Ensemble Theory for Force Networks in Hyperstatic Granular Matter

An ensemble approach for force networks in static granular packings is developed. The framework is based on the separation of packing and force scales, together with an a-priori flat measure in the force phase space under the constraints that the contact forces are repulsive and balance on every particle. In this paper we will give a general formulation of this force network ensemble, and derive the general expression for the force distribution $P(f)$. For small regular packings these probability densities are obtained in closed form, while for larger packings we present a systematic numerical analysis. Since technically the problem can be written as a non-invertible matrix problem (where the matrix is determined by the contact geometry), we study what happens if we perturb the packing matrix or replace it by a random matrix. The resulting $P(f)$'s differ significantly from those of normal packings, which touches upon the deep question of how network statistics is related to the underlying network structure. Overall, the ensemble formulation opens up a new perspective on force networks that is analytically accessible, and which may find applications beyond granular matter.Comment: 17 pages, 17 figure

Bayesian Centroid Estimation for Motif Discovery

Biological sequences may contain patterns that are signal important biomolecular functions; a classical example is regulation of gene expression by transcription factors that bind to specific patterns in genomic promoter regions. In motif discovery we are given a set of sequences that share a common motif and aim to identify not only the motif composition, but also the binding sites in each sequence of the set. We present a Bayesian model that is an extended version of the model adopted by the Gibbs motif sampler, and propose a new centroid estimator that arises from a refined and meaningful loss function for binding site inference. We discuss the main advantages of centroid estimation for motif discovery, including computational convenience, and how its principled derivation offers further insights about the posterior distribution of binding site configurations. We also illustrate, using simulated and real datasets, that the centroid estimator can differ from the maximum a posteriori estimator.Comment: 24 pages, 9 figure

A pilot study to evaluate the effects of C1 esterase inhibitor on the toxicity of high-dose interleukin 2.

In a pilot study six patients received 4 days' treatment with interleukin 2 (IL-2) [cumulative dose (CD) 264 +/- 26 x 10(6) IU m-2] and C1 esterase inhibitor (C1-INH) (loading dose 2,000 U, followed by 500-1,000 U twice daily). Toxicity was compared with that in patients given 4 days' treatment with standard (CD 66 +/- 12 x 10(6) IU m-2) or escalating-dose (CD 99 +/- 8 x 10(6) IU m-2) IL-2. IL-2-induced hypotension was equivalent and complement activation was less after IL-2 + C1-INH (C3a = 10.5 +/- 3.2 nmol l-1) than following standard (14.1 +/- 8.4 nmol l-1) or escalating-dose (18.3 +/- 2.9 nmol l-1) IL-2. This study demonstrates that C1-INH administration during IL-2 treatment is safe and warrants further study to evaluate its ability to ameliorate IL-2-induced toxicity

Chlamydial contribution to anaerobic metabolism during eukaryotic evolution

The origin of eukaryotes is a major open question in evolutionary biology. Multiple hypotheses posit that eukaryotes likely evolved from a syntrophic relationship between an archaeon and an alphaproteobacterium based on H-2 exchange. However, there are no strong indications that modern eukaryotic H-2 metabolism originated from archaea or alphaproteobacteria. Here, we present evidence for the origin of H-2 metabolism genes in eukaryotes from an ancestor of the Anoxychlamydiales-a group of anaerobic chlamydiae, newly described here, from marine sediments. Among Chlamydiae, these bacteria uniquely encode genes for H-2 metabolism and other anaerobiosis-associated pathways. Phylogenetic analyses of several components of H-2 metabolism reveal that Anoxychlamydiales homologs are the closest relatives to eukaryotic sequences. We propose that an ancestor of the Anoxychlamydiales contributed these key genes during the evolution of eukaryotes, supporting a mosaic evolutionary origin of eukaryotic metabolism

Blood pressure and urinary sodium excretion in relation to the A-1984G adrenomedullin polymorphism in a Chinese population

