Oscillatory stimuli differentiate adapting circuit topologies

This is the author accepted manuscript. The final version is available from Springer Nature via the DOI in this record.Biology emerges from interactions between molecules, which are challenging to elucidate with current techniques. An orthogonal approach is to probe for 'response signatures' that identify specific circuit motifs. For example, bistability, hysteresis, or irreversibility are used to detect positive feedback loops. For adapting systems, such signatures are not known. Only two circuit motifs generate adaptation: negative feedback loops (NFLs) and incoherent feed-forward loops (IFFLs). On the basis of computational testing and mathematical proofs, we propose differential signatures: in response to oscillatory stimulation, NFLs but not IFFLs show refractory-period stabilization (robustness to changes in stimulus duration) or period skipping. Applying this approach to yeast, we identified the circuit dominating cell cycle timing. In Caenorhabditis elegans AWA neurons, which are crucial for chemotaxis, we uncovered a Ca2+ NFL leading to adaptation that would be difficult to find by other means. These response signatures allow direct access to the outlines of the wiring diagrams of adapting systems.The work was supported by US National Institutes of Health grant 5RO1-GM078153-07 (F.R.C.), NRSA Training Grant CA009673-36A1 (S.J.R.), a Merck Postdoctoral Fellowship at The Rockefeller University (S.J.R.), and the Simons Foundation (S.J.R.). J.L. was supported by a fellowship from the Boehringer Ingelheim Fonds. E.D.S. was partially supported by the US Office of Naval Research (ONR N00014-13-1-0074) and the US Air Force Office of Scientific Research (AFOSR FA9550-14-1-0060)

Foundations of Black Hole Accretion Disk Theory

This review covers the main aspects of black hole accretion disk theory. We begin with the view that one of the main goals of the theory is to better understand the nature of black holes themselves. In this light we discuss how accretion disks might reveal some of the unique signatures of strong gravity: the event horizon, the innermost stable circular orbit, and the ergosphere. We then review, from a first-principles perspective, the physical processes at play in accretion disks. This leads us to the four primary accretion disk models that we review: Polish doughnuts (thick disks), Shakura-Sunyaev (thin) disks, slim disks, and advection-dominated accretion flows (ADAFs). After presenting the models we discuss issues of stability, oscillations, and jets. Following our review of the analytic work, we take a parallel approach in reviewing numerical studies of black hole accretion disks. We finish with a few select applications that highlight particular astrophysical applications: measurements of black hole mass and spin, black hole vs. neutron star accretion disks, black hole accretion disk spectral states, and quasi-periodic oscillations (QPOs).Comment: 91 pages, 23 figures, final published version available at http://www.livingreviews.org/lrr-2013-

Lysosomal protease deficiency or substrate overload induces an oxidative-stress mediated STAT3-dependent pathway of lysosomal homeostasis

How cells regulate their lysosomal proteolytic capacity is only partly understood. Here, the authors show that lysosomal protease deficiency or substrate overload induces lysosomal stress leading to activation of a STAT3-dependent, TFEB-independent pathway of lysosomal hydrolase expression

