HIF-mediated innate immune responses: cell signaling and therapeutic implications

Leukocytes recruited to infected, damaged, or inflamed tissues during an immune response must adapt to oxygen levels much lower than those in the circulation. Hypoxia inducible factors (HIFs) are key mediators of cellular responses to hypoxia and, as in other cell types, HIFs are critical for the upregulation of glycolysis, which enables innate immune cells to produce adenosine triphosphate anaerobically. An increasing body of evidence demonstrates that hypoxia also regulates many other innate immunological functions, including cell migration, apoptosis, phagocytosis of pathogens, antigen presentation and production of cytokines, chemokines, and angiogenic and antimicrobial factors. Many of these functions are mediated by HIFs, which are not only stabilized posttranslationally by hypoxia, but also transcriptionally upregulated by inflammatory signals. Here, we review the role of HIFs in the responses of innate immune cells to hypoxia, both in vitro and in vivo, with a particular focus on myeloid cells, on which the majority of studies have so far been carried out

Physical profile of junior and senior amateur boxers

© JPES. Purpose: The purpose of this study was to profile the physiological characteristics of amateur boxers using a battery of tests designed to assess the physiological and physical demands required for performance. Fifteen junior amateur (age 14.9 ± 2.0 years; stature 164 ± 12 cm; body mass 50.9 ± 11.3 kg) and sixteen senior amateur boxers (n = 16; age 20.5 ± 4.0 years; stature 174 ± 9 cm; body mass 65.2 ± 10.7 kg) provided informed consent to participate in the study. Body composition, squat jump (SJ), countermovement jump (CMJ), 5-and 10 m sprint (5SP/10SP), press up (PU), right and left medicine-ball single-arm throws (MBR, MBL), repeated sprint test (RST) and Yo-Yo intermittent recovery test level 1 (YY) were performed. The likelihood (% chance) of between-group differences were assessed using a magnitude based approach, standardised-difference score (Cohen’s d) and 90% confidence intervals [CI]. Linear regression (r) was used to examine the association between variables. Results: Senior boxers outperformed (79 to 99% chance) junior counterparts in PU, YY, CMJ, SJ, 10SP, MBL and MBR tests (d ≥ 0.50 [-0.34 to 1.61]). There were very large (r 0.70) correlations between fat free mass, upper-and lower body lean mass and medicine ball throw distance. There were large correlations (r 0.50 to 0.69) between medicine ball throw distance and CMJ, SJ, PU, 5SP and 10SP. Conclusions: A simple and time-effective test battery was able to differentiate performance between junior and amateur boxers. These assessments could be useful when profiling junior and senior amateur boxers

Investigation of the Fundamental Reliability Unit for Cu Dual-Damascene Metallization

An investigation has been carried out to determine the fundamental reliability unit of copper dual-damascene metallization. Electromigration experiments have been carried out on straight via-to-via interconnects in the lower metal (M1) and the upper metal (M2), and in a simple interconnect tree structure consisting of straight via-to-via line with an extra via in the middle of the line (a "dotted-I"). Multiple failure mechanisms have been observed during electromigration testing of via-to-via Cu interconnects. The failure times of the M2 test structures are significantly longer than that of identical M1 structures. It is proposed that this asymmetry is the result of a difference in the location of void formation and growth, which is believed to be related to the ease of electromigration-induced void nucleation and growth at the Cu/Si₃N₄ interface. However, voids were also detected in the vias instead of in the Cu lines for some cases of early failure of the test lines. These early failures are suspected to be related to the integrity and reliability of the Cu via. Different magnitudes and directions of electrical current were applied independently in two segments of the interconnect tree structure. As with Al-based interconnects, the reliability of a segment in this tree strongly depends on the stress conditions of the connected segment. Beyond this, there are important differences in the results obtained under similar test conditions for Al-based and Cu-based interconnect trees. These differences are thought to be associated with variations in the architectural schemes of the two metallizations. The absence of a conducting electromigration-resistant overlayer in Cu technology allows smaller voids to cause failure in Cu compared to Al. Moreover, the Si₃N₄ overlayer that serves as an interlevel diffusion barrier provides sites for easy nucleation of voids and also provides a high diffusivity path for electromigration. The results reported here suggest that while segments are not the fundamental reliability unit for circuit-level reliability assessments for Al or Cu, vias, rather than trees, might be the appropriate fundamental units for the assessment of Cu reliability.Singapore-MIT Alliance (SMA

Length Effects on the Reliability of Dual-Damascene Cu Interconnects

The effects of interconnect length on the reliability of dual-damascene Cu metallization have been investigated. As in Al-based interconnects, the lifetimes of Cu lines increase with decreasing length. However, unlike Al-based interconnects, no critical length exists, below which all Cu lines are âimmortal’. Furthermore, we found multi-modal failure statistics for long lines, suggesting multiple failure mechanisms. Some long Cu interconnect segments have very large lifetimes, whereas in Al segments, lifetimes decrease continuously with increasing line length. It is postulated that the large lifetimes observed in long Cu lines result from liner rupture at the bottom of the vias, which allows continuous flow of Cu between the two bond pads. As a consequence, the average lifetimes of short lines and long lines can be higher than those of lines with intermediate lengths.Singapore-MIT Alliance (SMA