Adrenomedullin (ADM) is a vasodilator and inhibits salt appetite. An A-to-G substitution at position -1984 in the promoter region of the ADM gene likely increases transcription. We therefore investigated this polymorphism in relation to blood pressure and urinary sodium in a Chinese population. We genotyped 427 Chinese enrolled in a family-based population study. We measured blood pressure by conventional sphygmomanometry and ambulatory monitoring. The frequencies of the ADM AA, AG, and GG genotypes were 50.6, 38.2, and 11.2%, respectively. In adjusted analyses, G allele carriers, compared to AA homozygotes, had significantly lower conventional (45.3 versus 48.5 mm Hg, P=0.004) and 24-h (42.6 versus 44.3 mm Hg, P=0.03) pulse pressures and urinary sodium excretion (143.8 versus 159.4 mmol/day, P=0.03). In parents, but not offspring, both systolic pressure and pulse pressure were significantly (P<0.01) lower in G allele carriers. The genotypic difference in sodium excretion was consistent across the age range. In 68 informative offspring, transmission of the G allele was associated with lower urinary sodium excretion (effect size, 40.1 mmol/day, P=0.01). In 81 healthy volunteers, the plasma ADM concentration was 15.2% higher in GG homozygotes than in sex- and age-matched AA subjects (11.4 versus 9.9 pmol/l, P=0.10). In conclusion, in Chinese, the ADM -1984G allele is associated with lower sodium excretion and in older subjects also with lower systolic pressure and narrower pulse pressure

Ethnic differences in proximal and distal tubular sodium reabsorption are heritable in black and white populations.

BACKGROUND: Segmental handling of sodium along the proximal and distal nephron might be heritable and different between black and white participants. METHODS: We randomly recruited 95 nuclear families of black South African ancestry and 103 nuclear families of white Belgian ancestry. We measured the (FENa) and estimated the fractional renal sodium reabsorption in the proximal (RNaprox) and distal (RNadist) tubules from the clearances of endogenous lithium and creatinine. In multivariable analyses, we studied the relation of RNaprox and RNadist with FENa and estimated the heritability (h) of RNaprox and RNadist. RESULTS: Independent of urinary sodium excretion, South Africans (n = 240) had higher RNaprox (unadjusted median, 93.9% vs. 81.0%; P &lt; 0.001) than Belgians (n = 737), but lower RNadist (91.2% vs. 95.1%; P &lt; 0.001). The slope of RNaprox on FENa was steeper in Belgians than in South Africans (-5.40 +/- 0.58 vs. -0.78 +/- 0.58 units; P &lt; 0.001), whereas the opposite was true for the slope of RNadist on FENa (-3.84 +/- 0.19 vs. -13.71 +/- 1.30 units; P &lt; 0.001). h of RNaprox and RNadist was high and significant (P &lt; 0.001) in both countries. h was higher in South Africans than in Belgians for RNaprox (0.82 vs. 0.56; P &lt; 0.001), but was similar for RNadist (0.68 vs. 0.50; P = 0.17). Of the filtered sodium load, black participants reabsorb more than white participants in the proximal nephron and less postproximally. CONCLUSION: Segmental sodium reabsorption along the nephron is highly heritable, but the capacity for regulation in the proximal and postproximal tubules differs between whites and blacks

Global and regional cardiac function in lifelong endurance athletes with and without myocardial fibrosis

The aim of the present study was to compare cardiac structure as well as global and regional cardiac function in athletes with and without myocardial fibrosis (MF). Cardiac magnetic resonance imaging with late gadolinium enhancement was used to detect MF and global cardiac structure in nine lifelong veteran endurance athletes (58 ± 5 years, 43 ± 5 years of training). Transthoracic echocardiography using tissue-Doppler and myocardial strain imaging assessed global and regional (18 segments) longitudinal left ventricular function. MF was present in four athletes (range 1–8 g) and not present in five athletes. MF was located near the insertion points of the right ventricular free wall on the left ventricle in three athletes and in the epicardial lateral wall in one athlete. Athletes with MF demonstrated a larger end diastolic volume (205 ± 24 vs 173 ± 18 ml) and posterior wall thickness (11 ± 1 vs 9 ± 1 mm) compared to those without MF. The presence of MF did not mediate global tissue velocities or global longitudinal strain and strain rate; however, regional analysis of longitudinal strain demonstrated reduced function in some fibrotic regions. Furthermore, base to apex gradient was affected in three out of four athletes with MF. Lifelong veteran endurance athletes with MF demonstrate larger cardiac dimensions and normal global cardiac function. Fibrotic areas may demonstrate some co-localised regional cardiac dysfunction, evidenced by an affected cardiac strain and base to apex gradient. These data emphasize the heterogeneous phenotype of MF in athletes

Optimally Dense Packings for Fully Asymptotic Coxeter Tilings by Horoballs of Different Types

