DNA replication is fundamental for life, yet a detailed understanding of bacterial DNA replication is limited outside the organisms Escherichia coli and Bacillus subtilis. Many bacteria, including mycobacteria, encode no identified homologs of helicase loaders or regulators of the initiator protein DnaA, despite these factors being essential for DNA replication in E. coli and B. subtilis. In this study we discover that a previously uncharacterized protein, Rv0004, from the human pathogen Mycobacterium tuberculosis is essential for bacterial viability and that depletion of Rv0004 leads to a block in cell cycle progression. Using a combination of genetic and biochemical approaches, we found that Rv0004 has a role in DNA replication, interacts with DNA and the replicative helicase DnaB, and affects DnaB-DnaA complex formation. We also identify a conserved domain in Rv0004 that is predicted to structurally resemble the N-terminal protein-protein interaction domain of DnaA. Mutation of a single conserved tryptophan within Rv0004’s DnaA N-terminal-like domain leads to phenotypes similar to those observed upon Rv0004 depletion and can affect the association of Rv0004 with DnaB. In addition, using live cell imaging during depletion of Rv0004, we have uncovered a previously unappreciated role for DNA replication in coordinating mycobacterial cell division and cell size. Together, our data support that Rv0004 encodes a homolog of the recently identified DciA family of proteins found in most bacteria that lack the DnaC-DnaI helicase loaders in E. coli and B. subtilis. Therefore, the mechanisms of Rv0004 elucidated here likely apply to other DciA homologs and reveal insight into the diversity of bacterial strategies in even the most conserved biological processes. DNA is the molecule that encodes all of the genetic information of an organism. In order to pass genes onto the next generation, DNA has to first be copied through a process called DNA replication. Most of the initial studies on bacterial DNA replication were performed in Escherichia coli and Bacillus subtilis. While these studies were very informative, there is an increasing appreciation that more distantly related bacteria have diverged from these organisms in even the most fundamental processes. Mycobacteria, a group of bacteria that includes the human pathogen Mycobacterium tuberculosis, are distantly related to E. coli and B. subtilis and lack some of the proteins used for DNA replication in those model organisms. In this study, we discover that a previously uncharacterized protein in Mycobacteria, named Rv0004, is essential for bacterial viability and involved in DNA replication. Rv0004 is conserved in most bacteria but is absent from E. coli and B. subtilis. Since Rv0004 is essential for mycobacterial viability, this study both identifies a future target for antibiotic therapy and expands our knowledge on the diversity of bacterial DNA replication strategies, which may be applicable to other organisms.

Stroke in patients with COVID-19 has received increasing attention throughout the global COVID-19 pandemic, perhaps due to the substantial disability and mortality that can result when the two conditions co-occur. We reviewed the existing literature and found that the proposed pathomechanism underlying COVID-19-associated ischemic stroke is broadly divided into the following three categories: vasculitis, endothelialitis, and endothelial dysfunction; hypercoagulable state; and cardioembolism secondary to cardiac dysfunction. There has been substantial debate as to whether there is a causal link between stroke and COVID-19. However, the distinct phenotype of COVID-19-associated strokes, with multivessel territory infarcts, higher proportion of large vessel occlusions, and cryptogenic stroke mechanism, that emerged in pooled analytic comparisons with non-COVID-19 strokes is compelling. Further, in this article, we review the various treatment approaches that have emerged as they relate to the proposed pathomechanisms. Finally, we briefly cover the logistical challenges, such as delays in treatment, faced by providers and health systems; the innovative approaches utilized, including the role of tele-stroke; and the future directions in COVID-19-associated stroke research and healthcare delivery.