Early-branching gut fungi possess a large, comprehensive array of biomass-degrading enzymes

The fungal kingdom is the source of almost all industrial enzymes in use for lignocellulose bioprocessing. We developed a systems-level approach that integrates transcriptomic sequencing, proteomics, phenotype, and biochemical studies of relatively unexplored basal fungi. Anaerobic gut fungi isolated from herbivores produce a large array of biomass-degrading enzymes that synergistically degrade crude, untreated plant biomass and are competitive with optimized commercial preparations from Aspergillus and Trichoderma. Compared to these model platforms, gut fungal enzymes are unbiased in substrate preference due to a wealth of xylan-degrading enzymes. These enzymes are universally catabolite-repressed and are further regulated by a rich landscape of noncoding regulatory RNAs. Additionally, we identified several promising sequence-divergent enzyme candidates for lignocellulosic bioprocessing

The lifelong impact of fetal growth restriction on cardiac development

Background: Maternal nutrient restriction (MNR) is a widespread cause of fetal growth restriction (FGR), an independent predictor of heart disease and cardiovascular mortality. Our objective was to examine the developmental and long-term impact of MNR-induced FGR on cardiac structure in a model that closely mimics human development. Methods: A reduction in total caloric intake spanning pregestation through to lactation in guinea pig sows was used to induce FGR. Proliferation, differentiation, and apoptosis of cardiomyocytes were assessed in late-gestation fetal, neonatal, and adult guinea pig hearts. Proteomic analysis and pathway enrichment were performed on fetal hearts. Results: Cardiomyocyte proliferation and the number of mononucleated cells were enhanced in the MNR–FGR fetal and neonatal heart, suggesting a delay in cardiomyocyte differentiation. In fetal hearts of MNR–FGR animals, apoptosis was markedly elevated and the total number of cardiomyocytes reduced, the latter remaining so throughout neonatal and into adult life. A reduction in total cardiomyocyte number in adult MNR–FGR hearts was accompanied by exaggerated hypertrophy and a disorganized architecture. Pathway analysis identified genes related to cell proliferation, differentiation, and survival. Conclusions: FGR influences cardiomyocyte development during critical windows of development, leading to a permanent deficiency in cardiomyocyte number and compensatory hypertrophy in a rodent model that recapitulates human development

Higher moments of nucleon spin structure functions in heavy baryon chiral perturbation theory and in a resonance model

The third moment $d_2$ of the twist-3 part of the nucleon spin structure function $g_2$ is generalized to arbitrary momentum transfer $Q^2$ and is evaluated in heavy baryon chiral perturbation theory (HBChPT) up to order ${\mathcal{O}}(p^4)$ and in a unitary isobar model (MAID). We show how to link $d_2$ as well as higher moments of the nucleon spin structure functions $g_1$ and $g_2$ to nucleon spin polarizabilities. We compare our results with the most recent experimental data, and find a good description of these available data within the unitary isobar model. We proceed to extract the twist-4 matrix element $f_2$ which appears in the $1/Q^2$ suppressed term in the twist expansion of the spin structure function $g_1$ for proton and neutron.Comment: 30 pages, 7 figure

Inverse magnetic catalysis in field theory and gauge-gravity duality

We investigate the surface of the chiral phase transition in the three-dimensional parameter space of temperature, baryon chemical potential and magnetic field in two different approaches, the field-theoretical Nambu-Jona-Lasinio (NJL) model and the holographic Sakai-Sugimoto model. The latter is a top-down approach to a gravity dual of QCD with an asymptotically large number of colors and becomes, in a certain limit, dual to an NJL-like model. Our main observation is that, at nonzero chemical potential, a magnetic field can restore chiral symmetry, in apparent contrast to the phenomenon of magnetic catalysis. This "inverse magnetic catalysis" occurs in the Sakai-Sugimoto model and, for sufficiently large coupling, in the NJL model and is related to the physics of the lowest Landau level. While in most parts our discussion is a pedagogical review of previously published results, we include new analytical results for the NJL approach and a thorough comparison of inverse magnetic catalysis in the two approaches.Comment: 37 pages, 11 figures, to appear in Lect. Notes Phys. "Strongly interacting matter in magnetic fields" (Springer), edited by D. Kharzeev, K. Landsteiner, A. Schmitt, H.-U. Ye

Heritability of the shape of subcortical brain structures in the general population

The volumes of subcortical brain structures are highly heritable, but genetic underpinnings of their shape remain relatively obscure. Here we determine the relative contribution of genetic factors to individual variation in the shape of seven bilateral subcortical structures: the nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen and thalamus. In 3,686 unrelated individuals aged between 45 and 98 years, brain magnetic resonance imaging and genotyping was performed. The maximal heritability of shape varies from 32.7 to 53.3% across the subcortical structures. Genetic contributions to shape extend beyond influences on intracranial volume and the gross volume of the respective structure. The regional variance in heritability was related to the reliability of the measurements, but could not be accounted for by technical factors only. These findings could be replicated in an independent sample of 1,040 twins. Differences in genetic contributions within a single region reveal the value of refined brain maps to appreciate the genetic complexity of brain structures