Characterization of the interaction between HMGB1 and H3-a possible means of positioning HMGB1 in chromatin.

High mobility group protein B1 (HMGB1) binds to the internucleosomal linker DNA in chromatin and abuts the nucleosome. Bending and untwisting of the linker DNA results in transmission of strain to the nucleosome core, disrupting histone/DNA contacts. An interaction between H3 and HMGB1 has been reported. Here we confirm and characterize the interaction of HMGB1 with H3, which lies close to the DNA entry/exit points around the nucleosome dyad, and may be responsible for positioning of HMGB1 on the linker DNA. We show that the interaction is between the N-terminal unstructured tail of H3 and the C-terminal unstructured acidic tail of HMGB1, which are presumably displaced from DNA and the HMG boxes, respectively, in the HMGB1-nucleosome complex. We have characterized the interaction by nuclear magnetic resonance spectroscopy and show that it is extensive for both peptides, and appears not to result in the acquisition of significant secondary structure by either partner

Highly disordered histone H1-DNA model complexes and their condensates.

Disordered proteins play an essential role in a wide variety of biological processes, and are often posttranslationally modified. One such protein is histone H1; its highly disordered C-terminal tail (CH1) condenses internucleosomal linker DNA in chromatin in a way that is still poorly understood. Moreover, CH1 is phosphorylated in a cell cycle-dependent manner that correlates with changes in the chromatin condensation level. Here we present a model system that recapitulates key aspects of the in vivo process, and also allows a detailed structural and biophysical analysis of the stages before and after condensation. CH1 remains disordered in the DNA-bound state, despite its nanomolar affinity. Phase-separated droplets (coacervates) form, containing higher-order assemblies of CH1/DNA complexes. Phosphorylation at three serine residues, spaced along the length of the tail, has little effect on the local properties of the condensate. However, it dramatically alters higher-order structure in the coacervate and reduces partitioning to the coacervate phase. These observations show that disordered proteins can bind tightly to DNA without a disorder-to-order transition. Importantly, they also provide mechanistic insights into how higher-order structures can be exquisitely sensitive to perturbation by posttranslational modifications, thus broadening the repertoire of mechanisms that might regulate chromatin and other macromolecular assemblies

Effects of Heating on Teflon(Registered Trademark) FEP Thermal Control Material from the Hubble Space Telescope

Metallized Teflon(Registered Trademark) FEP (fluorinated ethylene propylene) thermal control material on the Hubble Space Telescope (HST) is degrading in the space environment. Teflon(Registered Trademark) FEP thermal control blankets (space-facing FEP) retrieved during the first servicing mission (SM1) were found to be embrittled on solar facing surfaces and contained microscopic cracks. During the second servicing mission (SM2) astronauts noticed that the FEP outer layer of the multi-layer insulation (MLI) covering the telescope was cracked in many locations around the telescope. Large cracks were observed on the light shield, forward shell and equipment bays. A tightly curled piece of cracked FEP from the light shield was retrieved during SM2 and was severely embrittled, as witnessed by ground testing. A Failure Review Board (FRB) was organized to determine the mechanism causing the MLI degradation. Density, x-ray crystallinity and solid state nuclear magnetic resonance (NMR) analyses of FEP retrieved during SM1 were inconsistent with results of FEP retrieved during SM2. Because the retrieved SM2 material curled while in space, it experienced a higher temperature extreme during thermal cycling, estimated at 200 C, than the SM1 material, estimated at 50 C. An investigation on the effects of heating pristine and FEP exposed on HST was therefore conducted. Samples of pristine. SM1, and SM2 FEP were heated to 200 C and evaluated for changes in density and morphology. Elevated temperature exposure was found to have a major impact on the density of the retrieved materials. Characterization of polymer morphology of as-received and heated FEP samples by NMR provided results that were consistent with the density results. These findings have provided insight to the damage mechanisms of FEP in the space environment

Insights Developed Into the Damage Mechanism of Teflon FEP Thermal Control Material on the Hubble Space Telescope

