Cohesin cleavage by separase is enhanced by a substrate motif distinct from the cleavage site.

Chromosome segregation begins when the cysteine protease, separase, cleaves the Scc1 subunit of cohesin at the metaphase-to-anaphase transition. Separase is inhibited prior to metaphase by the tightly bound securin protein, which contains a pseudosubstrate motif that blocks the separase active site. To investigate separase substrate specificity and regulation, here we develop a system for producing recombinant, securin-free human separase. Using this enzyme, we identify an LPE motif on the Scc1 substrate that is distinct from the cleavage site and is required for rapid and specific substrate cleavage. Securin also contains a conserved LPE motif, and we provide evidence that this sequence blocks separase engagement of the Scc1 LPE motif. Our results suggest that rapid cohesin cleavage by separase requires a substrate docking interaction outside the active site. This interaction is blocked by securin, providing a second mechanism by which securin inhibits cohesin cleavage

Understanding adolescent health risk behaviour and socioeconomic position:A grounded theory study of UK young adults

Health risk behaviours such as tobacco smoking, excessive alcohol consumption, drug use, unhealthy diet and unprotected sexual intercourse contribute to the global burden of non‐communicable diseases and are often initiated in adolescence. An individualistic focus on ‘health risk behaviours’ has resulted in behaviour change strategies that are potentially ineffective and increase inequalities. We conducted a grounded theory study of 25 young adults to increase the limited qualitative evidence base surrounding young people, health risk behaviours and socioeconomic inequalities. We found that health risk behaviours were perceived as class markers, manifesting as class stigma, leading some participants from lower socioeconomic backgrounds to employ strategies to avoid such behaviours. Peers and family were core constructs for understanding the relationship between health risk behaviours and socioeconomic life trajectories. However, individualism and choice were consistently expressed as the overriding narrative for understanding health risk behaviour and socioeconomic position during the transition to adulthood. The use of ‘personal responsibility’ discourse by young adults, we argue, highlights the need for a public health focus on achieving structural changes as opposed to individualised approaches to avoid reinforcing neoliberal ideologies that serve to marginalise and maintain social inequalities

Use of neuroimaging to inform optimal neurocognitive criteria for detecting HIV-associated brain abnormalities

OBJECTIVE: Frascati international research criteria for HIV-associated neurocognitive disorders (HAND) are controversial; some investigators have argued that Frascati criteria are too liberal, resulting in a high false positive rate. Meyer et al. recommended more conservative revisions to HAND criteria, including exploring other commonly used methodologies for neurocognitive impairment (NCI) in HIV including the global deficit score (GDS). This study compares NCI classifications by Frascati, Meyer, and GDS methods, in relation to neuroimaging markers of brain integrity in HIV. METHOD: Two hundred forty-one people living with HIV (PLWH) without current substance use disorder or severe (confounding) comorbid conditions underwent comprehensive neurocognitive testing and brain structural magnetic resonance imaging and magnetic resonance spectroscopy. Participants were classified using Frascati criteria versus Meyer criteria: concordant unimpaired [Frascati(Un)/Meyer(Un)], concordant impaired [Frascati(Imp)/Meyer(Imp)], or discordant [Frascati(Imp)/Meyer(Un)] which were impaired via Frascati criteria but unimpaired via Meyer criteria. To investigate the GDS versus Meyer criteria, the same groupings were utilized using GDS criteria instead of Frascati criteria. RESULTS: When examining Frascati versus Meyer criteria, discordant Frascati(Imp)/Meyer(Un) individuals had less cortical gray matter, greater sulcal cerebrospinal fluid volume, and greater evidence of neuroinflammation (i.e., choline) than concordant Frascati(Un)/Meyer(Un) individuals. GDS versus Meyer comparisons indicated that discordant GDS(Imp)/Meyer(Un) individuals had less cortical gray matter and lower levels of energy metabolism (i.e., creatine) than concordant GDS(Un)/Meyer(Un) individuals. In both sets of analyses, the discordant group did not differ from the concordant impaired group on any neuroimaging measure. CONCLUSIONS: The Meyer criteria failed to capture a substantial portion of PLWH with brain abnormalities. These findings support continued use of Frascati or GDS criteria to detect HIV-associated CNS dysfunction

