In a wide class of cosmological models, a positive cosmological constant drives cosmological evolution toward an asymptotically de Sitter phase. Here we connect this behavior to the increase of ...entropy over time, based on the idea that de Sitter spacetime is a maximum-entropy state. We prove a cosmic no-hair theorem for Robertson-Walker and Bianchi I spacetimes that admit a Q-screen (“quantum” holographic screen) with certain entropic properties: If generalized entropy, in the sense of the cosmological version of the generalized second law conjectured by Bousso and Engelhardt, increases up to a finite maximum value along the screen, then the spacetime is asymptotically de Sitter in the future. Moreover, the limiting value of generalized entropy coincides with the de Sitter horizon entropy. We do not use the Einstein field equations in our proof, nor do we assume the existence of a positive cosmological constant. As such, asymptotic relaxation to a de Sitter phase can, in a precise sense, be thought of as cosmological equilibration.
Phagocytosis of apoptotic cells, termed efferocytosis, is critical for tissue homeostasis and drives anti-inflammatory programming in engulfing macrophages. Here, we assess metabolites in naive and ...inflammatory macrophages following engulfment of multiple cellular and non-cellular targets. Efferocytosis leads to increases in the arginine-derived polyamines, spermidine and spermine, in vitro and in vivo. Surprisingly, polyamine accumulation after efferocytosis does not arise from retention of apoptotic cell metabolites or de novo synthesis but from enhanced polyamine import that is dependent on Rac1, actin, and PI3 kinase. Blocking polyamine import prevents efferocytosis from suppressing macrophage interleukin (IL)-1β or IL-6. This identifies efferocytosis as a trigger for polyamine import and accumulation, and imported polyamines as mediators of efferocytosis-induced immune reprogramming.
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•Efferocytosis triggers macrophages to accumulate polyamines spermidine and spermine•Polyamine accumulation is mediated by Rac1-dependent endocytic import•Inhibition of polyamine import blunts immunomodulation in response to efferocytosis
McCubbrey et al. show that efferocytosis elicits accumulation of intracellular polyamines, spermidine and spermine, in engulfing macrophages. Efferocytosis does not increase polyamine synthesis but triggers endocytic import of polyamines. Blocking endocytic import prevents polyamine accumulation after efferocytosis and reduces the ability of efferocytosis to suppress IL-1β and IL-6.
We investigate the proposed connection between de Sitter spacetime and the multiscale entanglement renormalization ansatz (MERA) tensor network, and ask what can be learned via such a construction. ...We show that the quantum state obeys a cosmic no-hair theorem: the reduced density operator describing a causal patch of the MERA asymptotes to a fixed point of a quantum channel, just as spacetimes with a positive cosmological constant asymptote to de Sitter space. The MERA is potentially compatible with a weak form of complementarity (local physics only describes single patches at a time, but the overall Hilbert space is infinite dimensional) or, with certain specific modifications to the tensor structure, a strong form (the entire theory describes only a single patch plus its horizon, in a finite-dimensional Hilbert space). We also suggest that de Sitter evolution has an interpretation in terms of circuit complexity, as has been conjectured for anti–de Sitter space.
There is an urgent need for oral agents to combat resistant Gram-negative pathogens. Here, we describe the characterization of VNRX-5236, a broad-spectrum boronic acid β-lactamase inhibitor (BLI), ...and its orally bioavailable etzadroxil prodrug, VNRX-7145. VNRX-7145 is being developed in combination with ceftibuten, an oral cephalosporin, to combat strains of
expressing extended-spectrum β-lactamases (ESBLs) and serine carbapenemases. VNRX-5236 is a reversible covalent inhibitor of serine β-lactamases, with inactivation efficiencies on the order of 10
M
· sec
, and prolonged active site residence times (
, 5 to 46 min). The spectrum of inhibition includes Ambler class A ESBLs, class C cephalosporinases, and class A and D carbapenemases (KPC and OXA-48, respectively). Rescue of ceftibuten by VNRX-5236 (fixed at 4 μg/ml) in isogenic strains of Escherichia coli expressing class A, C, or D β-lactamases demonstrated an expanded spectrum of activity relative to oral comparators, including investigational penems, sulopenem, and tebipenem. VNRX-5236 rescued ceftibuten activity in clinical isolates of
expressing ESBLs (MIC
, 0.25 μg/ml), KPCs (MIC
, 1 μg/ml), class C cephalosporinases (MIC
, 1 μg/ml), and OXA-48-type carbapenemases (MIC
, 1 μg/ml). Frequency of resistance studies demonstrated a low propensity for recovery of resistant variants at 4× the MIC of the ceftibuten/VNRX-5236 combination.
