NaHCO3 modulates the bla operon and β-lactam susceptibility in borderline oxacillin-resistant Staphylococcus aureus (BORSA).

Background: Methicillin-resistant Staphylococcus aureus (MRSA) are resistant to nearly all β-lactam antibiotics under standard testing conditions. However, a novel phenotype exists wherein certain MRSA strains exhibit β-lactam susceptibility in the presence of bicarbonate (termed 'NaHCO3-responsive'), an abundant ion in mammalian tissues and blood. This suggests that specific MRSA infections may be treatable by β-lactams.

Phenotypic and genotypic correlates of the sodium bicarbonate-responsive phenotype among methicillin-resistant Staphylococcus aureus isolates from skin and soft-tissue infections.

Objectives: The objective of this study is to assess the frequency of the novel sodium bicarbonate (NaHCO)-responsive phenotype, wherein clinical methicillin-resistant Staphylococcus aureus (MRSA) isolates are rendered susceptible to standard-of-care β-lactams in the presence of NaHCO, in a collection of 103 clinical U.S. MRSA skin and soft-tissue infection (SSTI) isolates and 22 clinical European SSTI isolates.

Agreement of in-ear temperature to core body temperature measures during invasive whole-body cooling for hypothermic circulatory arrest in aortic arch surgery.

Targeted temperature management (TTM) with therapeutic hypothermia (TH) during aortic arch surgery requires valid estimations of core body temperature. The ear canal and epitympanic region might be an easy-to-assess, noninvasive site for the read-out of supra-aortic, cerebral temperature. This observational cohort study comparatively investigated in-ear temperature and different core body temperature (cBT) measurements during TTM/TH for moderate hypothermic circulatory arrest (mHCA) in aortic arch surgery.

Stress Response to Bicarbonate Depletion.

Bicarbonate and CO are essential substrates for carboxylation reactions in bacterial central metabolism. In , the bicarbonate transporter, MpsABC (membrane potential-generating system) is the only carbon concentrating system. An deletion mutant can hardly grow in ambient air.

Cytotoxic T cells drive doxorubicin-induced cardiac fibrosis and systolic dysfunction.

Doxorubicin, the most prescribed chemotherapeutic drug, causes dose-dependent cardiotoxicity and heart failure. However, our understanding of the immune response elicited by doxorubicin is limited. Here we show that an aberrant CD8 T cell immune response following doxorubicin-induced cardiac injury drives adverse remodeling and cardiomyopathy.

Genomic investigation and clinical correlates of the β-lactam: NaHCO responsiveness phenotype among methicillin-resistant isolates from a randomized clinical trial.

NaHCO responsiveness is a novel phenotype where some methicillin-resistant (MRSA) isolates exhibit significantly lower minimal inhibitory concentrations (MIC) to oxacillin and/or cefazolin in the presence of NaHCO. NaHCO responsiveness correlated with treatment response to β-lactams in an endocarditis animal model. We investigated whether treatment of NaHCO-responsive strains with β-lactams was associated with faster clearance of bacteremia.

Tensor modeling of MRSA bacteremia cytokine and transcriptional patterns reveals coordinated, outcome-associated immunological programs.

Methicillin-resistant (MRSA) bacteremia is a common and life-threatening infection that imposes up to 30% mortality even when appropriate therapy is used. Despite in vitro efficacy determined by minimum inhibitory concentration breakpoints, antibiotics often fail to resolve these infections in vivo, resulting in persistent MRSA bacteremia. Recently, several genetic, epigenetic, and proteomic correlates of persistent outcomes have been identified.

Deletion of MyD88 in T Cells Improves Antitumor Activity in Melanoma.

Cytotoxic CD8 T cells are central to the antitumor immune response by releasing cytotoxic granules that kill tumor cells. They are activated by antigen-presenting cells, which become activated by DAMPs (damage associated molecular patterns) through MyD88. However, the suppressive tumor microenvironment promotes T-cell tolerance to tumor antigens, in part by enhancing the activity of immune checkpoint molecules that prevent CD8 T-cell activation and cytotoxicity.

Phage-antibiotic synergy against daptomycin-nonsusceptible MRSA in an simulated endocardial pharmacokinetic/pharmacodynamic model.

