[LORENZO'S OIL AND ADRENOLEUKODYSTROPHY EXAMINING AN ARTIFICIAL INTELLIGENCE TOOL INTENDED FOR CONDUCTING LITERATURE SEARCHES AND ANALYSES].

Adrenoleukodystrophy is a genetic metabolic disorder characterized by a heterogeneous phenotype. Its severe form, known as cerebral adrenoleukodystrophy, involves unpredictable cerebral damage and progressive central nervous system deterioration. This rare condition became famous because of a Hollywood movie in which the Italian parents of a child with the condition supposedly discovered a medication for treating the condition.

Synthesis of 3-heteroaryl-pyrrolo[2,3-b]pyridines as potent inhibitors of AP-2-associated protein kinase 1 (AAK1) with antiviral activity.

Inhibition of AP-2-associated protein kinase 1 (AAK1) has been shown to be a promising avenue for the development of broad-spectrum antiviral agents. On a previously described AAK1 inhibitor based on a pyrrolo[2,3-b]pyridine scaffold, the concept of isosterism was applied, by replacing a carboxamide linker by various five-membered heterocycles. It led to the discovery of a novel series of AAK1 inhibitors with IC values in the low nM range, that also displayed antiviral activity against the dengue virus and Venezuelan equine encephalitis virus.

Replication capacity and susceptibility of nirmatrelvir-resistant mutants to next-generation Mpro inhibitors in a SARS-CoV-2 replicon system.

There is an ongoing need to expand the anti-SARS-CoV-2 armamentarium to include agents capable of suppressing replication of drug-resistant mutants emerging during monotherapy with approved direct-acting antivirals. Using a subgenomic SARS-CoV-2 replicon system, we studied the RNA replication capacity of nirmatrelvir (NTV)-resistant mutants and their susceptibility to next-generation Mpro inhibitors, including ibuzatrelvir (ITV), ensitrelvir (ETV), and ML2006a4. Our findings revealed that E166V Mpro mutants reduced viral RNA replication, whereas other Mpro mutations retained or increased the replication capacity, suggesting the potential of the latter to dominate under NTV selective pressure.

Using augmented intelligence to improve long term outcomes.

Purpose Of Review: For augmented intelligence (AI) tools to realize their potential, critical care clinicians must ensure they are designed to improve long-term outcomes. This overview is intended to align professionals with the state-of-the art of AI.

Recent Findings: Many AI tools are undergoing preliminary assessment of their ability to support the care of survivors and their caregivers at multiple time points after intensive care unit (ICU) discharge.

Anesthetic approach to pregnant patients with malaria: a narrative review of the literature.

Introduction: Anesthesiologists play an important role in the management of labor and delivery during acute malaria infection. The peripartum anesthesia considerations for such cases remain unclear.

Findings: Important peripartum considerations include the severity of thrombocytopenia and coagulopathy, hemodynamic status and cardiac disease, and the likelihood of central nervous system (CNS) involvement.

Back-Pocket Optimization of 2-Aminopyrimidine-Based Macrocycles Leads to Potent EPHA2/GAK Kinase Inhibitors.

Macrocyclization of acyclic compounds is a powerful strategy for improving inhibitor potency and selectivity. Here we have optimized 2-aminopyrimidine-based macrocycles to use these compounds as chemical tools for the ephrin kinase family. Starting with a promiscuous macrocyclic inhibitor, , we performed a structure-guided activity relationship and selectivity study using a panel of over 100 kinases.

Numb-associated kinases regulate sandfly-borne Toscana virus entry.

Sandfly-borne Toscana virus (TOSV) is an enveloped tri-segmented negative single-strand RNA . It is an emerging virus predominantly endemic in southwestern Europe and Northern Africa. Although TOSV infection is typically asymptomatic or results in mild febrile disease, it is neurovirulent and ranks among the three most common causes of summer meningitis in certain regions.

PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2.

In search for broad-spectrum antivirals, we discovered a small molecule inhibitor, RMC-113, that potently suppresses the replication of multiple RNA viruses including SARS-CoV-2 in human lung organoids. We demonstrated selective dual inhibition of the lipid kinases PIP4K2C and PIKfyve by RMC-113 and target engagement by its clickable analog. Advanced lipidomics revealed alteration of SARS-CoV-2-induced phosphoinositide signature by RMC-113 and linked its antiviral effect with functional PIP4K2C and PIKfyve inhibition.

The effect of ionic redistributions on the microwave dielectric response of cytosol water upon glucose uptake.

