Poly(ADP-ribose) polymerase-1 is a survival factor for radiation-exposed intestinal epithelial stem cells in vivo

Poly(ADP-ribose) polymerase-1 (PARP-1) is a key enzyme mediating the cellular response to DNA strand breaks. It plays a critical role in genomic stability and survival of proliferating cells in culture undergoing DNA damage. Intestinal epithelium is the most proliferative tissue in the mammalian body and its stem cells show extreme sensitivity to low-level genotoxic stress. We investigated the role of PARP-1 in the in vivo damage response of intestinal stem cells in crypts of PARP-1-/- and control mice following whole-body γ-irradiation (1 Gy). In the PARP-1-/- mice there was a significant delay during the first 6 h in the transient p53 accumulation in stem cells whereas an increased number of cells were positive for p21CIP1/WAF1. Either no or only marginal differences were noted in MDM2 expression, apoptosis, induction of or recovery from mitotic blockage, or inhibition of DNA synthesis. We further observed a dose-dependent reduction in crypt survival measured at 4 days post-irradiation in control mice, and this crypt-killing effect was significantly potentiated in PARP-1-/- mice. Our results thus establish that PARP-1 acts as a survival factor for intestinal stem cells in vivo and suggest a functional link with early p53 and p21CIP1/WAF1 responses

Frequency of coexistent eye diseases and cognitive impairment or dementia: a systematic review and meta-analysis

Objective: We aim to quantify the co-existence of age-related macular degeneration (AMD), glaucoma, or diabetic retinopathy (DR) and cognitive impairment or dementia. Method: MEDLINE, EMBASE, PsycINFO and CINAHL were searched (to June 2020). Observational studies reporting incidence or prevalence of AMD, glaucoma, or DR in people with cognitive impairment or dementia, and of cognitive impairment or dementia among people with AMD, glaucoma, or DR were included. Results: Fifty-six studies (57 reports) were included but marked by heterogeneities in the diagnostic criteria or definitions of the diseases, study design, and case mix. Few studies reported on the incidence. Evidence was sparse but consistent in individuals with mild cognitive impairment where 7.7% glaucoma prevalence was observed. Prevalence of AMD and DR among people with cognitive impairment ranged from 3.9% to 9.4% and from 11.4% to 70.1%, respectively. Prevalence of AMD and glaucoma among people with dementia ranged from 1.4 to 53% and from 0.2% to 25.9%, respectively. Prevalence of DR among people with dementia was 11%. Prevalence of cognitive impairment in people with AMD, glaucoma, and DR ranged from 8.4% to 52.4%, 12.3% to 90.2%, and 3.9% to 77.8%, respectively, and prevalence of dementia in people with AMD, glaucoma and DR ranged from 9.9% to 62.6%, 2.5% to 3.3% and was 12.5%, respectively. Conclusions: Frequency of comorbid eye disease and cognitive impairment or dementia varied considerably. While more population-based estimations of the co-existence are needed, interdisciplinary collaboration might be helpful in the management of these conditions to meet healthcare needs of an ageing population. Trial registration: PROSPERO registration: CRD42020189484

Loss of the acetate switch in <i>Vibrio vulnificus</i> enhances predation defence against <i>Tetrahymena pyriformis</i>.

Vibrio vulnificus is an opportunistic human pathogen and autochthonous inhabitant of coastal marine environments, where the bacterium is under constant predation by heterotrophic protists or protozoans. As a result of this selection pressure, genetic variants with anti-predation mechanisms are selected for and persist in the environment. Such natural variants may also be pathogenic to animal or human hosts, making it important to understand these defence mechanisms. To identify anti-predator strategies, thirteen V. vulnificus strains of different genotypes isolated from diverse environments were exposed to predation by the ciliated protozoan, Tetrahymena pyriformis, and only strain ENV1 was resistant to predation. Further investigation of the cell-free supernatant showed that ENV1 acidifies the environment by the excretion of organic acids, which is toxic to T. pyriformis. As this predation resistance was dependent on the availability of iron, transcriptomes of V. vulnificus in iron-replete and iron-deplete conditions were compared. This analysis revealed that ENV1 ferments pyruvate and the resultant acetyl-CoA leads to acetate synthesis under aerobic conditions, a hallmark of overflow metabolism. The anaerobic respiration global regulator, arcA, was upregulated when iron was available. An ΔarcA deletion mutant of ENV1 accumulated less acetate and importantly, was sensitive to grazing by T. pyriformis. Based on the transcriptome response and quantification of metabolites, we conclude that ENV1 has adapted to overflow metabolism and has lost a control switch that shifts metabolism from acetate excretion to acetate assimilation, enabling it to excrete acetate continuously. We show that overflow metabolism and the acetate switch contribute to prey-predator interactions. Importance Bacteria in the environment, including Vibrio spp., interact with protozoan predators. To defend against predation, bacteria evolve anti-predator mechanisms ranging from changing morphology, biofilm formation and secretion of toxins or virulence factors. Some of these adaptations may result in strains that are pathogenic to humans. Therefore, it is important to study predator defence strategies of environmental bacteria. V. vulnificus thrives in coastal waters and infects humans. Very little is know about the defence mechanisms V. vulnificus expresses against predation. Here we show that a V. vulnificus strain (ENV1) has rewired the central carbon metabolism enabling the production of excess organic acid that is toxic to the protozoan predator, T. pyriformis. This is a previously unknown mechanism of predation defence that protects against protozoan predators

