First-passage times in complex energy landscapes: a case study with nonmuscle myosin II assembly

Complex energy landscapes often arise in biological systems, e.g. for protein folding, biochemical reactions or intracellular transport processes. Their physical effects are often reflected in the first-passage times arising from these energy landscapes. However, their calculation is notoriously challenging and it is often difficult to identify the most relevant features of a given energy landscape. Here we show how this can be achieved by coarse-graining the Fokker-Planck equation to a master equation and decomposing its first-passage times in an iterative process. We apply this method to the electrostatic interaction between two rods of nonmuscle myosin II (NM2), which is the main molecular motor for force generation in nonmuscle cells. Energy landscapes are computed directly from the amino acid sequences of the three different isoforms. Our approach allows us to identify their most likely arrangements during self-assembly into nonmuscle myosin II minifilaments and how they change under force. In particular, we find that antiparallel configurations are more stable than parallel ones, but also show more changes under mechanical loading. Our work demonstrates the rich dynamics that can be expected for NM2-assemblies under mechanical load and in general shows how one can identify the most relevant energy barriers in complex energy landscapes.Comment: Revtex, 33 pages, 8 figure

Nuclear receptor CAR represses TNFα-induced cell death by interacting with the anti-apoptotic GADD45B

Background: Phenobarbital (PB) is the most well-known among numerous non-genotoxic carcinogens that cause the development of hepatocellular carcinoma (HCC). PB activates nuclear xenobiotic receptor Constitutive Active/Androstane Receptor (CAR; NR1I3) and this activation is shown to determine PB promotion of HCC in mice. The molecular mechanism of CAR-mediated tumor promotion, however, remains elusive at the present time. Here we have identified Growth Arrest and DNA Damage-inducible 45β (GADD45B) as a novel CAR target, through which CAR represses cell death. Methodology/Principal Findings: PB activation of nuclear xenobiotic receptor CAR is found to induce the Gadd45b gene in mouse liver throughout the development of HCC as well as in liver tumors. Given the known function of GADD45B as a factor that represses Mitogen-activated protein Kinase Kinase 7-c-Jun N-terminal Kinase (MKK7-JNK) pathway-mediated apoptosis, we have now demonstrated that CAR interacts with GADD45B to repress Tumor Necrosis Factor α (TNFα)-induced JNK1 phosphorylation as well as cell death. Primary hepatocytes, prepared from Car+/+, Car-/-, Gadd45b+/+ and Gadd45b-/- mice, were treated with TNFα and Actinomycin D to induce phosphorylation of JNK1 and cell death. Cotreatment with the CAR activating ligand TCPOBOP (1,4 bis[2-(3,5-dichloropyridyloxy)]benzene) has resulted in repression of both phosphorylation and cell death in the primary hepatocytes from Car+/+ but not Car2/2mice. Repression by TCPOBOP was not observed in those prepared from Gadd45b-/- mice. In vitro protein-protein interaction and phosphorylation assays have revealed that CAR interacts with MKK7 and represses the MKK7-mediated phosphorylation of JNK1. Conclusions/Significance: CAR can form a protein complex with GADD45B, through which CAR represses MKK7-mediated phosphorylation of JNK1. In addition to activating the Gadd45b gene, CAR may repress death of mouse primary hepatocytes by forming a GADD45B complex and repressing MKK7-mediated phosphorylation of JNK1. The present finding that CAR can repress cell death via its interaction with GADD45B provides an insight for further investigations into the CAR-regulated molecular mechanism by which PB promotes development of HCC

Factors Influencing the Green House Gas Footprint of US Dairy Farms

Environmental Economics and Policy, Livestock Production/Industries,

Design and Implementation of a Thermoelectric Cooling Solution for a CCD-based NUV Spectrograph

The Colorado Ultraviolet Transit Experiment (CUTE) is a 6U CubeSat designed to obtain transit spectra of more than ten close-orbiting exoplanets. To this end, CUTE houses a near-ultraviolet (~250 – 330 nm) spectrograph based around a novel rectangular Cassegrain telescope; the spectrograph sensor is an off-the-shelf Teledyne e2v CCD. To achieve desired spectral signal-to-noise ratio (SNR), dark current is reduced by cooling the CCD to a temperature of −50 °C with a thermoelectric cooler (TEC). The TEC is driven by a constant current buck converter with an H-bridge topology for bidirectional current control. The packaging of the CCD imposes a maximum time rate of change of temperature of 5 K/min. A cascaded software control loop (discussed here) was developed that constrains this time rate of change within allowable bounds while simultaneously driving the CCD temperature to a desired setpoint. Criteria for sizing a TEC to the application and initial laboratory results are discussed, as well as digital filtering methods employed and possible solutions to integral wind-up

