Stress granules and processing bodies are dynamically linked sites of mRNP remodeling

Stress granules (SGs) are cytoplasmic aggregates of stalled translational preinitiation complexes that accumulate during stress. GW bodies/processing bodies (PBs) are distinct cytoplasmic sites of mRNA degradation. In this study, we show that SGs and PBs are spatially, compositionally, and functionally linked. SGs and PBs are induced by stress, but SG assembly requires eIF2α phosphorylation, whereas PB assembly does not. They are also dispersed by inhibitors of translational elongation and share several protein components, including Fas-activated serine/threonine phosphoprotein, XRN1, eIF4E, and tristetraprolin (TTP). In contrast, eIF3, G3BP, eIF4G, and PABP-1 are restricted to SGs, whereas DCP1a and 2 are confined to PBs. SGs and PBs also can harbor the same species of mRNA and physically associate with one another in vivo, an interaction that is promoted by the related mRNA decay factors TTP and BRF1. We propose that mRNA released from disassembled polysomes is sorted and remodeled at SGs, from which selected transcripts are delivered to PBs for degradation

Ischemic Preconditioning in the Intensive Care Unit

Preconditioning is the premise that controlled preemptive exposure to sub-lethal doses of a stressor and can condition an organism or organ to later withstand a lethal dose. This process relies on marshaling endogenous survival resources that have evolved as part of an organism's evolutionary struggle to overcome at times harsh environmental conditions. This preconditioning response occurs through activation of myriad complex mechanisms that run the gamut from alterations in gene expression to the de novo synthesis and post-translational modification of proteins, and it may occur across exposure to a wide variety of stressors (i.e., ischemia, hypoxia, hypothermia, drugs). This review will focus on preconditioning in relation to an ischemic stressor (ischemic preconditioning) and how this process may be harnessed as a protective method to ameliorate targeted acute neurologic diseases especially. There has been considerable eagerness to translate ischemic preconditioning to the bedside, and to that end there have been recent trials examining its efficacy in various clinical settings. However, some of these trials have reached diverging conclusions with a protective effect seen in studies targeting acute kidney injury solely while no benefit was seen in larger trials targeting combined endpoints including cardio-, neuro-, and renoprotection in a cohort of patients undergoing cardiac surgery. While an extensive body of pre-clinical research offers ischemic preconditioning as a robust and highly faithful protective phenomenon, its clinical utility remains unproven. This current state may be due to persisting gaps in our understanding of how best to harness its power. This review will provide an overview of the biological mechanisms proposed to underlie ischemic preconditioning, explore initial disease targets, examine the challenges we must overcome to optimally engage this system, and report findings of recent clinical trials

Headache and focal neurologic deficits in a 37-year-old woman

A 37-year-old woman presented with progressively worsening headache. She had no headache history, and initial evaluation revealed hydrocephalus of unclear etiology. A ventriculoperitoneal shunt was placed with improvement. However, her headache returned and she developed neurologic deficits. Imaging studies demonstrated multiple cystic lesions in the posterior fossa. Serum and cerebrospinal fluid studies were unrevealing and a biopsy of the cystic lesions was performed. The clinical approach, differential diagnosis, and neuropathological findings are discussed

Stress Granule Assembly Is Mediated by Prion-like Aggregation of TIA-1

TIA-1 is an RNA binding protein that promotes the assembly of stress granules (SGs), discrete cytoplasmic inclusions into which stalled translation initiation complexes are dynamically recruited in cells subjected to environmental stress. The RNA recognition motifs of TIA-1 are linked to a glutamine-rich prion-related domain (PRD). Truncation mutants lacking the PRD domain do not induce spontaneous SGs and are not recruited to arsenite-induced SGs, whereas the PRD forms aggregates that are recruited to SGs in low-level–expressing cells but prevent SG assembly in high-level–expressing cells. The PRD of TIA-1 exhibits many characteristics of prions: concentration-dependent aggregation that is inhibited by the molecular chaperone heat shock protein (HSP)70; resistance to protease digestion; sequestration of HSP27, HSP40, and HSP70; and induction of HSP70, a feedback regulator of PRD disaggregation. Substitution of the PRD with the aggregation domain of a yeast prion, SUP35-NM, reconstitutes SG assembly, confirming that a prion domain can mediate the assembly of SGs. Mouse embryomic fibroblasts (MEFs) lacking TIA-1 exhibit impaired ability to form SGs, although they exhibit normal phosphorylation of eukaryotic initiation factor (eIF)2α in response to arsenite. Our results reveal that prion-like aggregation of TIA-1 regulates SG formation downstream of eIF2α phosphorylation in response to stress

