HDAC6-dependent deacetylation of SAE2 enhances SUMO1 conjugation for mitotic integrity.

Mammalian cells express three conjugatable SUMO variants: SUMO1 and the closely related SUMO2 and SUMO3 (together referred to as SUMO2/3). While some substrates are modified by both, others show a clear preference, though the basis for this selectivity remains unclear. Here, we examine a modification of the catalytic component of the human SUMO activation enzyme, SAE2.

Medetomidine-Associated Opioid Overdoses in Chicago, Illinois: A Report of 3 Cases.

Background: Medetomidine has recently emerged as an adulterant in street-level opioids and stimulants in North America, complicating opioid overdose presentations and resisting reversal with naloxone. Medetomidine is an alpha-2 adrenergic receptor agonist used in veterinary medicine as an anesthetic, analgesic, anxiolytic, and muscle relaxant and is not approved for human use by the Food and Drug Administration. Medetomidine's pharmacological profile resembles xylazine, another medication of the same class, but demonstrates higher potency and longer sedative effects in canine models.

PIN1-SUMO2/3 motif suppresses excessive RNF168 chromatin accumulation and ubiquitin signaling to promote IR resistance.

RNF168 is an E3 ubiquitin ligase critical to the mammalian DNA double-strand break repair response. The protein is recruited to and amplifies ubiquitin signals at damaged chromatin and, if not properly regulated, can drive an uncontrolled ubiquitin cascade potentially harmful to repair outcomes. Several indirect mechanisms restrict RNF168 positive feedback, and a longstanding question has been whether these alone suppress excessive RNF168 signaling or whether mechanisms to remove RNF168 from damaged chromatin exist.

Tissue-Specific Effects of the DNA Helicase FANCJ/BRIP1/BACH1 on Repeat Expansion in a Mouse Model of the Fragile X-Related Disorders.

Fragile X-related disorders (FXDs) are caused by the expansion of a CGG repeat tract in the 5'-UTR of the gene. The expansion mechanism is likely shared with the 45+ other human diseases resulting from repeat expansion, a process that has been shown to require key mismatch repair (MMR) factors. FANCJ, a DNA helicase involved in unwinding unusual DNA secondary structures, has been implicated in a number of DNA repair processes including MMR.

SUMO4 promotes SUMO deconjugation required for DNA double-strand-break repair.

The amplitudes of small-modifier protein signaling through ubiquitin and the small ubiquitin-like modifiers, SUMO1-3, are critical to the correct phasing of DNA repair protein accumulation, activity, and clearance and for the completion of mammalian DNA double-strand-break (DSB) repair. However, how SUMO-conjugate signaling in the response is delineated is poorly understood. At the same time, the role of the non-conjugated SUMO protein, SUMO4, has remained enigmatic.

Economic burden of chronic obstructive pulmonary disease and post-tuberculosis sequelae in low- and middle-income countries: a database compiled from a systematic review and meta-analysis.

Background: Chronic obstructive pulmonary disease (COPD) and tuberculosis (TB) impose a substantial economic burden globally. This systematic review summarised the evidence on the costs of COPD, including post-TB diseases in low- and middle-income countries.

Methods: A systematic review was conducted and studies published between 1 January 2013 and 28 March 2022 (the date of the search) were identified using various electronic databases without language restrictions.

Osteochondral Allograft Reaming Significantly Affects Chondrocyte Viability.

Background: Chondrocyte viability is associated with the clinical success of osteochondral allograft (OCA) transplantation.

Purpose: To investigate the effect of distal femoral OCA plug harvest and recipient site preparation on regional cell viability using traditional handheld saline irrigation versus saline submersion.

Study Design: Controlled laboratory study.

Reconciling the effects of PMS2 in different repeat expansion disease models supports a common therapeutic strategy.

Expansion of a disease-specific tandem repeat is responsible for >45 Repeat Expansion Diseases (REDs). The expansion mutation in each of these diseases has different pathological consequences and most are currently incurable. If the underlying mechanism of mutation is shared, a strategy that slows repeat expansion in one RED may be applicable to multiple REDs.

Outcomes of distal femoral replacement versus internal fixation for metastatic bone diseases of the distal femur.