Estrogen receptor-α and progesterone receptor are expressed in label-retaining mammary epithelial cells that divide asymmetrically and retain their template DNA strands

INTRODUCTION: Stem cells of somatic tissues are hypothesized to protect themselves from mutation and cancer risk through a process of selective segregation of their template DNA strands during asymmetric division. Mouse mammary epithelium contains label-retaining epithelial cells that divide asymmetrically and retain their template DNA. METHOD: Immunohistochemistry was used in murine mammary glands that had been labeled with [(3)H]thymidine during allometric growth to investigate the co-expression of DNA label retention and estrogen receptor (ER)-α or progesterone receptor (PR). Using the same methods, we investigated the co-localization of [(3)H]thymidine and ER-α or PR in mammary tissue from mice that had received treatment with estrogen, progesterone, and prolactin subsequent to a long chase period to identify label-retaining cells. RESULTS: Label-retaining epithelial cells (LRECs) comprised approximately 2.0% of the entire mammary epithelium. ER-α-positive and PR-positive cells represented about 30–40% of the LREC subpopulation. Administration of estrogen, progesterone, and prolactin altered the percentage of LRECs expressing ER-α. CONCLUSION: The results presented here support the premise that there is a subpopulation of LRECs in the murine mammary gland that is positive for ER-α and/or PR. This suggests that certain mammary LRECs (potentially stem cells) remain stably positive for these receptors, raising the possibility that LRECs comprise a hierarchy of asymmetrically cycling mammary stem/progenitor cells that are distinguished by the presence or absence of nuclear steroid receptor expression

The impact of angular momentum on black hole accretion rates in simulations of galaxy formation

Feedback from energy liberated by gas accretion onto black holes (BHs) is an attractive mechanism to explain the exponential cut-off at the massive end of the galaxy stellar mass function (SMF). Semi-analytic models of galaxy formation in which this form of feedback is assumed to suppress cooling in haloes where the gas cooling time is large compared to the dynamical time do indeed achieve a good match to the observed SMF. Furthermore, hydrodynamic simulations of individual halos in which gas is assumed to accrete onto the central BH at the Bondi rate have shown that a self-regulating regime is established in which the BH grows just enough to liberate an amount of energy comparable to the thermal energy of the halo. However, this process is efficient at suppressing the growth not only of massive galaxies but also of galaxies like the Milky Way, leading to disagreement with the observed SMF. The Bondi accretion rate, however, is inappropriate when the accreting material has angular momentum. We present an improved accretion model that takes into account the circularisation and subsequent viscous transport of infalling material and include it as a "subgrid" model in hydrodynamic simulations of the evolution of halos with a wide range of masses. The resulting accretion rates are generally low in low mass (\lsim 10^{11.5} \msun) halos, but show outbursts of Eddington-limited accretion during galaxy mergers. During outbursts these objects strongly resemble quasars. In higher mass haloes, gas accretion occurs continuously, typically at $~10$ % of the Eddington rate, which is conducive to the formation of radio jets. The resulting dependence of the accretion behaviour on halo mass induces a break in the relation between galaxy stellar mass and halo mass in these simulations that matches observations

The age of anxiety? It depends where you look: changes in STAI trait anxiety, 1970–2010

Purpose Population-level surveys suggest that anxiety has been increasing in several nations, including the USA and UK. We sought to verify the apparent anxiety increases by looking for systematic changes in mean anxiety questionnaire scores from research publications. Methods We analyzed all available mean State–Trait Anxiety Inventory scores published between 1970 and 2010. We collected 1703 samples, representing more than 205,000 participants from 57 nations. Results Results showed a significant anxiety increase worldwide, but the pattern was less clear in many individual nations. Our analyses suggest that any increase in anxiety in the USA and Canada may be limited to students, anxiety has decreased in the UK, and has remained stable in Australia. Conclusions Although anxiety may have increased worldwide, it might not be increasing as dramatically as previously thought, except in specific populations, such as North American students. Our results seem to contradict survey results from the USA and UK in particular. We do not claim that our results are more reliable than those of large population surveys. However, we do suggest that mental health surveys and other governmental sources of disorder prevalence data may be partially biased by changing attitudes toward mental health: if respondents are more aware and less ashamed of their anxiety, they are more likely to report it to survey takers. Analyses such as ours provide a useful means of double-checking apparent trends in large population surveys