Metalized Teflon FEP (DuPont; fluorinated ethylene propylene) thermal control material on the Hubble Space Telescope (HST) has been found to degrade in the space environment. Teflon FEP thermal control blankets retrieved during the first servicing mission were found to be embrittled on solar-facing surfaces and to contain microscopic cracks (the FEP surface is exposed to the space environment). During the second servicing mission, astronauts noticed that the FEP outer layer of the multilayer insulation blanketing covering the telescope was cracked in many locations. Large cracks were observed on the light shield, forward shell, and equipment bays. A tightly curled piece of cracked FEP from the light shield was retrieved during the second mission. This piece was severely embrittled, as witnessed by ground testing. A Failure Review Board was organized by NASA Goddard Space Flight Center to determine the mechanism causing the multilayer insulation degradation. This board included members of the Electro-Physics Branch of the NASA Glenn Research Center at Lewis Field. Density measurements of the retrieved materials obtained under the review board's investigations indicated that FEP from the first servicing mission was essentially unchanged from pristine FEP but that the second servicing mission FEP had increased in density in comparison to pristine FEP (ref. 1). The results were consistent with crystallinity measurements taken using x-ray diffraction and with results from solid-state nuclear magnetic resonance tests (see the table and ref. 1). Because the second servicing mission FEP was embrittled and its density and crystallinity had increased in comparison to pristine FEP, board researchers expected that the first servicing mission FEP, which was also embrittled, would also have increased in crystallinity and density, but it did not. Because the retrieved second servicing mission material curled while in space, it experienced a higher temperature extreme during thermal cycling (estimated at 200 C) than the first servicing mission material (estimated at 50 C). Therefore, Glenn initiated and conducted an investigation of the effects of heating pristine FEP and FEP that had been exposed on the Hubble Space Telescope. Samples of pristine and first and second servicing mission FEP were heated to 200 C and evaluated for changes in density and morphology. We hoped that the results would help explain why FEP degrades in the Hubble Space Telescope space environment

Regulation of Class-Switch Recombination and Plasma Cell Differentiation by Phosphatidylinositol 3-Kinase Signaling

SummaryClass-switch recombination (CSR) is essential for humoral immunity. However, the regulation of CSR is not completely understood. Here we demonstrate that phosphatidylinositol 3-kinase (PI3K) actively suppressed the onset and frequency of CSR in primary B cells. Consistently, mice lacking the lipid phosphatase, PTEN, in B cells exhibited a hyper-IgM condition due to impaired CSR, which could be restored in vitro by specific inhibition of PI3Kδ. Inhibition of CSR by PI3K was partially dependent on the transcription factor, BLIMP1, linking plasma cell commitment and cessation of CSR. PI3K-dependent activation of the serine-threonine kinase, Akt, suppressed CSR, in part, through the inactivation of the Forkhead Box family (Foxo) of transcription factors. Reduced PI3K signaling enhanced the expression of AID (activation-induced cytidine deaminase) and accelerated CSR. However, ectopic expression of AID could not fully overcome inhibition of CSR by PI3K, suggesting that PI3K regulates both the expression and function of AID

The Physical Activity and Redesigned Community Spaces (PARCS) Study: Protocol of a Natural Experiment to Investigate The Impact of Citywide Park Redesign and Renovation

Background: The built environment plays a critical role in promoting physical activity and health. The association between parks, as a key attribute of the built environment, and physical activity, however, remains inconclusive. This project leverages a natural experiment opportunity to assess the impact of the Community Parks Initiative (CPI), a citywide park redesign and renovation effort in New York City, on physical activity, park usage, psychosocial and mental health, and community wellbeing. Methods: The project will use a longitudinal design with matched controls. Thirty intervention park neighborhoods are socio-demographically matched to 20 control park neighborhoods. The study will investigate whether improvements in physical activity, park usage, psychosocial and mental health, and community wellbeing are observed from baseline to 3 years post-renovation among residents in intervention vs. control neighborhoods. Discussion: This study represents a rare opportunity to provide robust evidence to further our understanding of the complex relationship between parks and health. Findings will inform future investments in health-oriented urban design policies and offer evidence for addressing health disparities through built environment strategies

