254 research outputs found
Anisotropy dissipation in brane-world inflation
We examine the behavior of an anisotropic brane-world in the presence of
inflationary scalar fields. We show that, contrary to naive expectations, a
large anisotropy does not adversely affect inflation. On the contrary, a large
initial anisotropy introduces more damping into the scalar field equation of
motion, resulting in greater inflation. The rapid decay of anisotropy in the
brane-world significantly increases the class of initial conditions from which
the observed universe could have originated. This generalizes a similar result
in general relativity. A unique feature of Bianchi I brane-world cosmology
appears to be that for scalar fields with a large kinetic term the initial
expansion of the universe is quasi-isotropic. The universe grows more
anisotropic during an intermediate transient regime until anisotropy finally
disappears during inflationary expansion.Comment: 6 pages, 5 figures; minor typo corrected in Eq. (16); matches version
to appear in Phy Rev
Brane Decay of a (4+n)-Dimensional Rotating Black Hole. II: spin-1 particles
The present works complements and expands a previous one, focused on the
emission of scalar fields by a (4+n)-dimensional rotating black hole on the
brane, by studying the emission of gauge fields on the brane from a similar
black hole. A comprehensive analysis of the particle, energy and angular
momentum emission rates is undertaken, for arbitrary angular momentum of the
black hole and dimensionality of spacetime. Our analysis reveals the existence
of a number of distinct features associated with the emission of spin-1 fields
from a rotating black hole on the brane, such as the behaviour and magnitude of
the different emission rates, the angular distribution of particles and energy,
the relative enhancement compared to the scalar fields, and the magnitude of
the superradiance effect. Apart from their theoretical interest, these features
can comprise clear signatures of the emission of Hawking radiation from a
brane-world black hole during its spin-down phase upon successful detection of
this effect during an experiment.Comment: 35 pages, 19 figures, Latex fil
FGF21, a liver hormone that inhibits alcohol intake in mice, increases in human circulation after acute alcohol ingestion and sustained binge drinking at Oktoberfest
Objective: Excessive alcohol consumption is a leading cause of global morbidity and mortality. However, knowledge of the biological factors that influence ad libitum alcohol intake may be incomplete. Two large studies recently linked variants in the KLB locus with levels of alcohol intake in humans. KLB encodes Ξ²-klotho, co-receptor for the liver-derived hormone fibroblast growth factor 21 (FGF21). In mice, FGF21 reduces alcohol intake, and human Fgf21 variants are enriched among heavy drinkers. Thus, the liver may limit alcohol consumption by secreting FGF21. However, whether full-length, active plasma FGF21 (FGF21 (1β181)) levels in humans increase acutely or sub-chronically in response to alcohol ingestion is uncertain. Methods: We recruited 10 healthy, fasted male subjects to receive an oral water or alcohol bolus with concurrent blood sampling for FGF21 (1β181) measurement in plasma. In addition, we measured circulating FGF21 (1β181) levels, liver stiffness, triglyceride, and other metabolic parameters in three healthy Danish men before and after consuming an average of 22.6 beers/person/day (4.4Β g/kg/day of ethanol) for three days during Oktoberfest 2017 in Munich, Germany. We further correlated fasting FGF21 (1β181) levels in 49 healthy, non-alcoholic subjects of mixed sex with self-reports of alcohol-related behaviors, emotional responses, and problems. Finally, we characterized the effect of recombinant human FGF21 injection on ad libitum alcohol intake in mice. Results: We show that alcohol ingestion (25.3Β g or βΌ2.5 standard drinks) acutely increases plasma levels of FGF21 (1β181) 3.4-fold in fasting humans. We also find that binge drinking for three days at Oktoberfest is associated with a 2.1-fold increase in baseline FGF21 (1β181) levels, in contrast to minor deteriorations in metabolic and hepatic biomarkers. However, basal FGF21 (1β181) levels were not correlated with differences in alcohol-related behaviors, emotional responses, or problems in our non-alcoholic subjects. Finally, we show that once-daily injection of recombinant human FGF21 reduces ad libitum alcohol intake by 21% in mice. Conclusions: FGF21 (1β181) is markedly increased in circulation by both acute and sub-chronic alcohol intake in humans, and reduces alcohol intake in mice. These observations are consistent with a role for FGF21 as an endocrine inhibitor of alcohol appetite in humans. Keywords: Fibroblast growth factor 21, FGF21, Alcohol, Alcohol appetit
Dynamics of Brane-World Cosmological Models
We show that generically the initial singularity is isotropic in spatially
homogeneous cosmological models in the brane-world scenario. We then argue that
it is plausible that the initial singularity is isotropic in typical brane
world cosmological models. Therefore, brane cosmology naturally gives rise to a
set of initial data that provide the conditions for inflation to subsequently
take place, thereby solving the initial conditions problem and leading to a
self--consistent and viable cosmology.Comment: Final version. To appear in Physical Revie
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Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.
Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF β₯5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants
A genetically modified minipig model for Alzheimer's disease with SORL1 haploinsufficiency
The established causal genes in Alzheimerβs disease (AD), APP, PSEN1, and PSEN2, are functionally characterized using biomarkers, capturing an inΒ vivo profile reflecting the diseaseβs initial preclinical phase. Mutations in SORL1, encoding the endosome recycling receptor SORLA, are found in 2%β3% of individuals with early-onset AD, and SORL1 haploinsufficiency appears to be causal for AD. To test whether SORL1 can function as an AD causal gene, we use CRISPR-Cas9-based gene editing to develop a model of SORL1 haploinsufficiency in GΓΆttingen minipigs, taking advantage of porcine models for biomarker investigations. SORL1 haploinsufficiency in young adult minipigs is found to phenocopy the preclinical inΒ vivo profile of AD observed with APP, PSEN1, and PSEN2, resulting in elevated levels of Ξ²-amyloid (AΞ²) and tau preceding amyloid plaque formation and neurodegeneration, as observed in humans. Our study provides functional support for the theory that SORL1 haploinsufficiency leads to endosome cytopathology with biofluid hallmarks of autosomal dominant AD
Fraction of Inspired Oxygen During General Anesthesia for Non-Cardiac Surgery:Systematic Review and Meta-Analysis
BACKGROUND: Controversy exists regarding the effects of a high versus a low intraoperative fraction of inspired oxygen (FiO(2)) in adults undergoing general anesthesia. This systematic review and metaβanalysis investigated the effect of a high versus a low FiO(2) on postoperative outcomes. METHODS: PubMed and Embase were searched on March 22, 2022 for randomized clinical trials investigating the effect of different FiO(2) levels in adults undergoing general anesthesia for nonβcardiac surgery. Two investigators independently reviewed studies for relevance, extracted data, and assessed risk of bias. Metaβanalyses were performed for relevant outcomes, and potential effect measure modification was assessed in subgroup analyses and metaβregression. The evidence certainty was evaluated using GRADE. RESULTS: This review included 25 original trials investigating the effect of a high (mostly 80%) versus a low (mostly 30%) FiO(2). Risk of bias was intermediate for all trials. A high FiO(2) did not result in a significant reduction in surgical site infections (OR: 0.91, 95% CI 0.81β1.02 [pΒ =Β .10]). No effect was found for all other included outcomes, including mortality (ORΒ =Β 1.27, 95% CI: 0.90β1.79 [pΒ =Β .18]) and hospital length of stay (mean differenceΒ =Β 0.03βdays, 95% CI β0.25 to 0.30 [pΒ =Β .84). Results from subgroup analyses and metaβregression did not identify any clear effect modifiers across outcomes. The certainty of evidence (GRADE) was rated as low for most outcomes. CONCLUSIONS: In adults undergoing general anesthesia for nonβcardiac surgery, a high FiO(2) did not improve outcomes including surgical site infections, length of stay, or mortality. However, the certainty of the evidence was assessed as low
Goal-directed haemodynamic therapy during general anaesthesia for noncardiac surgery:a systematic review and meta-analysis
BACKGROUND: During general anaesthesia for noncardiac surgery, there remain knowledge gaps regarding the effect of goal-directed haemodynamic therapy on patient-centred outcomes. METHODS: Included clinical trials investigated goal-directed haemodynamic therapy during general anaesthesia in adults undergoing noncardiac surgery and reported at least one patient-centred postoperative outcome. PubMed and Embase were searched for relevant articles on March 8, 2021. Two investigators performed abstract screening, full-text review, data extraction, and bias assessment. The primary outcomes were mortality and hospital length of stay, whereas 15 postoperative complications were included based on availability. From a main pool of comparable trials, meta-analyses were performed on trials with homogenous outcome definitions. Certainty of evidence was evaluated using Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). RESULTS: The main pool consisted of 76 trials with intermediate risk of bias for most outcomes. Overall, goal-directed