The highly accurate anteriolateral portal for injecting the knee

<p>Abstract</p> <p>Background</p> <p>The extended knee lateral midpatellar portal for intraarticular injection of the knee is accurate but is not practical for all patients. We hypothesized that a modified anteriolateral portal where the synovial membrane of the medial femoral condyle is the target would be highly accurate and effective for intraarticular injection of the knee.</p> <p>Methods</p> <p>83 subjects with non-effusive osteoarthritis of the knee were randomized to intraarticular injection using the modified anteriolateral bent knee versus the standard lateral midpatellar portal. After hydrodissection of the synovial membrane with lidocaine using a mechanical syringe (reciprocating procedure device), 80 mg of triamcinolone acetonide were injected into the knee with a 2.0-in (5.1-cm) 21-gauge needle. Baseline pain, procedural pain, and pain at outcome (2 weeks and 6 months) were determined with the 10 cm Visual Analogue Pain Score (VAS). The accuracy of needle placement was determined by sonographic imaging.</p> <p>Results</p> <p>The lateral midpatellar and anteriolateral portals resulted in equivalent clinical outcomes including procedural pain (VAS midpatellar: 4.6 ± 3.1 cm; anteriolateral: 4.8 ± 3.2 cm; p = 0.77), pain at outcome (VAS midpatellar: 2.6 ± 2.8 cm; anteriolateral: 1.7 ± 2.3 cm; p = 0.11), responders (midpatellar: 45%; anteriolateral: 56%; p = 0.33), duration of therapeutic effect (midpatellar: 3.9 ± 2.4 months; anteriolateral: 4.1 ± 2.2 months; p = 0.69), and time to next procedure (midpatellar: 7.3 ± 3.3 months; anteriolateral: 7.7 ± 3.7 months; p = 0.71). The anteriolateral portal was 97% accurate by real-time ultrasound imaging.</p> <p>Conclusion</p> <p>The modified anteriolateral bent knee portal is an effective, accurate, and equivalent alternative to the standard lateral midpatellar portal for intraarticular injection of the knee.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00651625">NCT00651625</a></p

Swelling-Activated Ca2+ Channels Trigger Ca2+ Signals in Merkel Cells

Merkel cell-neurite complexes are highly sensitive touch receptors comprising epidermal Merkel cells and sensory afferents. Based on morphological and molecular studies, Merkel cells are proposed to be mechanosensory cells that signal afferents via neurotransmission; however, functional studies testing this hypothesis in intact skin have produced conflicting results. To test this model in a simplified system, we asked whether purified Merkel cells are directly activated by mechanical stimulation. Cell shape was manipulated with anisotonic solution changes and responses were monitored by Ca2+ imaging with fura-2. We found that hypotonic-induced cell swelling, but not hypertonic solutions, triggered cytoplasmic Ca2+ transients. Several lines of evidence indicate that these signals arise from swelling-activated Ca2+-permeable ion channels. First, transients were reversibly abolished by chelating extracellular Ca2+, demonstrating a requirement for Ca2+ influx across the plasma membrane. Second, Ca2+ transients were initially observed near the plasma membrane in cytoplasmic processes. Third, voltage-activated Ca2+ channel (VACC) antagonists reduced transients by half, suggesting that swelling-activated channels depolarize plasma membranes to activate VACCs. Finally, emptying internal Ca2+ stores attenuated transients by 80%, suggesting Ca2+ release from stores augments swelling-activated Ca2+ signals. To identify candidate mechanotransduction channels, we used RT-PCR to amplify ion-channel transcripts whose pharmacological profiles matched those of hypotonic-evoked Ca2+ signals in Merkel cells. We found 11 amplicons, including PKD1, PKD2, and TRPC1, channels previously implicated in mechanotransduction in other cells. Collectively, these results directly demonstrate that Merkel cells are activated by hypotonic-evoked swelling, identify cellular signaling mechanisms that mediate these responses, and support the hypothesis that Merkel cells contribute to touch reception in the Merkel cell-neurite complex

A Panchromatic Catalog of Early-Type Galaxies at Intermediate Redshift in the Hubble Space Telescope Wide Field Camera 3 Early Release Science Field