, whereas ceftibuten alone was ineffective (50% effective dose ED
, >128 mg/kg), ceftibuten/VNRX-7145 administered orally protected mice from lethal septicemia caused by Klebsiella pneumoniae producing KPC carbapenemase (ED
, 12.9 mg/kg). The data demonstrate potent, broad-spectrum rescue of ceftibuten activity by VNRX-5236 in clinical isolates of cephalosporin-resistant and carbapenem-resistant
.
A major antimicrobial resistance mechanism in Gram-negative bacteria is the production of β-lactamase enzymes. The increasing emergence of β-lactamase-producing multi-drug-resistant “superbugs” has ...resulted in increases in costly hospital Emergency Department (ED) visits and hospitalizations due to the requirement for parenteral antibiotic therapy for infections caused by these difficult-to-treat bacteria. To address the lack of outpatient treatment, we initiated an iterative program combining medicinal chemistry, biochemical testing, microbiological profiling, and evaluation of oral pharmacokinetics. Lead optimization focusing on multiple smaller, more lipophilic active compounds, followed by an exploration of oral bioavailability of a variety of their respective prodrugs, provided 36 (VNRX-7145/VNRX-5236 etzadroxil), the prodrug of the boronic acid-containing β-lactamase inhibitor 5 (VNRX-5236). In vitro and in vivo studies demonstrated that 5 restored the activity of the oral cephalosporin antibiotic ceftibuten against Enterobacterales expressing Ambler class A extended-spectrum β-lactamases, class A carbapenemases, class C cephalosporinases, and class D oxacillinases.
Barefoot peak plantar pressures (PPPs) are elevated in diabetes patients with neuropathic foot ulcer (DFU) history; however, there is limited reported evidence for a causative link between high ...barefoot PPP and DFU risk. We aimed to determine, using a simple mat-based methodology, the site-specific, barefoot PPP critical threshold that will identify a plantar site with a previous DFU.
In a cross-sectional study, barefoot, site-specific PPPs were measured with normal gait for patients with DFU history (
= 21) and healthy controls (
= 12), using a validated carbon footprint system. For each participant, PPP was recorded at twelve distinct plantar sites (1st-5th toes, 1st-5th metatarsal heads (MTHs), midfoot and heel), per right and left foot, resulting in the analysis of
= 504 distinct plantar sites in the diabetes group, and
= 288 sites in the control group. Receiver operator characteristic curve analysis determined the optimal critical threshold for sites with DFU history.
Median PPPs for the groups were: diabetes sites with DFU history (
= 32) = 5.0 (3.25-7.5) kg/cm
, diabetes sites without DFU history (
= 472) = 3.25 (2.0-5.0) kg/cm
, control sites (
= 288) = 2.0 (2.0-3.25) kg/cm
; (
< 0.0001). Diabetes sites with elevated PPP (>6 kg/cm
) were six times more likely to have had DFU than diabetes sites with PPP ≤ 6 kg/cm
(OR = 6.4 (2.8-14.6, 95% CI),
< 0.0001). PPP > 4.1 kg/cm
was determined as the optimal critical threshold for identifying DFU at a specific plantar site, with sensitivity/specificity = 100%/79% at midfoot; 80%/65% at 5th metatarsal head; 73%/62% at combined midfoot/metatarsal head areas.
We have demonstrated, for the first time, a strong, site-specific relationship between elevated barefoot PPP and previous DFU. We have determined a critical, highly-sensitive, barefoot PPP threshold value of >4.1 kg/cm
, which may be easily used to identify sites of previous DFU occurrence and, therefore, increased risk of re-ulceration. This site-specific approach may have implications for how high PPPs should be investigated in future trials.
