High-resolution 3D imaging uncovers organ-specific vascular control of tissue aging

Blood vessels provide supportive microenvironments for maintaining tissue functions. Age-associated vascular changes and their relation to tissue aging and pathology are poorly understood. Here, we perform 3D imaging of young and aging vascular beds. Multiple organs in mice and humans demonstrate an age-dependent decline in vessel density and pericyte numbers, while highly remodeling tissues such as skin preserve the vasculature. Vascular attrition precedes the appearance of cellular hallmarks of aging such as senescence. Endothelial VEGFR2 loss-of-function mice demonstrate that vascular perturbations are sufficient to stimulate cellular changes coupled with aging. Age-associated tissue-specific molecular changes in the endothelium drive vascular loss and dictate pericyte to fibroblast differentiation. Lineage tracing of perivascular cells with inducible PDGFRβ and NG2 Cre mouse lines demonstrated that increased pericyte to fibroblast differentiation distinguishes injury-induced organ fibrosis and zymosan-induced arthritis. To spur further discoveries, we provide a freely available resource with 3D vascular and tissue maps

SARS-CoV-2 anti-spike IgG antibody responses after second dose of ChAdOx1 or BNT162b2 and correlates of protection in the UK general population

Antibody responses are an important part of immunity after Coronavirus Disease 2019 (COVID-19) vaccination. However, antibody trajectories and the associated duration of protection after a second vaccine dose remain unclear. In this study, we investigated anti-spike IgG antibody responses and correlates of protection after second doses of ChAdOx1 or BNT162b2 vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the United Kingdom general population. In 222,493 individuals, we found significant boosting of anti-spike IgG by the second doses of both vaccines in all ages and using different dosing intervals, including the 3-week interval for BNT162b2. After second vaccination, BNT162b2 generated higher peak levels than ChAdOX1. Older individuals and males had lower peak levels with BNT162b2 but not ChAdOx1, whereas declines were similar across ages and sexes with ChAdOX1 or BNT162b2. Prior infection significantly increased antibody peak level and half-life with both vaccines. Anti-spike IgG levels were associated with protection from infection after vaccination and, to an even greater degree, after prior infection. At least 67% protection against infection was estimated to last for 2–3 months after two ChAdOx1 doses, for 5–8 months after two BNT162b2 doses in those without prior infection and for 1–2 years for those unvaccinated after natural infection. A third booster dose might be needed, prioritized to ChAdOx1 recipients and those more clinically vulnerable

Dermatofibrosarcoma protuberans treated by micrographic surgery

Dermatofibrosarcoma protuberans is an uncommon cutaneous tumour which rarely metastasises. However, local recurrence following apparently adequate surgical excision is well recognised, presumably as a result of sub-clinical contiguous growth, for which micrographically controlled excision would be a logical treatment. A retrospective study of all patients treated by micrographic surgery, from April 1995–March 2000, at a tertiary skin oncology centre. Twenty-one patients (11 males), age 14 to 71 years with dermatofibrosarcoma protuberans on the trunk (10 patients), groin (four), head and neck (four), and limbs (three) were treated. In 15 patients one micrographic layer cleared the tumour, and four were cleared with two layers. For one patient the second stage was completed by conventional excision guided by positive margins. Another patient with a multiply recurrent perineal dermatofibrosarcoma protuberans, not cleared in one area after two layers, died from a pulmonary embolus before total clearance could be achieved. There was no correlation between tumour size and lateral excision margin. No recurrence was observed during the follow-up, from 21 to 80 months, median 47 months. The study provides further support for micrographic surgery as the treatment of choice for dermatofibrosarcoma protuberans

Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer

Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies

Measurement of the cross-section of high transverse momentum vector bosons reconstructed as single jets and studies of jet substructure in pp collisions at √s = 7 TeV with the ATLAS detector

This paper presents a measurement of the cross-section for high transverse momentum W and Z bosons produced in pp collisions and decaying to all-hadronic final states. The data used in the analysis were recorded by the ATLAS detector at the CERN Large Hadron Collider at a centre-of-mass energy of √s = 7 TeV;{\rm Te}{\rm V}$and correspond to an integrated luminosity of$4.6\;{\rm f}{{{\rm b}}^{-1}}$. The measurement is performed by reconstructing the boosted W or Z bosons in single jets. The reconstructed jet mass is used to identify the W and Z bosons, and a jet substructure method based on energy cluster information in the jet centre-of-mass frame is used to suppress the large multi-jet background. The cross-section for events with a hadronically decaying W or Z boson, with transverse momentum${{p}_{{\rm T}}}\gt 320\;{\rm Ge}{\rm V}$and pseudorapidity$|\eta |\lt 1.9$, is measured to be${{\sigma }_{W+Z}}=8.5\pm 1.7$ pb and is compared to next-to-leading-order calculations. The selected events are further used to study jet grooming techniques

Search for direct pair production of the top squark in all-hadronic final states in proton-proton collisions at s√=8 TeV with the ATLAS detector

The results of a search for direct pair production of the scalar partner to the top quark using an integrated luminosity of 20.1fb−1 of proton–proton collision data at √s = 8 TeV recorded with the ATLAS detector at the LHC are reported. The top squark is assumed to decay via t˜→tχ˜01 or t˜→ bχ˜±1 →bW(∗)χ˜01 , where χ˜01 (χ˜±1 ) denotes the lightest neutralino (chargino) in supersymmetric models. The search targets a fully-hadronic final state in events with four or more jets and large missing transverse momentum. No significant excess over the Standard Model background prediction is observed, and exclusion limits are reported in terms of the top squark and neutralino masses and as a function of the branching fraction of t˜ → tχ˜01 . For a branching fraction of 100%, top squark masses in the range 270–645 GeV are excluded for χ˜01 masses below 30 GeV. For a branching fraction of 50% to either t˜ → tχ˜01 or t˜ → bχ˜±1 , and assuming the χ˜±1 mass to be twice the χ˜01 mass, top squark masses in the range 250–550 GeV are excluded for χ˜01 masses below 60 GeV