haemodynamic therapy might reduce mortality (odds ratio=0.84; 95% confidence interval [CI], 0.64 to 1.09) and shorten length of stay (mean difference=β0.72 days; 95% CI, β1.10 to β0.35) but with low certainty in the evidence. For both outcomes, larger effects favouring goal-directed haemodynamic therapy were seen in abdominal surgery, very high-risk surgery, and using targets based on preload variation by the respiratory cycle. However, formal tests for subgroup differences were not statistically significant. Goal-directed haemodynamic therapy decreased risk of several postoperative outcomes, but only infectious outcomes and anastomotic leakage reached moderate certainty of evidence. CONCLUSIONS: Goal-directed haemodynamic therapy during general anaesthesia might decrease mortality, hospital length of stay, and several postoperative complications. Only infectious postoperative complications and anastomotic leakage reached moderate certainty in the evidence
Vaccinia Scars Associated with Improved Survival among Adults in Rural Guinea-Bissau
BACKGROUND: In urban Guinea-Bissau, adults with a vaccinia scar had better survival but also a higher prevalence of HIV-2 infection. We therefore investigated the association between vaccinia scar and survival and HIV infection in a rural area of Guinea-Bissau. METHODOLOGY/PRINCIPAL FINDINGS: In connection with a study of HIV in rural Guinea-Bissau, we assessed vaccinia and BCG scars in 193 HIV-1 or HIV-2 infected and 174 uninfected participants. Mortality was assessed after 2Β½β3 years of follow-up. The analyses were adjusted for age, sex, village, and HIV status. The prevalence of vaccinia scar was associated with age, village, and HIV-2 status but not with sex and schooling. Compared with individuals without any scar, individuals with a vaccinia scar had better survival (mortality rate ratio (MR)β=β0.22 (95% CI 0.08β0.61)), the MR being 0.19 (95% CI 0.06β0.57) for women and 0.40 (95% CI 0.04β3.74) for men. Estimates were similar for HIV-2 infected and HIV-1 and HIV-2 uninfected individuals. The HIV-2 prevalence was higher among individuals with a vaccinia scar compared to individuals without a vaccinia scar (RRβ=β1.57 (95% CI 1.02β2.36)). CONCLUSION: The present study supports the hypothesis that vaccinia vaccination may have a non-specific beneficial effect on adult survival
HIV-1 Envelope Subregion Length Variation during Disease Progression
The V3 loop of the HIV-1 Env protein is the primary determinant of viral coreceptor usage, whereas the V1V2 loop region is thought to influence coreceptor binding and participate in shielding of neutralization-sensitive regions of the Env glycoprotein gp120 from antibody responses. The functional properties and antigenicity of V1V2 are influenced by changes in amino acid sequence, sequence length and patterns of N-linked glycosylation. However, how these polymorphisms relate to HIV pathogenesis is not fully understood. We examined 5185 HIV-1 gp120 nucleotide sequence fragments and clinical data from 154 individuals (152 were infected with HIV-1 Subtype B). Sequences were aligned, translated, manually edited and separated into V1V2, C2, V3, C3, V4, C4 and V5 subregions. V1-V5 and subregion lengths were calculated, and potential N-linked glycosylation sites (PNLGS) counted. Loop lengths and PNLGS were examined as a function of time since infection, CD4 count, viral load, and calendar year in cross-sectional and longitudinal analyses. V1V2 length and PNLGS increased significantly through chronic infection before declining in late-stage infection. In cross-sectional analyses, V1V2 length also increased by calendar year between 1984 and 2004 in subjects with early and mid-stage illness. Our observations suggest that there is little selection for loop length at the time of transmission; following infection, HIV-1 adapts to host immune responses through increased V1V2 length and/or addition of carbohydrate moieties at N-linked glycosylation sites. V1V2 shortening during early and late-stage infection may reflect ineffective host immunity. Transmission from donors with chronic illness may have caused the modest increase in V1V2 length observed during the course of the pandemic
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