Ischemic stroke is a leading cause of morbidity and mortality worldwide and, despite reperfusion either via thrombolysis or thrombectomy, stroke patients often suffer from lifelong disabilities. These persistent neurological deficits may be improved by treating the ischemia/reperfusion (I/R) injury that occurs following ischemic stroke. There are currently no approved therapies to treat I/R injury, and thus it is imperative to find new targets to decrease the burden of ischemic stroke and related diseases. Platelets, cell fragments from megakaryocytes, are primarily known for their role in hemostasis. More recently, investigators have studied the nonhemostatic role of platelets in inflammatory pathologies, such as I/R injury after ischemic stroke. In this review, we seek to provide an overview of how I/R can lead to platelet activation and how activated platelets, in turn, can exacerbate I/R injury after stroke. We will also discuss potential mechanisms by which platelets may ameliorate I/R injury.

The development of effective countermeasures against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent responsible for the COVID-19 pandemic, is a priority. We designed and produced ConVac, a replication-competent vesicular stomatitis virus (VSV) vaccine vector that expresses the S1 subunit of SARS-CoV-2 spike protein. We used golden Syrian hamsters as animal models of severe COVID-19 to test the efficacy of the ConVac vaccine. A single vaccine dose elicited high levels of SARS-CoV-2 specific binding and neutralizing antibodies; following intranasal challenge with SARS-CoV-2, animals were protected from weight loss and viral replication in the lungs. No enhanced pathology was observed in vaccinated animals upon challenge, but some inflammation was still detected. The data indicate rapid control of SARS-CoV-2 replication by the S1-based VSV-vectored SARS-CoV-2 ConVac vaccine.

The phosphorylated form of thiamine (Vitamin B₁), thiamine pyrophosphate (TPP) is essential for the metabolism of amino acids and carbohydrates in all organisms. Plants and microorganisms, such as yeast, synthesize thiamine de novo whereas animals do not. The thiamine signal transduction (THI) pathway in Saccharomyces cerevisiae is well characterized. The ~10 genes required for thiamine biosynthesis and uptake are transcriptionally upregulated during thiamine starvation by THI2, THI3, and PDC2. Candida glabrata, a human commensal and opportunistic pathogen, is closely related to S. cerevisiae but is missing half of the biosynthetic pathway, which limits its ability to make thiamine. We investigated the changes to the THI pathway in C. glabrata, confirming orthologous functions. We found that C. glabrata is unable to synthesize the pyrimidine subunit of thiamine as well as the thiamine precursor vitamin B₆. In addition, THI2 (the gene encoding a transcription factor) is not present in C. glabrata, indicating a difference in the transcriptional regulation of the pathway. Although the pathway is upregulated by thiamine starvation in both species, C. glabrata appears to upregulate genes involved in thiamine uptake to a greater extent than S. cerevisiae. However, the altered regulation of the THI pathway does not alter the concentration of thiamine and its vitamers in the two species as measured by HPLC. Finally, we demonstrate potential consequences to having a partial decay of the THI biosynthetic and regulatory pathway. When the two species are co-cultured, the presence of thiamine allows C. glabrata to rapidly outcompete S. cerevisiae, while absence of thiamine allows S. cerevisiae to outcompete C. glabrata. This simplification of the THI pathway in C. glabrata suggests its environment provides thiamine and/or its precursors to cells, whereas S. cerevisiae is not as reliant on environmental sources of thiamine.