In the first of a series of forthcoming publications, we present a panchromatic catalog of 102 visually-selected early-type galaxies (ETGs) from observations in the Early Release Science (ERS) program with the Wide Field Camera 3 (WFC3) on the Hubble Space Telescope (HST) of the Great Observatories Origins Deep Survey-South (GOODS-S) field. Our ETGs span a large redshift range, 0.35 < z < 1.5, with each redshift spectroscopically-confirmed by previous published surveys of the ERS field. We combine our measured WFC3 ERS and ACS GOODS-S photometry to gain continuous sensitivity from the rest-frame far-UV to near-IR emission for each ETG. The superior spatial resolution of the HST over this panchromatic baseline allows us to classify the ETGs by their small-scale internal structures, as well as their local environment. By fitting stellar population spectral templates to the broad-band photometry of the ETGs, we determine that the average masses of the ETGs are comparable to the characteristic stellar mass of massive galaxies, 11< log(M [Solar]) < 12. By transforming the observed photometry into the GALEX FUV and NUV, Johnson V, and SDSS g' and r' bandpasses we identify a noteworthy diversity in the rest-frame UV-optical colors and find the mean rest-frame (FUV-V)=3.5 and (NUV-V)=3.3, with 1$\sigma$ standard deviations approximately equal to 1.0. The blue rest-frame UV-optical colors observed for most of the ETGs are evidence for star-formation during the preceding gigayear, but no systems exhibit UV-optical photometry consistent with major recent (<~50 Myr) starbursts. Future publications which address the diversity of stellar populations likely to be present in these ETGs, and the potential mechanisms by which recent star-formation episodes are activated, are discussed.Comment: accepted to the Astrophysical Journal Supplement Serie

The Comparative Osteology of the Petrotympanic Complex (Ear Region) of Extant Baleen Whales (Cetacea: Mysticeti)

Anatomical comparisons of the ear region of baleen whales (Mysticeti) are provided through detailed osteological descriptions and high-resolution photographs of the petrotympanic complex (tympanic bulla and petrosal bone) of all extant species of mysticete cetaceans. Salient morphological features are illustrated and identified, including overall shape of the bulla, size of the conical process of the bulla, morphology of the promontorium, and the size and shape of the anterior process of the petrosal. We place our comparative osteological observations into a phylogenetic context in order to initiate an exploration into petrotympanic evolution within Mysticeti.The morphology of the petrotympanic complex is diagnostic for individual species of baleen whale (e.g., sigmoid and conical processes positioned at midline of bulla in Balaenoptera musculus; confluence of fenestra cochleae and perilymphatic foramen in Eschrichtius robustus), and several mysticete clades are united by derived characteristics. Balaenids and neobalaenids share derived features of the bulla, such as a rhomboid shape and a reduced anterior lobe (swelling) in ventral aspect, and eschrichtiids share derived morphologies of the petrosal with balaenopterids, including loss of a medial promontory groove and dorsomedial elongation of the promontorium. Monophyly of Balaenoidea (Balaenidae and Neobalaenidae) and Balaenopteroidea (Balaenopteridae and Eschrichtiidae) was recovered in phylogenetic analyses utilizing data exclusively from the petrotympanic complex.This study fills a major gap in our knowledge of the complex structures of the mysticete petrotympanic complex, which is an important anatomical region for the interpretation of the evolutionary history of mammals. In addition, we introduce a novel body of phylogenetically informative characters from the ear region of mysticetes. Our detailed anatomical descriptions, illustrations, and comparisons provide valuable data for current and future studies on the phylogenetic relationships, evolution, and auditory physiology of mysticetes and other cetaceans throughout Earth's history

Warm Body Temperature Facilitates Energy Efficient Cortical Action Potentials

The energy efficiency of neural signal transmission is important not only as a limiting factor in brain architecture, but it also influences the interpretation of functional brain imaging signals. Action potential generation in mammalian, versus invertebrate, axons is remarkably energy efficient. Here we demonstrate that this increase in energy efficiency is due largely to a warmer body temperature. Increases in temperature result in an exponential increase in energy efficiency for single action potentials by increasing the rate of Na+ channel inactivation, resulting in a marked reduction in overlap of the inward Na+, and outward K+, currents and a shortening of action potential duration. This increase in single spike efficiency is, however, counterbalanced by a temperature-dependent decrease in the amplitude and duration of the spike afterhyperpolarization, resulting in a nonlinear increase in the spike firing rate, particularly at temperatures above approximately 35°C. Interestingly, the total energy cost, as measured by the multiplication of total Na+ entry per spike and average firing rate in response to a constant input, reaches a global minimum between 37–42°C. Our results indicate that increases in temperature result in an unexpected increase in energy efficiency, especially near normal body temperature, thus allowing the brain to utilize an energy efficient neural code