Portrait of a Turnaround Leader in a High Needs District

Using portraiture methodology involving interview, observation, and artifact data, this study portrays a turnaround leader, Dr. Susan Gray, in a high needs, rural district in the Southeast. In three years, Gray led Lincoln Elementary from nearly being reconstituted to being an awardwinning school. Gray has subsequently been assigned other leadership roles that required a change agent. The study narrates Gray’s professional arc, highlighting her drive, ability to build relational trust, unapologetic disruption of deficit thinking, mission-orientation, and high expectations to guide the turnaround process. The paper concludes with implications for practice and research related to leadership preparation and school turnaround

The Colorado Ultraviolet Transit Experiment: The First Dedicated Ultraviolet Exoplanet Mission

The past few years of space mission development have seen an increase in the use of small satellites as platforms for dedicated astrophysical research; they offer unique capabilities for time-domain science and complementary advantages over large shared resource facilities like the Hubble Space Telescope, including: (1) low cost and relatively quick development timelines; (2) observing strategies dedicated to niche but important science questions; and (3) ample opportunity for students and early career scientists and engineers to be involved on the front lines of space mission development. The Colorado Ultraviolet Transit Experiment (CUTE) is a NASA-supported 6U CubeSat assembled and tested at the Laboratory for Atmospheric and Space Physics within the University of Colorado Boulder. It is designed to observe the evolving atmospheres on short-period exoplanets with a dedicated science mission unachievable by current and planned future space missions. CUTE operates with a bandpass of ∼2487 – 3376 Å and an average spectral resolution element of 3.9 Å. The mission launched in September of 2021 and is in the process of conducting transit spectroscopy of approximately one dozen short-period exoplanets during its primary mission. This proceeding describes the overall CUTE satellite program, including the mission development integration and testing, anticipated science return, and lessons learned to improve both universities’ and commercial companies’ ability to create and collaborate on successful academically and research-focused small satellite missions. While CubeSats are becoming increasingly accessible and utilized for scientific research and student education, CUTE serves as an example that university small satellite programs have specific needs to successfully and efficiently achieve both scientific and educational elements. These include (1) a minimum threshold of commercial-off-the-shelf product quality, performance, and support; (2) specific and timely guidelines from launch service providers regarding launch readiness and delivery requirements; (3) and sufficient funding to provide multi-disciplinary engineering and program management support across the developmental life-cycle of the mission

Evolutionary change in continuous reaction norms

Abstract Understanding the evolution of reaction norms remains a major challenge in ecology and evolution. Investigating evolutionary divergence in reaction norm shapes between populations and closely related species is one approach to providing insights. Here we use a meta-analytic approach to compare divergence in reaction norms of closely related species or populations of animals and plants across types of traits and environments. We quantified mean-standardized differences in overall trait means (Offset) and reaction norm shape (including both Slope and Curvature). These analyses revealed that differences in shape (Slope and Curvature together) were generally greater than differences in Offset. Additionally, differences in Curvature were generally greater than differences in Slope. The type of taxon contrast (species vs. population), trait, organism, and the type and novelty of environments all contributed to the best-fitting models, especially for Offset, Curvature, and the total differences (Total) between reaction norms. Congeneric species had greater differences in reaction norms than populations, and novel environmental conditions increased the differences in reaction norms between populations or species. These results show that evolutionary divergence of curvature is common and should be considered an important aspect of plasticity, together with slope. Biological details about traits and environments, including cryptic variation expressed in novel environmental conditions, may be critical to understanding how reaction norms evolve in novel and rapidly changing environments

Genomic resources for wild populations of the house mouse, Mus musculus and its close relative Mus spretus

