mSphere of Influence: The challenge of screening for essential protein kinases in .

Miguel Chiurillo works in the field of protein kinases, studying their role in cell signaling and cell cycle progression in . In this mSphere of Influence article, he reflects on how the research articles "Systematic functional analysis of protein kinases identifies regulators of differentiation or survival" by Baker et al. and "Screening the kinome with high throughput tagging identifies a regulator of invasion and egress" by Smith et al.

Characterization of spike S1/S2 processing and entry pathways of lentiviral pseudoviruses bearing seasonal human coronaviruses NL63, 229E, and HKU1 spikes.

Although much has been learned about the entry mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), many details of the entry mechanisms of seasonal human coronaviruses (HCoVs) remain less well understood. In the present study, we used 293T cell lines stably expressing angiotensin converting enzyme (ACE2), aminopeptidase N (APN), or transmembrane serine protease 2 (TMPRSS2), which support high-level transduction of lentiviral pseudoviruses bearing spike proteins of seasonal HCoVs, HCoV-NL63, -229E, or -HKU1, respectively, to compare spike processing and virus entry pathways among these viruses. Our results showed that the entry of HCoV-NL63, -229E, and -HKU1 pseudoviruses into cells is sensitive to endosomal acidification inhibitors (chloroquine and NHCl), indicating entry via the endocytosis route.

The circulating plasma microRNA signature in human visceral leishmaniasis.

Visceral leishmaniasis (VL) is a vector-borne disease caused by the obligate intracellular protozoan in India. VL can be complicated by post-kala-azar dermal leishmaniasis (PKDL), a macular or nodular rash that develops in 10%-20% of patients after treatment of VL in India. Patients with PKDL are infectious to sand flies, promoting further transmission of the parasite.

Inhibiting NLRP3 enhances cellular autophagy induced by outer membrane vesicles from .

The bacterium is able to invade lung epithelial cells and survive intracellularly. During this process, it secretes outer membrane vesicles (OMVs), however, it is currently unclear how OMVs from (PA-OMVs) affect lung epithelial cells and their impact on oxidative stress, autophagy, and other physiological activities of lung epithelial cells. In this study, we found that PA-OMVs activated oxidative stress and autophagy in cells.

Effective killing of biofilm by nanoemulsion delivery of plant phytochemicals.

Unlabelled: is an acid-fast, aerobic, non-motile, and biofilm-forming bacterium. The increasing prevalence of mycobacterial infections makes it necessary to find new methods to combat the resistance of bacteria to conventional antibiotics. is an emerging pathogen that is intrinsically drug resistant due to several factors, including an impermeable cell envelope, drug efflux pumps, target-modifying enzymes, and the ability to form thick, robust biofilms.

Restoring cefepime activity against multidrug-resistant KPC-producing by combination with boronic acid inhibitors, MB076 and S02030.

Foremost in the design of new β-lactamase inhibitors (BLIs) are the boronic acid transition state inhibitors (BATSIs). Two highly potent BATSIs being developed are S02030 and MB076 strategically designed to be active against cephalosporinases and carbapenemases, especially KPC. When combined with cefepime, S02030 and MB076 demonstrated potent antimicrobial activity against laboratory and clinical strains of expressing a variety of class A and class C β-lactamases, including and .

Restoring ceftolozane susceptibility: a role for diazabicyclooctane β-lactamase inhibitors?

Paired baseline and post-exposure isolates from 34 patients who developed ceftolozane-tazobactam (TOL-TAZ) resistance following treatment of multidrug-resistant (MDR) infections were analyzed to determine if ceftolozane with an alternative β-lactamase inhibitor could restore susceptibility. The median baseline TOL-TAZ MIC was 2 mg/L; 88% of post-exposure isolates harbored new mutations. Median MIC fold-increase from baseline was 32-, 24-, 16-, and 6-fold for ceftolozane-tazobactam, ceftolozane-avibactam (AVI), ceftolozane-relebactam (REL), and ceftolozane-durlobactam (DUR), respectively.

Laboratory evolution of with a natural vitamin B analog reveals roles for cobamide uptake and adenosylation in methionine synthase-dependent growth.

Bacteria encounter chemically similar nutrients in their environment, which impact their growth in distinct ways. Among such nutrients are cobamides, the structurally diverse family of cofactors related to vitamin B (cobalamin), which function as cofactors for diverse metabolic processes. Given that different environments contain varying abundances of different cobamides, bacteria are likely to encounter cobamides that enable them to grow robustly and also those that do not function efficiently for their metabolism.

Policy Recommendations to Support Equitable Access to Long-Acting Injectables for Human Immunodeficiency Virus Prevention and Treatment: A Policy Paper of the Infectious Diseases Society of America and the HIV Medicine Association.

Long-acting injectables (LAIs) for HIV prevention and treatment could dramatically improve health outcomes and health equity for people with HIV and those who could benefit from pre-exposure prophylaxis. Despite widespread acceptability and demand by providers and potential users of LAIs, implementation has been extremely limited since the introduction of cabotegravir/rilpivirine, the first LAI for HIV treatment, in January 2021, and long-acting cabotegravir, the first LAI for HIV prevention, in December 2021. We report results of a provider survey, conducted by the HIV Medicine Association, which identified LAI implementation barriers related to health insurance processes, staffing and administrative support, drug costs and acquisition, and access for individuals who are uninsured.

Conformational flexibility is a critical factor in designing broad-spectrum human norovirus protease inhibitors.

Unlabelled: Human norovirus (HuNoV) is a leading cause of gastroenteritis worldwide and is associated with significant morbidity, mortality, and economic impact. There are currently no licensed antiviral drugs for the treatment of HuNoV-associated gastroenteritis. The HuNoV protease plays a critical role in the initiation of virus replication by cleaving the polyprotein.