A Threshold Equation for Action Potential Initiation

In central neurons, the threshold for spike initiation can depend on the stimulus and varies between cells and between recording sites in a given cell, but it is unclear what mechanisms underlie this variability. Properties of ionic channels are likely to play a role in threshold modulation. We examined in models the influence of Na channel activation, inactivation, slow voltage-gated channels and synaptic conductances on spike threshold. We propose a threshold equation which quantifies the contribution of all these mechanisms. It provides an instantaneous time-varying value of the threshold, which applies to neurons with fluctuating inputs. We deduce a differential equation for the threshold, similar to the equations of gating variables in the Hodgkin-Huxley formalism, which describes how the spike threshold varies with the membrane potential, depending on channel properties. We find that spike threshold depends logarithmically on Na channel density, and that Na channel inactivation and K channels can dynamically modulate it in an adaptive way: the threshold increases with membrane potential and after every action potential. Our equation was validated with simulations of a previously published multicompartemental model of spike initiation. Finally, we observed that threshold variability in models depends crucially on the shape of the Na activation function near spike initiation (about −55 mV), while its parameters are adjusted near half-activation voltage (about −30 mV), which might explain why many models exhibit little threshold variability, contrary to experimental observations. We conclude that ionic channels can account for large variations in spike threshold

Aetiology and risk factors of musculoskeletal disorders in physically active conscripts: a follow-up study in the Finnish Defence Forces

<p>Abstract</p> <p>Background</p> <p>Musculoskeletal disorders (MSDs) are the main reason for morbidity during military training. MSDs commonly result in functional impairment leading to premature discharge from military service and disabilities requiring long-term rehabilitation. The purpose of the study was to examine associations between various risk factors and MSDs with special attention to the physical fitness of the conscripts.</p> <p>Methods</p> <p>Two successive cohorts of 18 to 28-year-old male conscripts (<it>N </it>= 944, median age 19) were followed for six months. MSDs, including overuse and acute injuries, treated at the garrison clinic were identified and analysed. Associations between MSDs and risk factors were examined by multivariate Cox's proportional hazard models.</p> <p>Results</p> <p>During the six-month follow-up of two successive cohorts there were 1629 MSDs and 2879 health clinic visits due to MSDs in 944 persons. The event-based incidence rate for MSD was 10.5 (95% confidence interval (CI): 10.0-11.1) per 1000 person-days. Most MSDs were in the lower extremities (65%) followed by the back (18%). The strongest baseline factors associated with MSDs were poor result in the combined outcome of a 12-minute running test and back lift test (hazard ratio (HR) 2.9; 95% CI: 1.9-4.6), high waist circumference (HR 1.7; 95% CI: 1.3-2.2), high body mass index (HR 1.8; 95% CI: 1.3-2.4), poor result in a 12-minute running test (HR 1.6; 95% CI: 1.2-2.2), earlier musculoskeletal symptoms (HR 1.7; 95% CI: 1.3-2.1) and poor school success (educational level and grades combined; HR 2.0; 95% CI: 1.3-3.0). In addition, risk factors of long-term MSDs (≥10 service days lost due to one or several MSDs) were analysed: poor result in a 12-minute running test, earlier musculoskeletal symptoms, high waist circumference, high body mass index, not belonging to a sports club and poor result in the combined outcome of the 12-minute running test and standing long jump test were strongly associated with long-term MSDs.</p> <p>Conclusions</p> <p>The majority of the observed risk factors are modifiable and favourable for future interventions. An appropriate intervention based on the present study would improve both aerobic and muscular fitness prior to conscript training. Attention to appropriate waist circumference and body mass index would strengthen the intervention. Effective results from well-planned randomised controlled studies are needed before initiating large-scale prevention programmes in a military environment.</p