Glomerular Function and Structure in Living Donors: Lessons from Single Nephron Studies

One third of the kidney transplants performed in the USA come from living kidney donors. The long-term outcome of healthy individuals who donate kidneys is mostly excellent, although recent studies have suggested that living donation is associated with a small absolute increase in the risk of end stage renal failure. Much of our understanding about the progression of kidney disease comes from experimental models of nephron loss. For this reason, living kidney donation has long been of great interest to renal physiologists. This review will summarize the determinants of glomerular filtration and the physiology that underlies post-donation hyperfiltration. We describe the ‘remnant kidney’ model of kidney disease and the reasons why such progressive kidney disease very rarely ensues in healthy humans following uninephrectomy. We also review some of the methods used to determine glomerular number and size and outline their associations

Star Formation in Disk Galaxies. I. Formation and Evolution of Giant Molecular Clouds via Gravitational Instability and Cloud Collisions

We investigate the formation and evolution of giant molecular clouds (GMCs) in a Milky-Way-like disk galaxy with a flat rotation curve. We perform a series of 3D adaptive mesh refinement (AMR) numerical simulations that follow both the global evolution on scales of ~20kpc and resolve down to scales ~<10pc with a multiphase atomic interstellar medium (ISM). In this first study, we omit star formation and feedback, and focus on the processes of gravitational instability and cloud collisions and interactions. We define clouds as regions with n_H>=100cm^-3 and track the evolution of individual clouds as they orbit through the galaxy from their birth to their eventual destruction via merger or via destructive collision with another cloud. After ~140Myr a large fraction of the gas in the disk has fragmented into clouds with masses ~10^6 Msun and a mass spectrum similar to that of Galactic GMCs. The disk settles into a quasi steady state in which gravitational scattering of clouds keeps the disk near the threshold of global gravitational instability. The cloud collision time is found to be a small fraction, ~1/5, of the orbital time, and this is an efficient mechanism to inject turbulence into the clouds. This helps to keep clouds only moderately gravitationally bound, with virial parameters of order unity. Many other observed GMC properties, such as mass surface density, angular momentum, velocity dispersion, and vertical distribution, can be accounted for in this simple model with no stellar feedback.Comment: 21 pages ApJ format, including 16 figures, accepted to Ap

Kiloparsec-scale simulations of star formation in disk galaxies. I. the unmagnetized and zero-feedback limit

We present hydrodynamic simulations of the evolution of self-gravitating dense gas on scales of 1 kpc down to ≲ parsec in a galactic disk, designed to study dense clump formation from giant molecular clouds (GMCs). These structures are expected to be the precursors to star clusters and this process may be the rate limiting step controlling star formation rates in galactic systems as described by the Kennicutt-Schmidt relation. We follow the thermal evolution of the gas down to 5 K using extinction-dependent heating and cooling functions. We do not yet include magnetic fields or localized stellar feedback, so the evolution of the GMCs and clumps is determined solely by self-gravity balanced by thermal and turbulent pressure support and the large-scale galactic shear. While cloud structures and densities change significantly during the simulation, GMC virial parameters remain mostly above unity for timescales exceeding the free-fall time of GMCs indicating that energy from galactic shear and large-scale cloud motions continuously cascades down to and within the GMCs. We implement star formation at a slow, inefficient rate of 2% per local free-fall time, but even this yields global star formation rates that are about two orders of magnitude larger than the observed Kennicutt-Schmidt relation due to overproduction of dense gas clumps. We expect a combination of magnetic support and localized stellar feedback is required to inhibit dense clump formation to 1% of the rate that results from the nonmagnetic, zero-feedback limit

GMC Collisions as Triggers of Star Formation. III. Density and Magnetically Regulated Star Formation