Allosteric regulation of pyruvate kinase enables efficient and robust gluconeogenesis by preventing metabolic conflicts and carbon overflow.

Gluconeogenesis, the reciprocal pathway of glycolysis, is an energy-consuming process that generates glycolytic intermediates from non-carbohydrate sources. In this study, we demonstrate that robust and efficient gluconeogenesis in bacteria relies on the allosteric inactivation of pyruvate kinase, the enzyme responsible for the irreversible final step of glycolysis. Using the model bacterium as an example, we discovered that pyruvate kinase activity is inhibited during gluconeogenesis via its extra C-terminal domain (ECTD), which is essential for autoinhibition and metabolic regulation.

Use of analytical strategies to understand spatial chemical variation in bacterial surface communities.

Not only do surface-growing microbes such as biofilms display specific traits compared to planktonic cells, but also they display many heterogeneous behaviors over many spatial and temporal contexts. While the application of molecular genetics tools to extract or visualize gene expression or regulatory function data is now common in studying surface growth, the use of analytical chemistry tools to visualize the spatiotemporal distribution of chemical products synthesized by these surface microbes is less common. Here, we review chemical imaging tools that have been used to inform our understanding of surface-growing microbes.

Frequently arising ESX-1-associated phase variants influence fitness in the presence of host and antibiotic pressures.

Unlabelled: (Mtb) exhibits an impressive ability to adapt to rapidly changing environments, despite its genome's apparent stability. Recently, phase variation through indel formation in homopolymeric tracts (HT) has emerged as a potentially important mechanism promoting adaptation in Mtb. This study examines the impact of common phase variants associated with the ESX-1 type VII secretion system, focusing on a highly variable HT upstream of the ESX-1 regulatory factor, .

Positive feedback regulation between RpoS and BosR in the Lyme disease pathogen.

In , the causative agent of Lyme disease, differential gene expression is primarily governed by the alternative sigma factor RpoS (σ). Understanding the regulation of RpoS is crucial for elucidating how is maintained throughout its enzootic cycle. Our recent studies have shown that the homolog of Fur/PerR repressor/activator BosR functions as an RNA-binding protein that controls the mRNA stability.

Evaluation of tumor-colonizing strains using the chick chorioallantoic membrane model.

The chick embryo chorioallantoic membrane (CAM) tumor model is a valuable preclinical model for studying the tumor-colonizing process of serovar Typhimurium. It offers advantages such as cost-effectiveness, rapid turnaround, reduced engraftment issues, and ease of observation. In this study, we explored and validated the applicability of the partially immune-deficient CAM tumor model.

Insulitis and exocrinitis in autoantibody-positive non-diabetic individuals: role of HLA genotypes.

Context: Type 1 diabetes (T1D) is characterized by the presence of autoantibodies on a genetic background largely determined by HLA class II haplotypes. Stage 1 T1D is characterized by the presence of multiple autoantibodies and normoglycemia.

Objective: To investigate the prevalence of high-risk HLA-DQB1 haplotypes and the extent of islet autoimmunity in pancreatic tissues from non-diabetic organ donors with autoantibodies.

Navigating the practical challenges and ethical dilemmas of surplus cryopreserved human embryos.

Cryopreservation, the use of very low temperatures to preserve structurally intact living cells and tissues, has seen exponential growth in the field of fertilization (IVF). In the last decade, cryopreservation of embryos and freeze-all protocols have become an essential aspect and a prerequisite for a successful IVF outcome. Moreover, vitrification, which is a fast and safe cryopreservation method, has proved to be an effective choice for cryopreserving gametes and embryos.

Effects of kinesiotaping on proprioception, pain, disability, and quality of life in patients with cervical spondylosis: a randomized controlled trial.

Objective: This study aimed to assess the effects of kinesiotaping (KT) adjunct to physical therapy (PT) on proprioception, cervical range of motion (ROM), pain, disability, anxiety, depression, and quality of life (QoL) in cervical spondylosis.

Methods: Sixty-nine patients aged 50-70 years were randomized into three groups: PT, PT plus KT(PT+KT), PT plus sham-taping(PT+ST). All participants underwent standardized 15-session PT, 5 days/week.

Epigenetic mechanisms underlying endometrial cancer (EC) outcomes: race-specific patterns of DNA methylation associated with molecular subtypes and survival.

Endometrial cancer [EC] is the fourth most common cancer in women in the United States. Stark racial disparities are present in EC outcomes in which Black women have significantly higher EC-related mortality than White women. The social and biologic factors that contribute to these disparities are complex, and may include racial differences in epigenetic landscapes.

Woven EndoBridge 17 device for intracranial aneurysms: A systematic review and meta-analysis.

Background: The Woven EndoBridge 17 (WEB-17) is the latest advancement in the WEB device family. Comprehensive data on its occlusion rates, procedural complications, and mortality is lacking. This meta-analysis aimed to evaluate the efficacy and safety of the WEB-17 device in intracranial aneurysms (IAs).

Recovery support services as part of the continuum of care for alcohol or drug use disorders.

Background: The definition of 'recovery' has evolved beyond merely control of problem substance use to include other aspects of health and wellbeing (known as 'recovery capital') which are important to prevent relapse to problematic alcohol or other drug (AOD) use. Developing a Recovery Oriented System of Care (ROSC) requires consideration of interventions or services (Recovery Support Services, RSS) designed to build recovery capital which are often delivered alongside established treatment structures. Lived experience and its application to the process of engaging people, changing behaviour and relapse prevention is an essential part of these services.