Phage-antibiotic combinations (PAC) offer a potential solution for treating refractory daptomycin-nonsusceptible (DNS) methicillin-resistant (MRSA) infections. We examined PAC activity against two well-characterized DNS MRSA strains (C4 and C37) and . PACs comprising daptomycin (DAP) ± ceftaroline (CPT) and a two-phage cocktail (Intesti13 + Sb-1) were evaluated for phage-antibiotic synergy (PAS) against high MRSA inoculum (10 CFU/mL) using (i) modified checkerboards (CB), (ii) 24-h time-kill assays (TKA), and (iii) 168-h simulated endocardial vegetation (SEV) models.

The Engineered Lysin CF-370 Is Active Against Antibiotic-Resistant Gram-Negative Pathogens In Vitro and Synergizes With Meropenem in Experimental Pseudomonas aeruginosa Pneumonia.

Background: Lysins (cell wall hydrolases) targeting gram-negative organisms require engineering to permeabilize the outer membrane and access subjacent peptidoglycan to facilitate killing. In the current study, the potential clinical utility for the engineered lysin CF-370 was examined in vitro and in vivo against gram-negative pathogens important in human infections.

Methods: Minimum inhibitory concentration (MICs) and bactericidal activity were determined using standard methods.

Sensitizing methicillin-resistant (MRSA) to cefuroxime: the synergic effect of bicarbonate and the wall teichoic acid inhibitor ticlopidine.

Methicillin-resistant (MRSA) strains are a major challenge for clinicians due, in part, to their resistance to most β-lactams, the first-line treatment for methicillin-susceptible . A phenotype termed "NaHCO-responsiveness" has been identified, wherein many clinical MRSA isolates are rendered susceptible to standard-of-care β-lactams in the presence of physiologically relevant concentrations of NaHCO, and ; moreover, such "NaHCO-responsive" isolates can be effectively cleared by β-lactams from target tissues in experimental infective endocarditis (IE). One mechanistic impact of NaHCO exposure on NaHCO-responsive MRSA is to repress WTA synthesis.

The Purine Biosynthesis Repressor, PurR, Contributes to Vancomycin Susceptibility of Methicillin-resistant Staphylococcus aureus in Experimental Endocarditis.

Background: Staphylococcus aureus is the most common cause of life-threatening endovascular infections, including infective endocarditis (IE). These infections, especially when caused by methicillin-resistant strains (MRSA), feature limited therapeutic options and high morbidity and mortality rates.

Methods: Herein, we investigated the role of the purine biosynthesis repressor, PurR, in virulence factor expression and vancomycin (VAN) treatment outcomes in experimental IE due to MRSA.

A Modular Turn-On Strategy to Profile E2-Specific Ubiquitination Events in Living Cells.

A cascade of three enzymes, E1-E2-E3, is responsible for transferring ubiquitin to target proteins, which controls many different aspects of cellular signaling. The role of the E2 has been largely overlooked, despite influencing substrate identity, chain multiplicity, and topology. Here we report a method-targeted charging of ubiquitin to E2 (tCUbE)-that can track a tagged ubiquitin through its entire enzymatic cascade in living mammalian cells.

Fluorinated captopril analogues inhibit metallo-β-lactamases and facilitate structure determination of NDM-1 binding pose.

Bacterial resistance to the majority of clinically used β-lactam antibiotics is a global health threat and, consequently, the driving force for the development of metallo-β-lactamase (MBL) inhibitors. The rapid evolution of new MBLs calls for new strategies and tools for inhibitor development. In this study, we designed and developed a series of trifluoromethylated captopril analogues as probes for structural studies of enzyme-inhibitor binding.

AKT2 Loss Impairs BRAF-Mutant Melanoma Metastasis.

Despite recent advances in treatment, melanoma remains the deadliest form of skin cancer due to its highly metastatic nature. Melanomas harboring oncogenic BRAF mutations combined with PTEN loss exhibit unrestrained PI3K/AKT signaling and increased invasiveness. However, the contribution of different AKT isoforms to melanoma initiation, progression, and metastasis has not been comprehensively explored, and questions remain about whether individual isoforms play distinct or redundant roles in each step.