The goal of this paper to determine the optimal horoball packing arrangements and their densities for all four fully asymptotic Coxeter tilings (Coxeter honeycombs) in hyperbolic 3-space $\mathbb{H}^3$. Centers of horoballs are required to lie at vertices of the regular polyhedral cells constituting the tiling. We allow horoballs of different types at the various vertices. Our results are derived through a generalization of the projective methodology for hyperbolic spaces. The main result states that the known B\"or\"oczky--Florian density upper bound for "congruent horoball" packings of $\mathbb{H}^3$ remains valid for the class of fully asymptotic Coxeter tilings, even if packing conditions are relaxed by allowing for horoballs of different types under prescribed symmetry groups. The consequences of this remarkable result are discussed for various Coxeter tilings.Comment: 26 pages, 10 figure

Route of Administration of the TLR9 Agonist CpG Critically Determines the Efficacy of Cancer Immunotherapy in Mice

Contains fulltext : 81648.pdf (publisher's version ) (Open Access)BACKGROUND: The TLR9 agonist CpG is increasingly applied in preclinical and clinical studies as a therapeutic modality to enhance tumor immunity. The clinical application of CpG appears, however, less successful than would be predicted from animal studies. One reason might be the different administration routes applied in most mouse studies and clinical trials. We studied whether the efficacy of CpG as an adjuvant in cancer immunotherapy is dependent on the route of CpG administration, in particular when the tumor is destructed in situ. METHODOLOGY/PRINCIPAL FINDINGS: In situ tumor destruction techniques are minimally invasive therapeutic alternatives for the treatment of (nonresectable) solid tumors. In contrast to surgical resection, tumor destruction leads to the induction of weak but tumor-specific immunity that can be enhanced by coapplication of CpG. As in situ tumor destruction by cryosurgery creates an instant local release of antigens, we applied this model to study the efficacy of CpG to enhance antitumor immunity when administrated via different routes: peritumoral, intravenous, and subcutaneous but distant from the tumor. We show that peritumoral administration is superior in the activation of dendritic cells, induction of tumor-specific CTL, and long-lasting tumor protection. Although the intravenous and subcutaneous (at distant site) exposures are commonly used in clinical trials, they only provided partial protection or even failed to enhance antitumor responses as induced by cryosurgery alone. CONCLUSIONS/SIGNIFICANCE: CpG administration greatly enhances the efficacy of in situ tumor destruction techniques, provided that CpG is administered in close proximity of the released antigens. Hence, this study helps to provide directions to fully benefit from CpG as immune stimulant in a clinical setting

Timing and Dose of Upper Limb Motor Intervention After Stroke: A Systematic Review

This systematic review aimed to investigate timing, dose, and efficacy of upper limb intervention during the first 6 months poststroke. Three online databases were searched up to July 2020. Titles/abstracts/full-text were reviewed independently by 2 authors. Randomized and nonrandomized studies that enrolled people within the first 6 months poststroke, aimed to improve upper limb recovery, and completed preintervention and postintervention assessments were included. Risk of bias was assessed using Cochrane reporting tools. Studies were examined by timing (recovery epoch), dose, and intervention type. Two hundred and sixty-one studies were included, representing 228 (n=9704 participants) unique data sets. The number of studies completed increased from one (n=37 participants) between 1980 and 1984 to 91 (n=4417 participants) between 2015 and 2019. Timing of intervention start has not changed (median 38 days, interquartile range [IQR], 22–66) and study sample size remains small (median n=30, IQR 20–48). Most studies were rated high risk of bias (62%). Study participants were enrolled at different recovery epochs: 1 hyperacute (<24 hours), 13 acute (1–7 days), 176 early subacute (8–90 days), 34 late subacute (91–180 days), and 4 were unable to be classified to an epoch. For both the intervention and control groups, the median dose was 45 (IQR, 600–1430) min/session, 1 (IQR, 1–1) session/d, 5 (IQR, 5–5) d/wk for 4 (IQR, 3–5) weeks. The most common interventions tested were electromechanical (n=55 studies), electrical stimulation (n=38 studies), and constraint-induced movement (n=28 studies) therapies. Despite a large and growing body of research, intervention dose and sample size of included studies were often too small to detect clinically important effects. Furthermore, interventions remain focused on subacute stroke recovery with little change in recent decades. A united research agenda that establishes a clear biological understanding of timing, dose, and intervention type is needed to progress stroke recovery research. Prospective Register of Systematic Reviews ID: CRD42018019367/CRD42018111629