of international collaborations among Spanish-speaking Latin American institutions and radiologists through a survey. MATERIALS AND METHODS: A group of radiologists and institutions from various countries, including the USA, Spain, and Argentina, who have been working together for several years to improve Radiology education across Latin America, were selected. An online survey was conducted. The survey included questions about interest in the activities, participation, and impact of radiologic education during these educational efforts. RESULTS: The survey received responses from 166 participants, all of whom reported knowledge of at least one type of educational activity. The most well-known activity was ALAT Webinars. The primary motivators for participation were the quality of the content and the opportunity to learn new information. Additionally, improving local education in radiology and receiving expert advice on radiology issues were identified as priorities for participation in international collaborations. The Cronbach alpha coefficient was calculated for individual and global Likert questions, resulting in a global score of 0.96. CONCLUSION: The study confirms the significance of a multifaceted approach to address gaps in radiology education. While traditional models have relied on hosting international visitors or sending US teachers abroad, the results suggest that using a variety of methods will have a greater impact than relying on a single technique for those who benefit most from collaborative efforts.

The oral nucleoside prodrug GS-5245 is efficacious against SARS-CoV-2 and other endemic, epidemic, and enzootic coronaviruses.

Despite the wide availability of several safe and effective vaccines that prevent severe COVID-19, the persistent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that can evade vaccine-elicited immunity remains a global health concern. In addition, the emergence of SARS-CoV-2 VOCs that can evade therapeutic monoclonal antibodies underscores the need for additional, variant-resistant treatment strategies. Here, we characterize the antiviral activity of GS-5245, obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved viral RNA-dependent RNA polymerase (RdRp). We show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, SARS-CoV, SARS-CoV-related bat-CoV RsSHC014, Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant. Moreover, in mouse models of SARS-CoV, SARS-CoV-2 (WA/1 and Omicron B1.1.529), MERS-CoV, and bat-CoV RsSHC014 pathogenesis, we observed a dose-dependent reduction in viral replication, body weight loss, acute lung injury, and pulmonary function with GS-5245 therapy. Last, we demonstrate that a combination of GS-5245 and main protease (Mpro) inhibitor nirmatrelvir improved outcomes in vivo against SARS-CoV-2 compared with the single agents. Together, our data support the clinical evaluation of GS-5245 against coronaviruses that cause or have the potential to cause human disease.

The influence of thioether-substituted ligands in dicopper(II) complexes: Enhancing oxidation and biological activities.

This paper describes the synthesis, structural analysis, as well as the magnetic and spectroscopic characterizations of three new dicopper(II) complexes with dinucleating phenol-based ligands containing different thioether donor substituents: aromatic (1), aliphatic (2) or thiophene (3). Temperature-dependent magnetometry reveals the presence of antiferromagnetic coupling for 1 and 3 (J = -2.27 cm-1 and -5.01 cm-1, respectively, H = -2JS1S2) and ferromagnetic coupling for 2 (J = 5.72 cm-1). Broken symmetry DFT calculations attribute this behavior to a major contribution from the dz2 orbitals for 1 and 3, and from the dx2-y2 orbitals for 2, along with the p orbitals of the oxygens. The bioinspired catalytic activities of these complexes related to catechol oxidase were studied using 3,5-di-tert-butylcatechol as substrate. The order of catalytic rates for the substrate oxidation follows the trend 1 > 2 > 3 with kcat of (90.79 ± 2.90) × 10-3 for 1, (64.21 ± 0.99) × 10-3 for 2 and (14.20 ± 0.32) × 10-3 s-1 for 3. The complexes also cleave DNA through an oxidative mechanism with minor-groove preference, as indicated by experimental and molecular docking assays. Antimicrobial potential of these highly active complexes has shown that 3 inhibits both Staphylococcus aureus bacterium and Epidermophyton floccosum fungus. Notably, the complexes were found to be nontoxic to normal cells but exhibited cytotoxicity against epidermoid carcinoma cells, surpassing the activity of the metallodrug cisplatin. This research shows the multifaceted properties of these complexes, making them promising candidates for various applications in catalysis, nucleic acids research, and antimicrobial activities.

Genetic identification of three CITES-listed sharks using a paper-based Lab-on-a-Chip (LOC).

Threatened shark species are caught in large numbers by artisanal and commercial fisheries and traded globally. Monitoring both which shark species are caught and sold in fisheries, and the export of CITES-restricted products, are essential in reducing illegal fishing. Current methods for species identification rely on visual examination by experts or DNA barcoding techniques requiring specialist laboratory facilities and trained personnel. The need for specialist equipment and/or input from experts means many markets are currently not monitored. We have developed a paper-based Lab-on-a-Chip (LOC) to facilitate identification of three threatened and CITES-listed sharks, bigeye thresher (Alopias superciliosus), pelagic thresher (A. pelagicus) and shortfin mako shark (Isurus oxyrinchus) at market source. DNA was successfully extracted from shark meat and fin samples and combined with DNA amplification and visualisation using Loop Mediated Isothermal Amplification (LAMP) on the LOC. This resulted in the successful identification of the target species of sharks in under an hour, with a working positive and negative control. The LOC provided a simple "yes" or "no" result via a colour change from pink to yellow when one of the target species was present. The LOC serves as proof-of-concept (PoC) for field-based species identification as it does not require specialist facilities. It can be used by non-scientifically trained personnel, especially in areas where there are suspected high frequencies of mislabelling or for the identification of dried shark fins in seizures.