To examine sex differences in risk factors for anorexia nervosa (AN).
This population-based study involved 44,743 individuals (6,239 AN cases including 5,818 females and 421 males, and 38,504 ...controls including 18,818 females and 19,686 males) born in Denmark between May 1981 and December 2009. Follow-up began on the individual's sixth birthday and ended at AN diagnosis, emigration, death, or December 31, 2016, whichever occurred first. Exposures included socioeconomic status (SES), pregnancy, birth, and early childhood factors based on data from Danish registers, and psychiatric and metabolic polygenic risk scores (PRS) based on genetic data. Hazard ratios were estimated using weighted Cox proportional hazards models stratified by sex (assigned at birth), with AN diagnosis as the outcome.
The effects of early life exposures and PRS on AN risk were comparable between females and males. Although we observed some differences in the magnitude and direction of effects, there were no significant interactions between sex and SES, pregnancy, birth, or early childhood exposures. The effects of most PRS on AN risk were highly similar between the sexes. We observed significant sex-specific effects of parental psychiatric history and body mass index PRS, though these effects did not survive corrections for multiple comparisons.
Risk factors for AN are comparable between females and males. Collaboration across countries with large registers is needed to further investigate sex-specific effects of genetic, biological, and environmental exposures on AN risk, including exposures in later childhood and adolescence as well as the additive effects of exposures.
Sex differences in the prevalence and clinical presentation of AN warrant examination of sex-specific risk factors. This population-based study indicates that the effects of polygenic risk and early life exposures on AN risk are comparable between females and males. Collaboration between countries with large registers is needed to further investigate sex-specific AN risk factors and improve early identification of AN.
•An insole system continuously monitors daily plantar pressure for 18 months.•Personalised pressure feedback reduces foot pressure in feet at high-risk of ulcers.•Pressure feedback induced a learning ...response.
High plantar pressure is a major risk factor in the development of diabetic foot ulcers (DFUs) and recent evidence shows plantar pressure feedback reduces DFU recurrence. This study investigated whether continued use of an intelligent insole system by patients at high-risk of DFUs causes a reduction in plantar pressures.
Forty-six patients with diabetic peripheral neuropathy and previous DFU were randomised to intervention (IG) or control groups (CG). Patients received an intelligent insole system, consisting of pressure-sensing insoles and digital watch. Patients wore the device during all daily activity for 18-months or until ulceration, and integrated pressure was recorded continuously. The device provided high-pressure feedback to IG only via audio-visual-vibrational alerts. High-pressure parameters at the whole foot, forefoot and rearfoot were compared between groups, with multilevel binary logistic regression analysis.
CG experienced more high-pressure bouts over time than IG across all areas of the foot (P < 0.05). Differences between groups became apparent >16 weeks of wearing the device.
Continuous plantar pressure feedback via an intelligent insole system reduces number of bouts of high-pressure in patients at high-risk of DFU. These findings suggest that patients were learning which activities generated high-pressure, and pre-emptively offloading to avoid further alerts.
We discuss the branching structure of the quantum-gravitational wave function that describes the evaporation of a black hole. A global wave function which initially describes a classical ...Schwarzschild geometry is continually decohered into distinct semiclassical branches by the emission of Hawking radiation. The laws of quantum mechanics dictate that the wave function evolves unitarily, but this unitary evolution is only manifest when considering the global description of the wave function; it is not implemented by time evolution on a single semiclassical branch. Conversely, geometric notions like the position or smoothness of a horizon only make sense on the level of individual branches. We consider the implications of this picture for probes of black holes by classical observers in definite geometries, like those involved in the Almheiri-Marolf-Polchinski-Sully construction. We argue that individual branches can describe semiclassical geometries free of firewalls, even as the global wave function evolves unitarily. We show that the pointer states of infalling detectors that are robust under Hamiltonian evolution are distinct from, and incompatible with, those of exterior detectors stationary with respect to the black hole horizon, in the sense that the pointer bases are related to each other via nontrivial transformations that mix the system, apparatus, and environment. This result describes a Hilbert-space version of black hole complementarity.
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