TLR9 Agonist Protects Mice from Radiation-Induced Gastrointestinal Syndrome

Radiation-induced gastrointestinal syndrome (RIGS) is due to the clonogenic loss of crypt cells and villi depopulation, resulting in disruption of mucosal barrier, bacterial invasion, inflammation and sepsis. Intestinal macrophages could recognize invading bacterial DNA via TLR9 receptors and transmit regenerative signals to the neighboring crypt. We therefore investigated whether systemic administration of designer TLR9 agonist could ameliorate RIGS by activating TLR9.Male C57Bl6 mice were distributed in four experimental cohorts, whole body irradiation (WBI) (8.4-10.4 Gy), TLR9 agonist (1 mg/kg s.c.), 1 h pre- or post-WBI and TLR9 agonist+WBI+iMyd88 (pretreatment with inhibitory peptide against Myd88). Animals were observed for survival and intestine was harvested for histological analysis. BALB/c mice with CT26 colon tumors in abdominal wall were irradiated with 14 Gy single dose of whole abdominal irradiation (AIR) for tumor growth study.Mice receiving pre-WBI TLR9 agonist demonstrated improvement of survival after 10.4 Gy (p<0.03), 9.4 Gy (p<0.008) and 8.4 Gy (p<0.002) of WBI, compared to untreated or iMyd88-treated controls. Post-WBI TLR9 agonist mitigates up to 8.4 Gy WBI (p<0.01). Histological analysis and xylose absorption test demonstrated significant structural and functional restitution of the intestine in WBI+TLR9 agonist cohorts. Although, AIR reduced tumor growth, all animals died within 12 days from RIGS. TLR9 agonist improved the survival of mice beyond 28 days post-AIR (p<0.008) with significant reduction of tumor growth (p<0.0001).TLR9 agonist treatment could serve both as a prophylactic or mitigating agent against acute radiation syndrome and also as an adjuvant therapy to increase the therapeutic ratio of abdominal Radiation Therapy for Gastro Intestinal malignancies

Health services research in the public healthcare system in Hong Kong: An analysis of over 1 million antihypertensive prescriptions between 2004-2007 as an example of the potential and pitfalls of using routinely collected electronic patient data

&lt;b&gt;Objectives&lt;/b&gt; Increasing use is being made of routinely collected electronic patient data in health services research. The aim of the present study was to evaluate the potential usefulness of a comprehensive database used routinely in the public healthcare system in Hong Kong, using antihypertensive drug prescriptions in primary care as an example.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods&lt;/b&gt; Data on antihypertensive drug prescriptions were retrieved from the electronic Clinical Management System (e-CMS) of all primary care clinics run by the Health Authority (HA) in the New Territory East (NTE) cluster of Hong Kong between January 2004 and June 2007. Information was also retrieved on patients’ demographic and socioeconomic characteristics, visit type (new or follow-up), and relevant diseases (International Classification of Primary Care, ICPC codes). &lt;p&gt;&lt;/p&gt; &lt;b&gt;Results&lt;/b&gt; 1,096,282 visit episodes were accessed, representing 93,450 patients. Patients’ demographic and socio-economic details were recorded in all cases. Prescription details for anti-hypertensive drugs were missing in only 18 patients (0.02%). However, ICPC-code was missing for 36,409 patients (39%). Significant independent predictors of whether disease codes were applied included patient age &gt; 70 years (OR 2.18), female gender (OR 1.20), district of residence (range of ORs in more rural districts; 0.32-0.41), type of clinic (OR in Family Medicine Specialist Clinics; 1.45) and type of visit (OR follow-up visit; 2.39). &lt;p&gt;&lt;/p&gt; In the 57,041 patients with an ICPC-code, uncomplicated hypertension (ICPC K86) was recorded in 45,859 patients (82.1%). The characteristics of these patients were very similar to those of the non-coded group, suggesting that most non-coded patients on antihypertensive drugs are likely to have uncomplicated hypertension. &lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusion&lt;/b&gt; The e-CMS database of the HA in Hong Kong varies in quality in terms of recorded information. Potential future health services research using demographic and prescription information is highly feasible but for disease-specific research dependant on ICPC codes some caution is warranted. In the case of uncomplicated hypertension, future research on pharmaco-epidemiology (such as prescription patterns) and clinical issues (such as side-effects of medications on metabolic parameters) seems feasible given the large size of the data set and the comparability of coded and non-coded patients