Background: In clinical practice, internal fixation (IF) is a commonly utilized technique for metastatic bone disease (MBD) to the distal femur. Additionally, distal femoral reconstruction (DFR) has shown to be an effective surgical technique for primary tumors and MBD in the distal femur. The existing body of research comparing these methods has not focused on MBD or pathological fractures and thus does not guide surgical approach in the case of distal femoral MBD.

Status of zoonotic disease research in refugees, asylum seekers and internally displaced people, globally: A scoping review of forty clinically important zoonotic pathogens.

Background: At the end of 2022, there were over 108 million forcibly displaced people globally, including refugees, asylum seekers (AS) and internally displaced people (IDPs). Forced migration increases the risk of infectious disease transmission, and zoonotic pathogens account for 61% of emerging and re-emerging infectious diseases. Zoonoses create a high burden of disease and have the potential to cause large-scale outbreaks.

USP50 suppresses alternative RecQ helicase use and deleterious DNA2 activity during replication.

Mammalian DNA replication employs several RecQ DNA helicases to orchestrate the faithful duplication of genetic information. Helicase function is often coupled to the activity of specific nucleases, but how helicase and nuclease activities are co-directed is unclear. Here we identify the inactive ubiquitin-specific protease, USP50, as a ubiquitin-binding and chromatin-associated protein required for ongoing replication, fork restart, telomere maintenance and cellular survival during replicative stress.

Outcomes of surgical treatment with patterns of bacterial culture and antimicrobial susceptibility testing in cases of cervical abscessation in dogs: 82 cases (2018-2021).

Objective: The objective of this study was to summarize the presentation, diagnosis, and outcome for dogs surgically treated for chronic cervical abscessation following suspected or reported cervical or oropharyngeal trauma, as well as to report on culture results and antimicrobial susceptibility patterns.

Results: Eighty-two dogs were identified by retrospective review. Successful surgical outcome was achieved in 92.

The contribution of white matter pathology, hypoperfusion, lesion load, and stroke recurrence to language deficits following acute subcortical left hemisphere stroke.

Aphasia, the loss of language ability following damage to the brain, is among the most disabling and common consequences of stroke. Subcortical stroke, occurring in the basal ganglia, thalamus, and/or deep white matter can result in aphasia, often characterized by word fluency, motor speech output, or sentence generation impairments. The link between greater lesion volume and acute aphasia is well documented, but the independent contributions of lesion location, cortical hypoperfusion, prior stroke, and white matter degeneration (leukoaraiosis) remain unclear, particularly in subcortical aphasia.

An Analysis of Right Hemisphere Stroke Discourse in the Modern Cookie Theft Picture.

Purpose: Adults with right hemisphere damage demonstrate differences in connected speech compared to controls, but systematic, quantitative methods to capture these differences are lacking. The current study aimed to (a) investigate if measures using the Modern Cookie Theft picture description would identify discourse differences in acute right hemisphere stroke, and (b) examine if discourse differences were associated with documented cognitive impairment.

Method: Eighty-four participants completed the Modern Cookie Theft picture description within 5 days of right hemisphere stroke.

Enhanced Imaging and Language Assessments for Primary Progressive Aphasia.

Background And Objectives: It is widely agreed that primary progressive aphasia (PPA) is a clinical syndrome with at least 3 distinct variants that differ in phenotype, areas of atrophy, and most common underlying neurodegenerative disease. The distinction between logopenic variant PPA (lvPPA) and other variants is important for prognosis and medical management. However, differentiating logopenic from nonfluent agrammatic variant can be difficult.

Dysfunctional Tissue Correlates of Unrelated Naming Errors in Acute Left Hemisphere Stroke.

Most naming error lesion-symptom mapping (LSM) studies have focused on semantic and/or phonological errors. Anomic individuals also produce unrelated word errors, which may be linked to semantic or modality-independent lexical deficits. To investigate the neural underpinnings of rarely-studied unrelated errors, we conducted LSM analyses in 100 individuals hospitalized with a left hemisphere stroke who completed imaging protocols and language assessments.