Clinical stakeholders' opinions on the use of selective decontamination of the digestive tract in critically ill patients in intensive care units : an international Delphi study

Peer reviewedPublisher PD

2014-2015 Illinois Hunter Harvest Report

A random sample of 3,000 hunters wasselected from 2014Illinois resident Habitat Stampand hunting licenseholdersandmailed an 8-page self-administered questionnaire designed to query hunters about their hunting activities and harvest in Illinois. We received1,296questionnaires,1,207of which were usable, for a 43% response rate. Illinois resident license salesdecreased1.0% from 2013(281,399) to the 2014seasons(278,546).Total days afield decreased for 12 game species (rabbit, dove, snipe, rail, crow, turkey, deer, raccoon, coyote, opossum, red and gray fox) from 2013-14, but increased for 4 species (woodcock, groundhog, and red and gray squirrel).Harvest decreased for 9game species(dove, woodcock, snipe, crow, raccoon, red and gray fox, coyote, and opossum) from 2013-2014, butincreasedfor 3species (groundhog, gray squirrel and fox squirrel). Harvestdid not change for onegame species (rail)and could not be compared for fourgame species (rabbit, wild quail, wild pheasant, and wild gray partridge).Hunters were also asked about small game hunting, applying for Free Upland Game Permits, and the effects of Epizootic Hemorrhagic Disease (EHD) and Blue Tongue Virus (BTV) on deer hunting, as well as their opinionsabouthunting experiences and regulationsin Illinois.Federal Aid Project Number W-112-R-24IDNR Division of WildlifeU.S. Fish & Wildlife Serviceunpublishednot peer reviewe

The Structural Basis of Actin Organization by Vinculin and Metavinculin

Vinculin is an essential adhesion protein that links membrane-bound integrin and cadherin receptors through their intracellular binding partners to filamentous actin, facilitating mechanotransduction. Here we present an 8.5-Å-resolution cryo-electron microscopy reconstruction and pseudo-atomic model of the vinculin tail (Vt) domain bound to F-actin. Upon actin engagement, the N-terminal "strap" and helix 1 are displaced from the Vt helical bundle to mediate actin bundling. We find that an analogous conformational change also occurs in the H1' helix of the tail domain of metavinculin (MVt) upon actin binding, a muscle-specific splice isoform that suppresses actin bundling by Vt. These data support a model in which metavinculin tunes the actin bundling activity of vinculin in a tissue-specific manner, providing a mechanistic framework for understanding metavinculin mutations associated with hereditary cardiomyopathies

An analysis of inpatient pediatric sickle cell disease: Incidence, costs, and outcomes

ObjectiveTo identify characteristics of pediatric sickle cell disease (SCD) hospitalizations and to examine admission demographics and medical expenditures.MethodsAdmissions with SCD were identified from the 2009 and 2012 releases of the Healthcare and Cost Utilization Project’s Kids Inpatient Database. Diseaseâ specific secondary diagnoses including acute chest syndrome (ACS), vasoâ occlusive pain crisis (VOC), splenic sequestration, and stroke/transient ischemic attack were analyzed for patient and hospital demographics. Analytical endpoints included total healthcare expenditures and mortality.ResultsWe reviewed 75,234 inpatient hospitalizations with a diagnosis of SCD. Over $900,000,000 was spent annually in associated healthcare expenditure. The median length of hospitalization stay (LOS) for all admissions was 3 days (interquartile range [IQR] 2â 5 days). VOC was the most frequent secondary diagnosis, recording 48,698 total hospitalizations and a median LOS of 3 days (IQR 2â 6 days). Of the 8,490 hospitalizations with ACS, the infant population had a significantly higher mortality rate compared to other age groups (2$18,956), behind ACS ($22,631). A high proportion of Caucasian patients died during hospitalization for VOC (0.4% vs. 0.1%, P = 0.014) and ACS (4% vs. 0.2%, P < 0.001) when compared to nonâ Caucasians.ConclusionInpatient hospitalizations for secondary manifestations of pediatric SCD were associated with significant healthcare expenditures. Patients with an increased statistical risk for death during hospitalization included Caucasians with SCD complications of ACS and VOC, and patients <1â yearâ old with ACS. Further research is needed to substantiate the associated clinical significance of these findings.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140014/1/pbc26758.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/140014/2/pbc26758_am.pd

