The FKBP5 Gene Affects Alcohol Drinking in Knockout Mice and Is Implicated in Alcohol Drinking in Humans

FKBP5 encodes FK506-binding protein 5, a glucocorticoid receptor (GR)-binding protein implicated in various psychiatric disorders and alcohol withdrawal severity. The purpose of this study is to characterize alcohol preference and related phenotypes in Fkbp5 knockout (KO) mice and to examine the role of FKBP5 in human alcohol consumption. The following experiments were performed to characterize Fkpb5 KO mice. (1) Fkbp5 KO and wild-type (WT) EtOH consumption was tested using a two-bottle choice paradigm; (2) The EtOH elimination rate was measured after intraperitoneal (IP) injection of 2.0 g/kg EtOH; (3) Blood alcohol concentration (BAC) was measured after 3 h limited access of alcohol; (4) Brain region expression of Fkbp5 was identified using LacZ staining; (5) Baseline corticosterone (CORT) was assessed. Additionally, two SNPs, rs1360780 (C/T) and rs3800373 (T/G), were selected to study the association of FKBP5 with alcohol consumption in humans. Participants were college students (n = 1162) from 21–26 years of age with Chinese, Korean or Caucasian ethnicity. The results, compared to WT mice, for KO mice exhibited an increase in alcohol consumption that was not due to differences in taste sensitivity or alcohol metabolism. Higher BAC was found in KO mice after 3 h of EtOH access. Fkbp5 was highly expressed in brain regions involved in the regulation of the stress response, such as the hippocampus, amygdala, dorsal raphe and locus coeruleus. Both genotypes exhibited similar basal levels of plasma corticosterone (CORT). Finally, single nucleotide polymorphisms (SNPs) in FKBP5 were found to be associated with alcohol drinking in humans. These results suggest that the association between FKBP5 and alcohol consumption is conserved in both mice and humans

Multiple populations in globular clusters. Lessons learned from the Milky Way globular clusters

Recent progress in studies of globular clusters has shown that they are not simple stellar populations, being rather made of multiple generations. Evidence stems both from photometry and spectroscopy. A new paradigm is then arising for the formation of massive star clusters, which includes several episodes of star formation. While this provides an explanation for several features of globular clusters, including the second parameter problem, it also opens new perspectives about the relation between globular clusters and the halo of our Galaxy, and by extension of all populations with a high specific frequency of globular clusters, such as, e.g., giant elliptical galaxies. We review progress in this area, focusing on the most recent studies. Several points remain to be properly understood, in particular those concerning the nature of the polluters producing the abundance pattern in the clusters and the typical timescale, the range of cluster masses where this phenomenon is active, and the relation between globular clusters and other satellites of our Galaxy.Comment: In press (The Astronomy and Astrophysics Review

STOX1 deficiency is associated with renin-mediated gestational hypertension and placental defects

The pathogenesis of preeclampsia and other hypertensive disorders of pregnancy remains poorly defined despite the substantial burden of maternal and neonatal morbidity associated with these conditions. In particular, the role of genetic variants as determinants of disease susceptibility is understudied. Storkhead-box protein 1 (STOX1) was first identified as a preeclampsia risk gene through family-based genetic linkage studies in which loss-of-function variants were proposed to underlie increased preeclampsia susceptibility. We generated a genetic Stox1 loss-of-function mouse model (Stox1 KO) to evaluate whether STOX1 regulates blood pressure in pregnancy. Pregnant Stox1-KO mice developed gestational hypertension evidenced by a significant increase in blood pressure compared with WT by E17.5. While severe renal, placental, or fetal growth abnormalities were not observed, the Stox1-KO phenotype was associated with placental vascular and extracellular matrix abnormalities. Mechanistically, we found that gestational hypertension in Stox1-KO mice resulted from activation of the uteroplacental renin-angiotensin system. This mechanism was supported by showing that treatment of pregnant Stox1-KO mice with an angiotensin II receptor blocker rescued the phenotype. Our study demonstrates the utility of genetic mouse models for uncovering links between genetic variants and effector pathways implicated in the pathogenesis of hypertensive disorders of pregnancy