Transcranial Direct Current Stimulation Paired With Verb Network Strengthening Treatment Improves Verb Naming in Primary Progressive Aphasia: A Case Series.

Purpose: There are few evidence-based treatments for language deficits in primary progressive aphasia (PPA). PPA treatments are often adopted from the poststroke aphasia literature. The poststroke aphasia literature has shown promising results using Verb Network Strengthening Treatment (VNeST), a behavioral therapy that focuses on improving naming by producing verbs and their arguments in phrases and sentences.

Hyperintense vessels on imaging account for neurological function independent of lesion volume in acute ischemic stroke.

In acute ischemic stroke, reported relationships between lesion metrics and behavior have largely focused on lesion volume and location. However, hypoperfusion has been shown to correlate with deficits in the acute stage. Hypoperfusion is typically identified using perfusion imaging in clinical settings, which requires contrast.

Simultaneous Hemodynamic and Structural Imaging of Ischemic Stroke With Magnetic Resonance Fingerprinting Arterial Spin Labeling.

Background: Perfusion and structural imaging play an important role in ischemic stroke. Magnetic resonance fingerprinting (MRF) arterial spin labeling (ASL) is a novel noninvasive method of ASL perfusion that allows simultaneous estimation of cerebral blood flow (CBF), bolus arrival time (BAT), and tissue T map in a single scan of <4 minutes. Here, we evaluated the utility of MRF-ASL in patients with ischemic stroke in terms of detecting hemodynamic and structural damage and predicting neurological deficits and disability.

Disruptions of the Human Connectome Associated With Hemispatial Neglect.

Background And Objectives: Hemispatial neglect is a heterogeneous and complex disorder that can be classified by frame of reference for "left" vs "right," including viewer-centered neglect (VCN, affecting the contralesional side of the view), stimulus-centered neglect (SCN, affecting the contralesional side of the stimulus, irrespective of its location with respect to the viewer), or both. We investigated the effect of acute stroke lesions on the connectivity of neural networks that underlie VCN or SCN.

Methods: A total of 174 patients within 48 hours of acute right hemispheric infarct underwent a detailed hemispatial neglect assessment that included oral reading, scene copy, line cancellation, gap detection, horizontal line bisection tests, and MRI.

Health trends, inequalities and opportunities in South Africa's provinces, 1990-2019: findings from the Global Burden of Disease 2019 Study.

Background: Over the last 30 years, South Africa has experienced four 'colliding epidemics' of HIV and tuberculosis, chronic illness and mental health, injury and violence, and maternal, neonatal, and child mortality, which have had substantial effects on health and well-being. Using data from the 2019 Global Burden of Diseases, Injuries and Risk Factors Study (GBD 2019), we evaluated national and provincial health trends and progress towards important Sustainable Development Goal targets from 1990 to 2019.

Methods: We analysed GBD 2019 estimates of mortality, non-fatal health loss, summary health measures and risk factor burden, comparing trends over 1990-2007 and 2007-2019.

One cat, Two cats, Red cat, Blue cats: Eliciting morphemes from individuals with primary progressive aphasia.

Background: Progressive neurodegenerative impairment with central language features, primary progressive aphasia (PPA), can be further distinguished for many individuals into one of three variants: semantic, non-fluent/agrammatic, and logopenic variant PPA. Variants differ in their relative preservation and deficits of language skills, particularly in word finding and grammar. The majority of elicited language assessments used in this population focus on single noun and verb production, while modifiers and inflectional morphemes are far less commonly examined.

Longitudinal decline in spoken word recognition and object knowledge in primary progressive aphasia.

The premise of this study is that spoken word recognition and object knowledge are impaired in semantic variant primary progressive aphasia (PPA) (svPPA) and are spared in logopenic variant (lvPPA) and nonfluent agrammatic primary progressive aphasia (nfaPPA) at disease onset. Over time, however, there may be heterogeneity in these abilities in lvPPA and nfaPPA. We hypothesized that individuals with svPPA would demonstrate poorer performance on baseline spoken word recognition and object knowledge than those with lvPPA and nfaPPA) as documented in the literature, but that rates of decline over time on spoken word recognition and object knowledge would be similar in all 3 PPA variants because these become less distinguishable with disease progression.