We study giant molecular cloud (GMC) collisions and their ability to trigger star cluster formation. We further develop our three dimensional magnetized, turbulent, colliding GMC simulations by implementing star formation sub-grid models. Two such models are explored: (1) Density-Regulated, i.e., fixed efficiency per free-fall time above a set density threshold; (2) Magnetically- Regulated, i.e., fixed efficiency per free-fall time in regions that are magnetically supercritical. Variations of parameters associated with these models are also explored. In the non-colliding simulations, the overall level of star formation is sensitive to model parameter choices that relate to effective density thresholds. In the GMC collision simulations, the final star formation rates and efficiencies are relatively independent of these parameters. Between non-colliding and colliding cases, we compare the morphologies of the resulting star clusters, properties of star-forming gas, time evolution of the star formation rate (SFR), spatial clustering of the stars, and resulting kinematics of the stars in comparison to the natal gas. We find that typical collisions, by creating larger amounts of dense gas, trigger earlier and enhanced star formation, resulting in 10 times higher SFRs and efficiencies. The star clusters formed from GMC collisions show greater spatial sub-structure and more disturbed kinematics

Biomimetic rehabilitation engineering: the importance of somatosensory feedback for brain-machine interfaces.

Brain-machine interfaces (BMIs) re-establish communication channels between the nervous system and an external device. The use of BMI technology has generated significant developments in rehabilitative medicine, promising new ways to restore lost sensory-motor functions. However and despite high-caliber basic research, only a few prototypes have successfully left the laboratory and are currently home-deployed. The failure of this laboratory-to-user transfer likely relates to the absence of BMI solutions for providing naturalistic feedback about the consequences of the BMI's actions. To overcome this limitation, nowadays cutting-edge BMI advances are guided by the principle of biomimicry; i.e. the artificial reproduction of normal neural mechanisms. Here, we focus on the importance of somatosensory feedback in BMIs devoted to reproducing movements with the goal of serving as a reference framework for future research on innovative rehabilitation procedures. First, we address the correspondence between users' needs and BMI solutions. Then, we describe the main features of invasive and non-invasive BMIs, including their degree of biomimicry and respective advantages and drawbacks. Furthermore, we explore the prevalent approaches for providing quasi-natural sensory feedback in BMI settings. Finally, we cover special situations that can promote biomimicry and we present the future directions in basic research and clinical applications. The continued incorporation of biomimetic features into the design of BMIs will surely serve to further ameliorate the realism of BMIs, as well as tremendously improve their actuation, acceptance, and use

GMC Collisions as Triggers of Star Formation. II. 3D Turbulent, Magnetized Simulations

We investigate giant molecular cloud (GMCs) collisions and their ability to induce gravitational instability and thus star formation. This mechanism may be a major driver of star formation activity in galactic disks. We carry out a series of three dimensional, magnetohydrodynamics (MHD), adaptive mesh refinement (AMR) simulations to study how cloud collisions trigger formation of dense filaments and clumps. Heating and cooling functions are implemented based on photo-dissociation region (PDR) models that span the atomic to molecular transition and can return detailed diagnostic information. The clouds are initialized with supersonic turbulence and a range of magnetic field strengths and orientations. Collisions at various velocities and impact parameters are investigated. Comparing and contrasting colliding and non-colliding cases, we characterize morphologies of dense gas, magnetic field structure, cloud kinematic signatures, and cloud dynamics. We present key observational diagnostics of cloud collisions, especially: relative orientations between magnetic fields and density structures, like filaments; 13CO(J=2-1), 13CO(J=3-2), and 12CO(J=8-7) integrated intensity maps and spectra; and cloud virial parameters. We compare these results to observed Galactic clouds