The sensitivity of cytosol water's microwave dielectric (MD) response to D-glucose uptake in Red Blood Cells (RBCs) allows the detailed study of cellular mechanisms as a function of controlled exposures to glucose and other related analytes like electrolytes. However, the underlying mechanism behind the sensitivity to glucose exposure remains a topic of debate. In this research, we utilize MDS within the frequency range of 0.

Dissemination of clinical and scientific practice through social media: a SIAARTI consensus-based document.

Background: Dissemination of medical practice and scientific information through social media (SoMe) by clinicians and researchers is increasing. Broad exposure of information can promote connectivity within the scientific community, overcome barriers to access to sources, increase debate, and reveal layperson perspectives and preferences. On the other hand, practices lacking scientific evidence may also be promoted, laypeople may misunderstand the professional message, and clinician may suffer erosion of professional status.

An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations.

Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing the severity of COVID-19, but the presence of resistance-conferring mutations in sequenced viral genomes raises concerns about future drug resistance. Second-generation oral drugs that retain function against these mutants are thus urgently needed. We hypothesized that the covalent hepatitis C virus protease inhibitor boceprevir (BPV) could serve as the basis for orally bioavailable drugs that inhibit SARS-CoV-2 M more efficiently than existing drugs.

Back-pocket optimization of 2-aminopyrimidine-based macrocycles leads to potent dual EPHA2/GAK kinase inhibitors with antiviral activity.

Macrocyclization of acyclic compounds is a powerful strategy for improving inhibitor potency and selectivity. Here, we developed a 2-aminopyrimidine-based macrocyclic dual EPHA2/GAK kinase inhibitor as a chemical tool to study the role of these two kinases in viral entry and assembly. Starting with a promiscuous macrocyclic inhibitor, , we performed a structure-guided activity relationship and selectivity study using a panel of over 100 kinases.

Chemical inactivation strategies for SARS-CoV-2-infected cells and organoids.

Infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) research, conducted in high-containment laboratories, requires transferring samples to lower containment labs for downstream applications, mandating sample inactivation. Here, we present a stepwise protocol for chemical inactivation of SARS-CoV-2 virus in culture supernatants or within infected cells and organoids, using eight chemical reagents validated via plaque assays. Additionally, we describe steps for troubleshooting virus inactivation, titer calculation, and log reduction.

Systems immunology of transcriptional responses to viral infection identifies conserved antiviral pathways across macaques and humans.

Viral pandemics and epidemics pose a significant global threat. While macaque models of viral disease are routinely used, it remains unclear how conserved antiviral responses are between macaques and humans. Therefore, we conducted a cross-species analysis of transcriptomic data from over 6,088 blood samples from macaques and humans infected with one of 31 viruses.

In-Hospital Violence and Its Impact on Critical Care Practitioners.

Objectives: To provide a narrative review of hospital violence (HV) and its impact on critical care clinicians.

Data Sources: Detailed search strategy using PubMed and OVID Medline for English language articles describing HV, risk factors, precipitating events, consequences, and mitigation strategies.

Study Selection: Studies that specifically addressed HV involving critical care medicine clinicians or their practice settings were selected.

Peri-operative night-time work of anaesthesiologists: A qualitative study of critical issues and proposals.

Background: Qualitative data on the opinions of anaesthesiologists regarding the impact of peri-operative night-time working conditions on patient safety are lacking.

Objectives: This study aimed to achieve in-depth understanding of anaesthesiologists' perceptions regarding the impact of night-time working conditions on peri-operative patient safety and actions that may be undertaken to mitigate perceived risks.

Design: Qualitative analysis of responses to two open-ended questions.

Global and cell type-specific immunological hallmarks of severe dengue progression identified via a systems immunology approach.

Severe dengue (SD) is a major cause of morbidity and mortality. To define dengue virus (DENV) target cells and immunological hallmarks of SD progression in children's blood, we integrated two single-cell approaches capturing cellular and viral elements: virus-inclusive single-cell RNA sequencing (viscRNA-Seq 2) and targeted proteomics with secretome analysis and functional assays. Beyond myeloid cells, in natural infection, B cells harbor replicating DENV capable of infecting permissive cells.

Single B cell transcriptomics identifies multiple isotypes of broadly neutralizing antibodies against flaviviruses.

Sequential dengue virus (DENV) infections often generate neutralizing antibodies against all four DENV serotypes and sometimes, Zika virus. Characterizing cross-flavivirus broadly neutralizing antibody (bnAb) responses can inform countermeasures that avoid enhancement of infection associated with non-neutralizing antibodies. Here, we used single cell transcriptomics to mine the bnAb repertoire following repeated DENV infections.