DESIGN, ENGINEERING, AND ASSESSMENT OF MOBILE MINEFIELDS

Naval mine warfare typically supports a sea denial strategy through the denial and/or delay of the enemy’s use of the water space or by controlling sea traffic in a designated area. Sea mines have been effective for decades. However, with technological progress, mine countermeasure (MCM) efforts have reduced the risks of a minefield by detecting and/or neutralizing mines to establish and maintain a Q-route for safe passage. The concept of a mobile minefield is proposed to increase the difficulty of the enemy’s MCM and improve the survivability of the minefield by adding mobility. This research explores both the physical design concepts and the operational effectiveness of mobile mines based on simulations and models. The simulation results show that, compared to static mines, mobile mines improved the number of enemy ships destroyed by at least 200% and increased the time it took the enemy to transition through the minefield by 50%. The results suggest that the mobile minefield would be operationally useful for the Department of the Navy and this technology is worth pursing and exploring.Distribution Statement A. Approved for public release: Distribution is unlimited.Captain, Singapore ArmyCaptain, Singapore ArmyMajor, Singapore ArmyLieutenant, Taiwan NavyMajor, United States ArmyCivilian, Department of the NavyLieutenant, United States NavyCivilian, Singapore Technologies Engineering, SingaporeMajor, Singapore ArmyMajor, Singapore ArmyMajor, Singapore ArmyCommander, United States NavyCivilian, Defense Science and Technology Agency (DSTA), SingaporeMajor, Singapore ArmyMajor, Republic of Singapore Air ForceTenente-Coronel, Brazilian Air ForceLieutenant, United States NavyCivilian, Department of the ArmyMajor, Singapore ArmyMajor, Israel Defense ForcesCivilian, Defense Science Organisation, SingaporeCaptain, Singapore Arm

Bi-galileon theory II: phenomenology

We continue to introduce bi-galileon theory, the generalisation of the single galileon model introduced by Nicolis et al. The theory contains two coupled scalar fields and is described by a Lagrangian that is invariant under Galilean shifts in those fields. This paper is the second of two, and focuses on the phenomenology of the theory. We are particularly interesting in models that admit solutions that are asymptotically self accelerating or asymptotically self tuning. In contrast to the single galileon theories, we find examples of self accelerating models that are simultaneously free from ghosts, tachyons and tadpoles, able to pass solar system constraints through Vainshtein screening, and do not suffer from problems with superluminality, Cerenkov emission or strong coupling. We also find self tuning models and discuss how Weinberg's no go theorem is evaded by breaking Poincar\'e invariance in the scalar sector. Whereas the galileon description is valid all the way down to solar system scales for the self-accelerating models, unfortunately the same cannot be said for self tuning models owing to the scalars backreacting strongly on to the geometry

Differential Effects of Peptidoglycan Recognition Proteins on Experimental Atopic and Contact Dermatitis Mediated by Treg and Th17 Cells

Skin protects the body from the environment and is an important component of the innate and adaptive immune systems. Atopic dermatitis and contact dermatitis are among the most frequent inflammatory skin diseases and are both determined by multigenic predisposition, environmental factors, and aberrant immune response. Peptidoglycan Recognition Proteins (Pglyrps) are expressed in the skin and we report here that they modulate sensitivity to experimentally-induced atopic dermatitis and contact dermatitis. Pglyrp3−/− and Pglyrp4−/− mice (but not Pglyrp2−/− mice) develop more severe oxazolone-induced atopic dermatitis than wild type (WT) mice. The common mechanism underlying this increased sensitivity of Pglyrp3−/− and Pglyrp4−/− mice to atopic dermatitis is reduced recruitment of Treg cells to the skin and enhanced production and activation Th17 cells in Pglyrp3−/− and Pglyrp4−/− mice, which results in more severe inflammation and keratinocyte proliferation. This mechanism is supported by decreased inflammation in Pglyrp3−/− mice following in vivo induction of Treg cells by vitamin D or after neutralization of IL-17. By contrast, Pglyrp1−/− mice develop less severe oxazolone-induced atopic dermatitis and also oxazolone-induced contact dermatitis than WT mice. Thus, Pglyrp3 and Pglyrp4 limit over-activation of Th17 cells by promoting accumulation of Treg cells at the site of chronic inflammation, which protects the skin from exaggerated inflammatory response to cell activators and allergens, whereas Pglyrp1 has an opposite pro-inflammatory effect in the skin