WOS: 000390231600001PubMed ID: 27622383Wild populations of the house mouse (Mus musculus) represent the raw genetic material for the classical inbred strains in biomedical research and are a major model system for evolutionary biology. We provide whole genome sequencing data of individuals representing natural populations of M. m. domesticus (24 individuals from 3 populations), M. m. helgolandicus (3 individuals), M. m. musculus (22 individuals from 3 populations) and M. spretus (8 individuals from one population). We use a single pipeline to map and call variants for these individuals and also include 10 additional individuals of M. m. castaneus for which genomic data are publically available. In addition, RNAseq data were obtained from 10 tissues of up to eight adult individuals from each of the three M. m. domesticus populations for which genomic data were collected. Data and analyses are presented via tracks viewable in the UCSC or IGV genome browsers. We also provide information on available outbred stocks and instructions on how to keep them in the laboratory.Max-Planck Society; DFG [HA 3139/4-1]; ERC [322564]; contract-research-project for the Bundeswehr Medical Service [M/SABX/005]This work was mostly financed by institutional resources of the Max-Planck Society, a DFG grant to B.H. and M.T. (HA 3139/4-1) and an ERC grant to D.T. (NewGenes, 322564). We thank Sonja Ihle, Susanne Krochter, Ruth Rottscheidt for contributing to collecting animals in the wild and our animal care takers for active involvement of optimizing the scheme for wild mouse keeping. The initial analysis of mice from Afghanistan was funded by contract-research-project for the Bundeswehr Medical Service M/SABX/005. We thank Bastian Pfeifer for help with software package PopGenome, Leslie Turner for discussion and Daniel M. Hooper and Trevor Price for helpful comments on the manuscript. D.T. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis

protocol of a prospective, longitudinal study

Background Natural killer (NK) cells comprise the main components of lymphocyte-mediated nonspecific immunity. Through their effector function they play a crucial role combating bacterial and viral challenges. They are also thought to be key contributors to the systemic spinal cord injury-induced immune-deficiency syndrome (SCI-IDS). SCI-IDS increases susceptibility to infection and extends to the post-acute and chronic phases after SCI. Methods and design The prospective study of NK cell function after traumatic SCI was carried out in two centers in Berlin, Germany. SCI patients and control patients with neurologically silent vertebral fracture also undergoing surgical stabilization were enrolled. Furthermore healthy controls were included to provide reference data. The NK cell function was assessed at 7 (5–9) days, 14 days (11–28) days, and 10 (8–12) weeks post-trauma. Clinical documentation included the American Spinal Injury Association (ASIA) impairment scale (AIS), neurological level of injury, infection status, concomitant injury, and medications. The primary endpoint of the study is CD107a expression by NK cells (cytotoxicity marker) 8–12 weeks following SCI. Secondary endpoints are the NK cell’s TNF-α and IFN-γ production by the NK cells 8–12 weeks following SCI. Discussion The protocol of this study was developed to investigate the hypotheses whether i) SCI impairs NK cell function throughout the post-acute and sub-acute phases after SCI and ii) the degree of impairment relates to lesion height and severity. A deeper understanding of the SCI-IDS is crucial to enable strategies for prevention of infections, which are associated with poor neurological outcome and elevated mortality. Trial registration DRKS00009855

Recent progress in translational research on neurovascular and neurodegenerative disorders

The already established and widely used intravenous application of recombinant tissue plasminogen activator as a re-opening strategy for acute vessel occlusion in ischemic stroke was recently added by mechanical thrombectomy, representing a fundamental progress in evidence-based medicine to improve the patient’s outcome. This has been paralleled by a swift increase in our understanding of pathomechanisms underlying many neurovascular diseases and most prevalent forms of dementia. Taken together, these current advances offer the potential to overcome almost two decades of marginally successful translational research on stroke and dementia, thereby spurring the entire field of translational neuroscience. Moreover, they may also pave the way for the renaissance of classical neuroprotective paradigms. This review reports and summarizes some of the most interesting and promising recent achievements in neurovascular and dementia research. It highlights sessions from the 9th International Symposium on Neuroprotection and Neurorepair that have been discussed from April 19th to 22nd in Leipzig, Germany. To acknowledge the emerging culture of interdisciplinary collaboration and research, special emphasis is given on translational stories ranging from fundamental research on neurode- and -regeneration to late stage translational or early stage clinical investigations