The microRNA-29 family in cartilage homeostasis and osteoarthritis

MicroRNAs have been shown to function in cartilage development and homeostasis, as well as in progression of osteoarthritis. The objective of the current study was to identify microRNAs involved in the onset or early progression of osteoarthritis and characterise their function in chondrocytes. MicroRNA expression in mouse knee joints post-DMM surgery was measured over 7 days. Expression of miR-29b-3p was increased at day 1 and regulated in the opposite direction to its potential targets. In a mouse model of cartilage injury and in end-stage human OA cartilage, the miR-29 family were also regulated. SOX9 repressed expression of miR-29a-3p and miR-29b-3p via the 29a/b1 promoter. TGFβ1 decreased expression of miR-29a, b and c (3p) in primary chondrocytes, whilst IL-1β increased (but LPS decreased) their expression. The miR-29 family negatively regulated Smad, NFκB and canonical WNT signalling pathways. Expression profiles revealed regulation of new WNT-related genes. Amongst these, FZD3, FZD5, DVL3, FRAT2, CK2A2 were validated as direct targets of the miR-29 family. These data identify the miR-29 family as microRNAs acting across development and progression of OA. They are regulated by factors which are important in OA and impact on relevant signalling pathways

Continued 26S proteasome dysfunction in mouse brain cortical neurons impairs autophagy and the Keap1-Nrf2 oxidative defence pathway

The ubiquitin–proteasome system (UPS) and macroautophagy (autophagy) are central to normal proteostasis and interdependent in that autophagy is known to compensate for the UPS to alleviate ensuing proteotoxic stress that impairs cell function. UPS and autophagy dysfunctions are believed to have a major role in the pathomechanisms of neurodegenerative disease. Here we show that continued 26S proteasome dysfunction in mouse brain cortical neurons causes paranuclear accumulation of fragmented dysfunctional mitochondria, associated with earlier recruitment of Parkin and lysine 48-linked ubiquitination of mitochondrial outer membrane (MOM) proteins, including Mitofusin-2. Early events also include phosphorylation of p62/SQSTM1 (p62) and increased optineurin, as well as autophagosomal LC3B and removal of some mitochondria, supporting the induction of selective autophagy. Inhibition of the degradation of ubiquitinated MOM proteins with continued 26S proteasome dysfunction at later stages may impede efficient mitophagy. However, continued 26S proteasome dysfunction also decreases the levels of essential autophagy proteins ATG9 and LC3B, which is characterised by decreases in their gene expression, ultimately leading to impaired autophagy. Intriguingly, serine 351 phosphorylation of p62 did not enhance its binding to Keap1 or stabilise the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor in this neuronal context. Nrf2 protein levels were markedly decreased despite transcriptional activation of the Nrf2 gene. Our study reveals novel insights into the interplay between the UPS and autophagy in neurons and is imperative to understanding neurodegenerative disease where long-term proteasome inhibition has been implicated

Identification, characterization, and gene expression analysis of nucleotide binding site (NB)-type resistance gene homologues in switchgrass

Abstract Background Switchgrass (Panicum virgatum L.) is a warm-season perennial grass that can be used as a second generation bioenergy crop. However, foliar fungal pathogens, like switchgrass rust, have the potential to significantly reduce switchgrass biomass yield. Despite its importance as a prominent bioenergy crop, a genome-wide comprehensive analysis of NB-LRR disease resistance genes has yet to be performed in switchgrass. Results In this study, we used a homology-based computational approach to identify 1011 potential NB-LRR resistance gene homologs (RGHs) in the switchgrass genome (v 1.1). In addition, we identified 40 RGHs that potentially contain unique domains including major sperm protein domain, jacalin-like binding domain, calmodulin-like binding, and thioredoxin. RNA-sequencing analysis of leaf tissue from ‘Alamo’, a rust-resistant switchgrass cultivar, and ‘Dacotah’, a rust-susceptible switchgrass cultivar, identified 2634 high quality variants in the RGHs between the two cultivars. RNA-sequencing data from field-grown cultivar ‘Summer’ plants indicated that the expression of some of these RGHs was developmentally regulated. Conclusions Our results provide useful insight into the molecular structure, distribution, and expression patterns of members of the NB-LRR gene family in switchgrass. These results also provide a foundation for future work aimed at elucidating the molecular mechanisms underlying disease resistance in this important bioenergy crop