Prolonged Heightened Blood Pressure Following Mechanical Thrombectomy for Acute Stroke is Associated with Worse Outcomes

Most data evaluating the relationship of post-mechanical thrombectomy (MT) blood pressure (BP) management and outcomes of patients with large vessel occlusion (LVO) focus on early BP control within the first 24 h. We investigated the correlation of daily BP trends up to the third day following MT with patient outcomes. We retrospectively reviewed our prospectively maintained database for LVO patients treated with MT from February 2015 to December 2017. Recorded BP values for 72 h post-reperfusion were reviewed. Daily peak systolic and diastolic blood pressures (SBP, DBP) were extracted for each day post-procedure. The association and importance between BP increments of 10 mmHg and mortality, hemorrhage, and functional independence (FI = mRS ≤ 2) was analyzed in a multivariable logistic regression and random forest (RF) analyses modeling. A total of 212 thrombectomies were included. An increase in peak 24-h SBP was independently associated with higher likelihood of symptomatic hemorrhage (OR 1.2, p = 0.048) and decreased functional independence (OR 0.85, p = 0.03). Higher day 2 and day 3 peak SBP was strongly correlated with decreased functional independence and higher mortality. Third day SBP < 140 was independently associated with higher likelihood of functional independence (OR 4.3, p = 0.0004). Post-MT patients with and without functional independence demonstrated a similar relative decrease in peak SBP between the first 2 days following thrombectomy (p = 0.26); however, those without functional independence experienced a significant rebound increase in peak SBP on the third day following MT (mean change from day 2 to 3: FI - 3.5 mmHg, non-FI + 3.9 mmHg; p = 0.005). High daily maximum SBP and a rebound SBP on the third day following MT is independently associated with increased likelihood of functional dependence

Stress granules and processing bodies are dynamically linked sites of mRNP remodeling.

Stress granules (SGs) are cytoplasmic aggregates of stalled translational preinitiation complexes that accumulate during stress. GW bodies/processing bodies (PBs) are distinct cytoplasmic sites of mRNA degradation. In this study, we show that SGs and PBs are spatially, compositionally, and functionally linked. SGs and PBs are induced by stress, but SG assembly requires eIF2alpha phosphorylation, whereas PB assembly does not. They are also dispersed by inhibitors of translational elongation and share several protein components, including Fas-activated serine/threonine phosphoprotein, XRN1, eIF4E, and tristetraprolin (TTP). In contrast, eIF3, G3BP, eIF4G, and PABP-1 are restricted to SGs, whereas DCP1a and 2 are confined to PBs. SGs and PBs also can harbor the same species of mRNA and physically associate with one another in vivo, an interaction that is promoted by the related mRNA decay factors TTP and BRF1. We propose that mRNA released from disassembled polysomes is sorted and remodeled at SGs, from which selected transcripts are delivered to PBs for degradation

Molecular Subtyping and Characterization of Bovine and Human Streptococcus agalactiae Isolates