Impact of a ground intermediate transport from the helicopter landing site at a hospital on transport duration and patient safety.

Background: Helicopter emergency medical service provides timely care and rapid transport of severely injured or critically ill patients. Due to constructional or regulatory provisions at some hospitals, a remote helicopter landing site necessitates an intermediate ground transport to the emergency department by ambulance which might lengthen patient transport time and comprises the risk of disconnection or loss of vascular access lines, breathing tubes or impairment of other relevant equipment during the loading processes. The aim of this study was to evaluate if a ground intermediate transport at the hospital site prolonged patient transport times and operating times or increases complication rates.

Impaired T cell IRE1α/XBP1 signaling directs inflammation in experimental heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a widespread syndrome with limited therapeutic options and poorly understood immune pathophysiology. Using a 2-hit preclinical model of cardiometabolic HFpEF that induces obesity and hypertension, we found that cardiac T cell infiltration and lymphoid expansion occurred concomitantly with cardiac pathology and that diastolic dysfunction, cardiomyocyte hypertrophy, and cardiac phospholamban phosphorylation were T cell dependent. Heart-infiltrating T cells were not restricted to cardiac antigens and were uniquely characterized by impaired activation of the inositol-requiring enzyme 1α/X-box-binding protein 1 (IRE1α/XBP1) arm of the unfolded protein response.

Predictors and prognosis of population-based subjective cognitive decline: longitudinal evidence from the Caerphilly Prospective Study (CaPS).

Objectives: To understand associations between the subjective experience of cognitive decline and objective cognition. This subjective experience is often conceptualised as an early step towards neurodegeneration, but this has not been scrutinised at the population level. An alternative explanation is poor meta-cognition, the extreme of which is seen in functional cognitive disorder (FCD).

Benefits and trade-offs of optimizing global land use for food, water, and carbon.

Current large-scale patterns of land use reflect history, local traditions, and production costs, much more so than they reflect biophysical potential or global supply and demand for food and freshwater, or-more recently-climate change mitigation. We quantified alternative land-use allocations that consider trade-offs for these demands by combining a dynamic vegetation model and an optimization algorithm to determine Pareto-optimal land-use allocations under changing climate conditions in 2090-2099 and alternatively in 2033-2042. These form the outer bounds of the option space for global land-use transformation.

From drab to Fab; PLP1's fit is redressed for MS.

Curated expression of proteolipid protein 1 (PLP1) is essential for multiple sclerosis-derived autoantibody recognition.

A single polymorphic residue in humans underlies species-specific restriction of HSV-1 by the antiviral protein MxB.

Herpesviruses present a major global disease burden. Understanding the host cell mechanisms that block viral infections, as well as how viruses can evolve to counteract these host defenses, is critically important for understanding viral disease pathogenesis. This study reveals that the major human variant of the antiviral protein myxovirus resistance protein B (MxB) inhibits the human pathogen herpes simplex virus (HSV-1), whereas a minor human variant and orthologous MxB genes from even closely related primates do not.

A Diagnostic Test Accuracy Study Investigating General Practitioner Clinical Impression and Brief Cognitive Assessments for Dementia in Primary Care, Compared to Specialized Assessment.

Background: Many health systems are interested in increasing the number of uncomplicated and typical dementia diagnoses that are made in primary care, but the comparative accuracy of tests is unknown.

Objective: Calculate diagnostic accuracy of brief cognitive tests in primary care.

Methods: We did a diagnostic test accuracy study in general practice, in people over 70 years who had consulted their GP with cognitive symptoms but had no prior diagnosis of dementia.

AKT2 Loss Impairs BRAF-Mutant Melanoma Metastasis.

Despite recent advances in treatment, melanoma remains the deadliest form of skin cancer, due to its highly metastatic nature. Melanomas harboring oncogenic BRAF mutations combined with PTEN loss exhibit unrestrained PI3K/AKT signaling and increased invasiveness. However, the contribution of different AKT isoforms to melanoma initiation, progression, and metastasis has not been comprehensively explored, and questions remain whether individual isoforms play distinct or redundant roles in each step.