Convergent evolution is often due to selective pressures generating a similar phenotype. We observe relatively recent duplications in a spectrum of Saccharomycetaceae yeast species resulting in multiple phosphatases that are regulated by different nutrient conditions - thiamine and phosphate starvation. This specialization is both transcriptional and at the level of phosphatase substrate specificity. In Candida glabrata, loss of the ancestral phosphatase family was compensated by the co-option of a different histidine phosphatase family with three paralogs. Using RNA-seq and functional assays, we identify one of these paralogs, CgPMU3, as a thiamine phosphatase. We further determine that the 81% identical paralog CgPMU2 does not encode thiamine phosphatase activity; however, both are capable of cleaving the phosphatase substrate, 1-napthyl-phosphate. We functionally demonstrate that members of this family evolved novel enzymatic functions for phosphate and thiamine starvation, and are regulated transcriptionally by either nutrient condition, and observe similar trends in other yeast species. This independent, parallel evolution involving two different families of histidine phosphatases suggests that there were likely similar selective pressures on multiple yeast species to recycle thiamine and phosphate. In this work, we focused on duplication and specialization, but there is also repeated loss of phosphatases, indicating that the expansion and contraction of the phosphatase family is dynamic in many Ascomycetes. The dynamic evolution of the phosphatase gene families is perhaps just one example of how gene duplication, co-option, and transcriptional and functional specialization together allow species to adapt to their environment with existing genetic resources.

Status epilepticus (SE) is a life-threatening neurologic emergency. Although health disparities in epilepsy are well-documented, disparities in SE mortality are not fully understood. This study analyzes mortality trends and demographics in the United States from 1999 through 2020. This was a retrospective study of national data from the Center for Disease Control and Prevention's Wide-Ranging Online Data for Epidemiologic Research platform. We identified annual deaths due to SE for the years 1999 through 2020, stratified by age and by race and ethnicity. From 1999 through 2020, there were 16,491 deaths due to SE in the United States. Overall, there was nearly a 2-fold increase in the age-standardized mortality due to the SE rate from 1999 to 2020 (0.13 per 100,000 persons [95% CI 0.11-0.15] in 1999 to 0.25 per 100,000 persons [95% CI 0.23-0.27] in 2020). This increase was most pronounced among older individuals (aged 75 years and older, followed by ages 50-74 years), and in non-Hispanic Black or African American individuals. Over the past 2 decades, deaths attributed to SE have increased. This increase was most pronounced among individuals aged 75 years or older and Black or African Americans. Investigation into the underlying causes of SE-related mortality and reasons for these disparities is needed.

Sleep is a critical component of health and recovery. Awakening sleeping patients for routine vital sign monitoring overnight is a common inpatient practice, but its benefits are uncertain. This study asked 3 questions: (1) How often are routine overnight vital signs abnormal? (2) How often are those abnormal vital signs clinically actionable? (3) Are there patients who may not need routine overnight vital sign monitoring? We analyzed observational retrospective data extracted from electronic health records of patients admitted to inpatient neurology floors at our institution between 2017 and 2024. We defined routine vital signs as collected by nursing assistants at least 3 hours apart. The outcome measure was an urgent clinical action (stat orders, rapid responses, or transfers to a higher level of care) within 1 hour of vital sign events. We compared the rate of urgent clinical actions after abnormal vital signs with the base rate of those events after normal vital signs. Statistical analysis used generalized estimating equations to account for repeated measures. We analyzed 102,184 routine vital sign events from 5,569 neurology admissions. In total, 9% of vital sign events were abnormal. The likelihood of urgent clinical actions increased after abnormal vital sign events, compared with after normal vital sign events during the day (4.3% vs 2.4%, odds ratio (OR) 1.8 [1.6-2.1]); at night (2.4% vs 0.9%, OR 2.8 [2.2-3.7]); during the night in low-risk patients with normal daytime vitals (2.0% vs 0.7%, OR 3.0 [1.8-4.9]); and at night in high-risk patients with abnormal daytime vitals (2.6% vs 1.1%, OR 2.5 [1.7-3.6]). The number needed to treat (NNT), i.e., the number of vital sign events needed to initiate 1 extra urgent clinical action above the base rate, was 1,856 [943; 4,598] in low-risk patients. The NNT for low-risk stroke patients was 1,570 [679; 4,707] and for general neurology patients was 2,231 [797; 5,423]. Urgent clinical actions attributable to abnormal routine vital signs were uncommon in neurology inpatients, especially overnight in patients with normal daytime vital signs. Determining the risks and benefits of routine overnight vital sign monitoring will help hospitals and health care providers move toward more patient-centered inpatient neurologic care.