Streptococcus agalactiae causes severe invasive disease in humans and mastitis in cattle. Temporally matched bovine milk isolates and clinical human invasive isolates (52 each) collected in New York State over 18 months were characterized by molecular subtyping and phenotypic methods to probe the interspecies transmission potential of this species. EcoRI ribotyping differentiated 17 ribotypes, and DNA sequencing of the housekeeping gene sodA and the putative virulence gene hylB differentiated 7 and 17 allelic types, respectively. Human and bovine isolates were not randomly distributed between ribotypes or hylB and sodA clusters. The combined analysis of all subtyping data allowed the differentiation of 39 clonal groups; 26 groups contained only bovine isolates, and 2 groups contained both human and bovine isolates. The EcoRI ribotype diversity among bovine isolates (Simpson's numerical index of discrimination [mean ± standard deviation], 0.90 ± 0.05) being significantly higher than that among human isolates (0.42 ± 0.15) further supports that these isolates represent distinct populations. Eight human isolates, but no bovine isolates, showed an IS1548 transposon insertion in hylB, which encodes a hyaluronidase. Based on data for 43 representative isolates, human isolates, on average, showed lower hyaluronidase activities than bovine isolates. Isolates with the IS1548 insertion in hylB showed no hyaluronidase activity. Human and bovine isolates did not differ in their abilities to invade HeLa human epithelial cells. Our data show that (i) EcoRI ribotyping, combined with hylB and sodA sequencing, provides a discriminatory subtype analysis of S. agalactiae; (ii) most human invasive and bovine S. agalactiae isolates represent distinct subtypes, suggesting limited interspecies transmission; and (iii) hyaluronidase activity is not required for all human infections

Abstract P877: Race-Ethnic Disparities in Intracerebral Hemorrhage Outcomes

Introduction: Prior literature has reported differences in outcomes following stroke by race/ethnicity. While more attention has been focused on ischemic stroke, we sought to identify race/ethnic disparities in hospital outcomes at discharge following intracerebral hemorrhage (ICH). Methods: Data were obtained from the Florida Stroke Registry (FSR) consisting of stroke centers utilizing the Get With the Guidelines-Stroke (GWTG-S) tool. Pearson Chi-square and Kruskall-Wallis tests were used to compare descriptive statistics by race/ethnicity on 26,113 Florida cases with ICH discharged 2010-2018. Outcomes at discharge included in-hospital mortality, disposition, ambulation, modified Rankin Scale score & timing of initiation of comfort measures only (CMO). Generalized estimating equations logistic models accounted for age, sex, insurance, smoking, hypertension, diabetes, dyslipidemia, prior anti-coagulant/platelet use, history of stroke/TIA, admission NIHSS, ICH score, arrival mode, hospital size, teaching status & years in GWTG-S. Results: 65% were non-Hispanic White (NHW), 20% non-Hispanic Black (NHB) and 15% Hispanic. NHB were younger at ICH onset (median 60, IQR 52-71; NHW: 71, 58-81; Hispanic: 69, 52-80; p < 0.0001), had higher risk of hypertension (HTN; 74%; NHW: 66%; Hispanic: 64%; p < 0.0001), diabetes (29%; NHW: 20%; Hispanic: 27%; p < 0.0001), smoking (14%; NHW: 12%; Hispanic: 9%; p < 0.0001) and chronic renal insufficiency (8%; NHW: 4%; Hispanic: 4% ; p < 0.0001). NHW had higher risk of dyslipidemia (35%; NHB: 21%; Hispanic: 27%; p < 0.0001), atrial fibrillation/flutter (20%; NHB: 6%; Hispanic: 10%; p < 0.0001) and a higher use of prior anticoagulants (13%; NHB: 6%, Hispanic: 8%, p < 0.0001). NHB had lower odds of in-hospital mortality (adjusted OR=0.77, 95% CI=[0.61-0.96]) and CMO on days 0/1 (0.63, 0.45-0.87) compared to NHW. Conclusions: Differences in risk factor profiles, such as higher rates of HTN in NHB and greater use of anticoagulants among NHW, raises the possibility of tailoring preventive and acute care responses to ICH by race/ethnicity. Moreover, despite observing persistently lower odds of mortality and CMO among NHB after adjustment, more data are needed to identify the unobserved effects leading to these disparities