Sacral agenesis: a pilot whole exome sequencing and copy number study

Background: Caudal regression syndrome (CRS) or sacral agenesis is a rare congenital disorder characterized by a constellation of congenital caudal anomalies affecting the caudal spine and spinal cord, the hindgut, the urogenital system, and the lower limbs. CRS is a complex condition, attributed to an abnormal development of the caudal mesoderm, likely caused by the effect of interacting genetic and environmental factors. A well-known risk factor is maternal type 1 diabetes. Method: Whole exome sequencing and copy number variation (CNV) analyses were conducted on 4 Caucasian trios to identify de novo and inherited rare mutations. Results: In this pilot study, exome sequencing and copy number variation (CNV) analyses implicate a number of candidate genes, including SPTBN5, MORN1, ZNF330, CLTCL1 and PDZD2. De novo mutations were found in SPTBN5, MORN1 and ZNF330 and inherited predicted damaging mutations in PDZD2 (homozygous) and CLTCL1 (compound heterozygous). Importantly, predicted damaging mutations in PTEN (heterozygous), in its direct regulator GLTSCR2 (compound heterozygous) and in VANGL1 (heterozygous) were identified. These genes had previously been linked with the CRS phenotype. Two CNV deletions, one de novo (chr3q13.13) and one homozygous (chr8p23.2), were detected in one of our CRS patients. These deletions overlapped with CNVs previously reported in patients with similar phenotype. Conclusion: Despite the genetic diversity and the complexity of the phenotype, this pilot study identified genetic features common across CRS patients

Supervised exercise training in patients with cancer during anthracycline-based chemotherapy to mitigate cardiotoxicity: a randomized-controlled-trial

Background: Exercise training (ET) has been shown to mitigate cardiotoxicity of anthracycline-based chemotherapies (AC) in animal models. Data from randomized controlled trials in patients with cancer are sparse. Methods: Patients with breast cancer or lymphoma receiving AC were recruited from four cancer centres and randomly assigned to 3 months supervised ET. Primary outcome was change in left ventricular global longitudinal strain (GLS) from baseline (before AC) to post AC (AC-end) compared between the EXduringAC group, who participated in an exercise intervention during AC including the provision of an activity tracker, and the control group EXpostAC, who received an activity tracker only. Secondary outcome parameters were changes in high sensitivity Troponin T (hsTnT), NT-pro-brain natriuretic peptide (NT-proBNP), peak oxygen consumption (peak VO2) and objectively measured physical activity (PA) during this same time-period. All assessments were repeated at a 12-week follow-up from AC-end, when also the EXpostAC group had completed the ET, that started after AC. In exploratory analyses, robust linear models were performed to assess the association of PA with changes in echocardiographic parameters and biomarkers of LV function. Results: Fifty-seven patients (median age 47 years; 95% women) were randomized to EXduringAC (n = 28) and EXpostAC (n = 29) group. At AC-end, GLS deteriorated in both study groups (albeit insignificantly) with 7.4% and 1.0% in EXduringAC (n = 18) and EXpostAC (n = 18), respectively, and hsTnT and NT-proBNP significantly increased in both groups, without difference between groups for any parameter. Change in peak VO2 (−1.0 and −1.1 ml/kg/min) at AC-end was also similar between groups as was duration of moderate-to-vigorous PA (MVPA) with a median of 33 [26, 47] min/day and 32 [21, 59] min/day in the EXduringAC and EXpostAC group, respectively. In the robust linear model including the pooled patient population, MVPA was significantly associated with a more negative GLS and lesser increase in hsTnT at AC-end. Conclusion: In this small scale RCT, supervised ET during AC was not superior to wearing a PA tracker to mitigate cardiotoxicity. The dose-response relationship between PA and cardioprotective effects during AC found in our and previous data supports the notion that PA should be recommended to patients undergoing AC. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03850171