Background: Traumatic brain injury can lead to venous sinus injury and thrombosis, which may be associated with elevated intracranial pressure and poor outcomes. We sought to examine the risk factors, management, and clinical outcomes of traumatic venous sinus thrombosis (tVST). Methods: We conducted a comprehensive search of our institutional radiology database for final radiology reports from 2013 to 2022 that contained the terms “venous sinus thrombosis,” “sinus thrombosis,” or “venous occlusion.” tVST was detected on computed tomography and confirmed by a board-certified neuroradiologist. Results: We identified 135 patients on initial screening and entered 112 into our final analysis. Patients were predominantly male (76.8%) and had a mean age of 44 years. Initial Glasgow Coma Scale scores of 13–15, 9–12, and 3–8 were found in 60.7%, 12.5%, and 26.8% of our cohort, respectively. Eighty-nine patients (79.5%) were alive at hospital discharge. Most patients sustained skull fractures ( n = 109, 97.3%), including skull base fractures. Seventeen patients required interventions for refractory intracranial hypertension, of whom 16 (94.1%) had multiple tVST. We observed heterogeneity in tVST monitoring and treatment practices. Patients received anticoagulation (AC; 13.4%), antiplatelet (AP; 34.8%), or conservative (no AC or AP; 51.8%) treatment for tVST. Follow-up imaging was available for 52 patients, showing recanalization of venous sinuses in 26 patients (50%) by 6 months post injury. Recanalization rates were higher in the AP group than in the AC group. However, this was likely the result of selection bias, in which patients with mild to moderate injuries were more likely to be assigned to AP therapy. We noted more bleeding complications in AC- and AP-treated patients (20.0% and 12.8%) than in conservatively managed patients (3.4%), even after adjusting for lower survival in the conservative group. Conclusions: Differences between treatment groups should be cautiously interpreted due to selection bias and confounding by indication. More studies are needed to determine the optimal management of tVST.

The hippocampus is a crucial component of the circuits involved in memory formation and recall. Bilateral hippocampal lesions can lead to profound anterograde amnesia. As a highly vascularized structure, the hippocampus is susceptible to ischemia from hypoxic and toxic insults. Infarction of bilateral hippocampi as a result of cocaine use, while rare, is well described in the literature. Combined opiate and stimulant abuse also cause dysfunction of this structure. We present a case of complete bilateral hippocampal diffusion restriction and anterograde amnesia after heroin, cocaine, and benzodiazepine abuse, consistent with opioid-associated amnestic syndrome, as well as a remarkable resolution of amnesia months later.

Stroke-like migraine attacks after radiation therapy (SMART) syndrome is a rare, delayed complication of cranial radiation therapy that consists of migraine-like headaches and focal neurologic deficits such as visual loss, aphasia, hemiparesis, hemisensory loss, and unconsciousness. SMART syndrome may be mistaken for tumor recurrence, radiation necrosis, and stroke. Timely recognition of SMART syndrome prevents unnecessary brain biopsies and enables appropriate anticipatory guidance. We present a 38 year-old right handed male with new headaches, vertigo, visual symptoms, and left-sided paresthesias. Neuroimaging revealed a heterogeneously enhancing mass with invasion into the transverse sinus, diagnosed as an epithelioid hemangioendothelioma by surgical pathology. After resection, the patient underwent proton beam radiation for maximal tissue-sparing. Six months later, he developed radiation necrosis. After another year, he developed recurrent headaches with transient language difficulties and blurry vision during each headache. Neuroimaging was consistent with SMART syndrome, and the patient was started on valproate. Verapamil was added after a second attack. The patient’s headaches improved, but he remains dyslexic. Subsequent imaging shows resolution of gyriform contrast enhancement and continued left temporo-occipital T2/FLAIR hyperintensity. We present a case of early SMART syndrome following proton beam radiotherapy, as well as the dual occurrence of radiation necrosis and SMART syndrome in this individual. Radiation necrosis and SMART syndrome are known complications of radiotherapy, with the latter less well-described. We discuss a possible shared pathophysiology involving endothelial cell dysfunction and impaired cerebrovascular autoregulation, and we question whether proton RT increases risk of early SMART syndrome development.