Search for pair-produced long-lived neutral particles decaying to jets in the ATLAS hadronic calorimeter in ppcollisions at √s=8TeV

The ATLAS detector at the Large Hadron Collider at CERN is used to search for the decay of a scalar boson to a pair of long-lived particles, neutral under the Standard Model gauge group, in 20.3fb−1of data collected in proton–proton collisions at √s=8TeV. This search is sensitive to long-lived particles that decay to Standard Model particles producing jets at the outer edge of the ATLAS electromagnetic calorimeter or inside the hadronic calorimeter. No significant excess of events is observed. Limits are reported on the product of the scalar boson production cross section times branching ratio into long-lived neutral particles as a function of the proper lifetime of the particles. Limits are reported for boson masses from 100 GeVto 900 GeV, and a long-lived neutral particle mass from 10 GeVto 150 GeV

Assessing an organizational culture instrument based on the Competing Values Framework: Exploratory and confirmatory factor analyses

BACKGROUND: The Competing Values Framework (CVF) has been widely used in health services research to assess organizational culture as a predictor of quality improvement implementation, employee and patient satisfaction, and team functioning, among other outcomes. CVF instruments generally are presented as well-validated with reliable aggregated subscales. However, only one study in the health sector has been conducted for the express purpose of validation, and that study population was limited to hospital managers from a single geographic locale. METHODS: We used exploratory and confirmatory factor analyses to examine the underlying structure of data from a CVF instrument. We analyzed cross-sectional data from a work environment survey conducted in the Veterans Health Administration (VHA). The study population comprised all staff in non-supervisory positions. The survey included 14 items adapted from a popular CVF instrument, which measures organizational culture according to four subscales: hierarchical, entrepreneurial, team, and rational. RESULTS: Data from 71,776 non-supervisory employees (approximate response rate 51%) from 168 VHA facilities were used in this analysis. Internal consistency of the subscales was moderate to strong (α = 0.68 to 0.85). However, the entrepreneurial, team, and rational subscales had higher correlations across subscales than within, indicating poor divergent properties. Exploratory factor analysis revealed two factors, comprising the ten items from the entrepreneurial, team, and rational subscales loading on the first factor, and two items from the hierarchical subscale loading on the second factor, along with one item from the rational subscale that cross-loaded on both factors. Results from confirmatory factor analysis suggested that the two-subscale solution provides a more parsimonious fit to the data as compared to the original four-subscale model. CONCLUSION: This study suggests that there may be problems applying conventional CVF subscales to non-supervisors, and underscores the importance of assessing psychometric properties of instruments in each new context and population to which they are applied. It also further highlights the challenges management scholars face in assessing organizational culture in a reliable and comparable way. More research is needed to determine if the emergent two-subscale solution is a valid or meaningful alternative and whether these findings generalize beyond VHA

Predicting Inactive Conformations of Protein Kinases Using Active Structures: Conformational Selection of Type-II Inhibitors

Protein kinases have been found to possess two characteristic conformations in their activation-loops: the active DFG-in conformation and the inactive DFG-out conformation. Recently, it has been very interesting to develop type-II inhibitors which target the DFG-out conformation and are more specific than the type-I inhibitors binding to the active DFG-in conformation. However, solving crystal structures of kinases with the DFG-out conformation remains a challenge, and this seriously hampers the application of the structure-based approaches in development of novel type-II inhibitors. To overcome this limitation, here we present a computational approach for predicting the DFG-out inactive conformation using the DFG-in active structures, and develop related conformational selection protocols for the uses of the predicted DFG-out models in the binding pose prediction and virtual screening of type-II ligands. With the DFG-out models, we predicted the binding poses for known type-II inhibitors, and the results were found in good agreement with the X-ray crystal structures. We also tested the abilities of the DFG-out models to recognize their specific type-II inhibitors by screening a database of small molecules. The AUC (area under curve) results indicated that the predicted DFG-out models were selective toward their specific type-II inhibitors. Therefore, the computational approach and protocols presented in this study are very promising for the structure-based design and screening of novel type-II kinase inhibitors

Addiction Treatment and Stable Housing among a Cohort of Injection Drug Users

Background: Unstable housing and homelessness is prevalent among injection drug users (IDU). We sought to examine whether accessing addiction treatment was associated with attaining stable housing in a prospective cohort of IDU in Vancouver, Canada. Methods: We used data collected via the Vancouver Injection Drug User Study (VIDUS) between December 2005 and April 2010. Attaining stable housing was defined as two consecutive ‘‘stable housing’ ’ designations (i.e., living in an apartment or house) during the follow-up period. We assessed exposure to addiction treatment in the interview prior to the attainment of stable housing among participants who were homeless or living in single room occupancy (SRO) hotels at baseline. Bivariate and multivariate associations between the baseline and time-updated characteristics and attaining stable housing were examined using Cox proportional hazard regression models. Principal Findings: Of the 992 IDU eligible for this analysis, 495 (49.9%) reported being homeless, 497 (50.1%) resided in SRO hotels, and 380 (38.3%) were enrolled in addiction treatment at the baseline interview. Only 211 (21.3%) attained stable housing during the follow-up period and of this group, 69 (32.7%) had addiction treatment exposure prior to achieving stable housing. Addiction treatment was inversely associated with attaining stable housing in a multivariate model (adjusted hazard ratio [AHR] = 0.71; 95 % CI: 0.52–0.96). Being in a partnered relationship was positively associated with the primary outcom