Quantifying humpback whale song sequences to understand the dynamics of song exchange at the ocean basin scale

Humpback whales have a continually evolving vocal sexual display, or "song," that appears to undergo both evolutionary and "revolutionary" change. All males within a population adhere to the current content and arrangement of the song. Populations within an ocean basin share similarities in their songs; this sharing is complex as multiple variations of the song (song types) may be present within a region at any one time. To quantitatively investigate the similarity of song types, songs were compared at both the individual singer and population level using the Levenshtein distance technique and cluster analysis. The highly stereotyped sequences of themes from the songs of 211 individuals from populations within the western and central South Pacific region from 1998 through 2008 were grouped together based on the percentage of song similarity, and compared to qualitatively assigned song types. The analysis produced clusters of highly similar songs that agreed with previous qualitative assignments. Each cluster contained songs from multiple populations and years, confirming the eastward spread of song types and their progressive evolution through the study region. Quantifying song similarity and exchange will assist in understanding broader song dynamics and contribute to the use of vocal displays as population identifiers

Oral anticoagulant underutilization among elderly patients with atrial fibrillation: insights from the United States Medicare database

Background Oral anticoagulants (OACs) mitigate stroke risk in patients with atrial fibrillation (AF). The study aim was to analyze prevalence and predictors of OAC underutilization. Methods Newly diagnosed AF patients with a CHA2DS2-VASc score ≥ 2 were identified from the US CMS Database (January 1, 2013–December 31, 2017). Patients were stratified based on having an OAC prescription versus not and the OAC prescription group was stratified by direct OAC (DOACs) versus warfarin. Multivariable logistic regression models were used to examine predictors of OAC underutilization. Results Among 1,204,507 identified AF patients, 617,611 patients (51.3%) were not prescribed an OAC during follow-up (mean: 2.4 years), and 586,896 patients (48.7%) were prescribed an OAC during this period (DOAC: 388,629 [66.2%]; warfarin: 198,267 [33.8%]). Age ≥ 85 years (odds ratio [OR] 0.55, 95% confidence interval [CI] 0.55–0.56), female sex (OR 0.96, 95% CI 0.95–0.96), Black race (OR 0.78, 95% CI 0.77–0.79) and comorbidities such as gastrointestinal (GI; OR 0.43, 95% CI 0.41–0.44) and intracranial bleeding (OR 0.29, 95% CI 0.28–0.31) were associated with lower utilization of OACs. Furthermore, age ≥ 85 years (OR 0.92, 95% CI 0.91–0.94), Black race (OR 0.78, 95% CI 0.76–0.80), ischemic stroke (OR 0.77, 95% CI 0.75–0.80), GI bleeding (OR 0.73, 95% CI 0.68–0.77), and intracranial bleeding (OR 0.72, 95% CI 0.65–0.80) predicted lower use of DOACs versus warfarin. Conclusions Although OAC therapy prescription is the standard of care for stroke prevention in AF patients, its overall utilization is still low among Medicare patients ≥ 65 years old, with specific patient characteristics that predict underutilization

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Scientific Advice to Public Policy-Making

A feature of policy-making today is its dependence on scientific advice to deliver public policies that are robust, credible, and effective. This paper discusses how policy-making profits from scientific advice in areas where science and technology are significant. Particular attention is given to issues holding a high level of uncertainty, either because of inherent variability, because science is incomplete or controversial, or because data are inadequate to support a definitive answer. First, we analyse the social context that characterises the relationship between science and policy-making, with a focus on the decrease of public confidence in politicians and scientists. Second, we compare three different sets of guidelines on the collection and use of expertise in policy-making (issued by the UK, Canada and the European Commission, respectively) and identify two different approaches to scientific advice in policy-making. Third, based on a set of cross-national and multi-disciplinary case studies, we look at how the relationship between science and policy-making works in practice and propose a set of recommendations towards the establishment of a more robust and effective policy-making process