ATOMS : ALMA three-millimeter observations of massive star-forming regions - III. Catalogues of candidate hot molecular cores and hyper/ultra compact H II regions

A correction has been published: Monthly Notices of the Royal Astronomical Society, Volume 511, Issue 1, March 2022, Pages 501–505, https://doi.org/10.1093/mnras/stac039We have identified 453 compact dense cores in 3mm continuum emission maps in the ALMA Three-millimetre Observations of Massive Star-forming regions survey, and compiled three catalogues of high-mass star-forming cores. One catalogue, referred to as hyper/ultra compact (H/UC)-HII catalogue, includes 89 cores that enshroud H/UC HII regions as characterized by associated compact H40 alpha emission. A second catalogue, referred to as pure s-cHMC, includes 32 candidate hot molecular cores (HMCs) showing rich spectra (N >= 20 lines) of complex organic molecules (COMs) and not associated with H/UC-HII regions. The third catalogue, referred to as pure w-cHMC, includes 58 candidate HMCs with relatively low levels of COM richness and not associated with H/UC-Hii regions. These three catalogues of dense cores provide an important foundation for future studies of the early stages of high-mass star formation across the Milky Way. We also find that nearly half of H/UC-HII cores are candidate HMCs. From the number counts of COM-containing and H/UC-HII cores, we suggest that the duration of high-mass protostellar cores showing chemically rich features is at least comparable to the lifetime of H/UC-HII regions. For cores in the H/UC-HII catalogue, the width of the H40 alpha line increases as the core size decreases, suggesting that the non-thermal dynamical and/or pressure line-broadening mechanisms dominate on the smaller scales of the H/UC-HII cores.Peer reviewe

Oxidative Stress in Zebrafish (Danio rerio) Sperm

Laboratories around the world have produced tens of thousands of mutant and transgenic zebrafish lines. As with mice, maintaining all of these valuable zebrafish genotypes is expensive, risky, and beyond the capacity of even the largest stock centers. Because reducing oxidative stress has become an important aspect of reducing the variability in mouse sperm cryopreservation, we examined whether antioxidants might improve cryopreservation of zebrafish sperm. Four experiments were conducted in this study. First, we used the xanthine-xanthine oxidase (X-XO) system to generate reactive oxygen species (ROS). The X-XO system was capable of producing a stress reaction in zebrafish sperm reducing its sperm motility in a concentration dependent manner (P<0.05). Second, we examined X-XO and the impact of antioxidants on sperm viability, ROS and motility. Catalase (CAT) mitigated stress and maintained viability and sperm motility (P>0.05), whereas superoxide dismutase (SOD) and vitamin E did not (P<0.05). Third, we evaluated ROS in zebrafish spermatozoa during cryopreservation and its effect on viability and motility. Methanol (8%) reduced viability and sperm motility (P<0.05), but the addition of CAT mitigated these effects (P>0.05), producing a mean 2.0 to 2.9-fold increase in post-thaw motility. Fourth, we examined the effect of additional cryoprotectants and CAT on fresh sperm motility. Cryoprotectants, 8% methanol and 10% dimethylacetamide (DMA), reduced the motility over the control value (P<0.5), whereas 10% dimethylformamide (DMF) with or without CAT did not (P>0.05). Zebrafish sperm protocols should be modified to improve the reliability of the cryopreservation process, perhaps using a different cryoprotectant. Regardless, the simple addition of CAT to present-day procedures will significantly improve this process, assuring increased and less variable fertilization success and allowing resource managers to dependably plan how many straws are needed to safely cryopreserve a genetic line

The quality of research synthesis in surgery: the case of laparoscopic surgery for colorectal cancer

Peer reviewedPublisher PD

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700