Magnetic Resonance Imaging Pilot Study of Intravenous Glyburide in Traumatic Brain Injury.

Pre-clinical studies of traumatic brain injury (TBI) show that glyburide reduces edema and hemorrhagic progression of contusions. We conducted a small Phase II, three-institution, randomized placebo-controlled trial of subjects with TBI to assess the safety and efficacy of intravenous (IV) glyburide. Twenty-eight subjects were randomized and underwent a 72-h infusion of IV glyburide or placebo, beginning within 10 h of trauma. Of the 28 subjects, 25 had Glasgow Coma Scale (GCS) scores of 6-10, and 14 had contusions. There were no differences in adverse events (AEs) or severe adverse events (ASEs) between groups. The magnetic resonance imaging (MRI) percent change at 72-168 h from screening/baseline was compared between the glyburide and placebo groups. Analysis of contusions (7 per group) showed that lesion volumes (hemorrhage plus edema) increased 1036% with placebo versus 136% with glyburide (p = 0.15), and that hemorrhage volumes increased 11.6% with placebo but decreased 29.6% with glyburide (p = 0.62). Three diffusion MRI measures of edema were quantified: mean diffusivity (MD), free water (FW), and tissue MD (MDt), corresponding to overall, extracellular, and intracellular water, respectively. The percent change with time for each measure was compared in lesions (n = 14) versus uninjured white matter (n = 24) in subjects receiving placebo (n = 20) or glyburide (n = 18). For placebo, the percent change in lesions for all three measures was significantly different compared with uninjured white matter (analysis of variance [ANOVA], p < 0.02), consistent with worsening of edema in untreated contusions. In contrast, for glyburide, the percent change in lesions for all three measures was not significantly different compared with uninjured white matter. Further study of IV glyburide in contusion TBI is warranted

Energy Transduction of Isothermal Ratchets: Generic Aspects and Specific Examples Close to and Far from Equilibrium

We study the energetics of isothermal ratchets which are driven by a chemical reaction between two states and operate in contact with a single heat bath of constant temperature. We discuss generic aspects of energy transduction such as Onsager relations in the linear response regime as well as the efficiency and dissipation close to and far from equilibrium. In the linear response regime where the system operates reversibly the efficiency is in general nonzero. Studying the properties for specific examples of energy landscapes and transitions, we observe in the linear response regime that the efficiency can have a maximum as a function of temperature. Far from equilibrium in the fully irreversible regime, we find a maximum of the efficiency with values larger than in the linear regime for an optimal choice of the chemical driving force. We show that corresponding efficiencies can be of the order of 50%. A simple analytic argument allows us to estimate the efficiency in this irreversible regime for small external forces.Comment: 16 pages, 10 figure

Starting fresh: a mixed method study of follower job satisfaction, trust, and views of their leader’s behavior

IntroductionThe leadership literature has been dominated by the study of broad styles rather than the identification of specific key behaviors. To address this deficiency, a mixed method approach was utilized to explore how follower behavioral descriptions of their leaders would relate to potential outcomes of trust in that leader and job satisfaction.MethodsData were collected from 273 hospital direct reports of 44 managers. They were asked to first describe the leadership approach of their managers in their own words, and then complete quantitative measures of the two potential outcomes.ResultsThe qualitative responses were coded into nine leadership behavior themes listed here in order from most to least often mentioned: Kindness, Supportive, Open to Input, Allow Autonomy, Engage with Team, Transparency, Fairness, Professionalism, Hold Accountable. All behavior themes related significantly to trust of the leader, with three themes relating significantly to job satisfaction (Transparency, Fairness, and Professionalism).DiscussionThese results provide a more specific view of leader behavior than does the typical style approach

Single-molecule experiments in biological physics: methods and applications

I review single-molecule experiments (SME) in biological physics. Recent technological developments have provided the tools to design and build scientific instruments of high enough sensitivity and precision to manipulate and visualize individual molecules and measure microscopic forces. Using SME it is possible to: manipulate molecules one at a time and measure distributions describing molecular properties; characterize the kinetics of biomolecular reactions and; detect molecular intermediates. SME provide the additional information about thermodynamics and kinetics of biomolecular processes. This complements information obtained in traditional bulk assays. In SME it is also possible to measure small energies and detect large Brownian deviations in biomolecular reactions, thereby offering new methods and systems to scrutinize the basic foundations of statistical mechanics. This review is written at a very introductory level emphasizing the importance of SME to scientists interested in knowing the common playground of ideas and the interdisciplinary topics accessible by these techniques. The review discusses SME from an experimental perspective, first exposing the most common experimental methodologies and later presenting various molecular systems where such techniques have been applied. I briefly discuss experimental techniques such as atomic-force microscopy (AFM), laser optical tweezers (LOT), magnetic tweezers (MT), biomembrane force probe (BFP) and single-molecule fluorescence (SMF). I then present several applications of SME to the study of nucleic acids (DNA, RNA and DNA condensation), proteins (protein-protein interactions, protein folding and molecular motors). Finally, I discuss applications of SME to the study of the nonequilibrium thermodynamics of small systems and the experimental verification of fluctuation theorems. I conclude with a discussion of open questions and future perspectives.Comment: Latex, 60 pages, 12 figures, Topical Review for J. Phys. C (Cond. Matt

Covid-19: Urgent actions, critical reflections and future relevance of “WaSH”: Lessons for the current and future pandemics

The COVID-19 pandemic placed hygiene at the centre of disease prevention. Yet, access to the levels of water supply that support good hand hygiene and institutional cleaning, our understanding of hygiene behaviours, and access to soap are deficient in low-, middle- and high-income countries. This paper reviews the role of water, sanitation and hygiene (WaSH) in disease emergence, previous outbreaks, combatting COVID-19 and in preparing for future pandemics. We consider settings where these factors are particularly important and identify key preventive contributions to disease control and gaps in the evidence base. Urgent substantial action is required to remedy deficiencies in WaSH, particularly the provision of reliable, continuous piped water on-premises for all households and settings. Hygiene promotion programmes, underpinned by behavioural science, must be adapted to high-risk populations (such as the elderly and marginalised) and settings (such as healthcare facilities, transport hubs and workplaces). WaSH must be better integrated into preparation plans and with other sectors in prevention efforts. More finance and better use of financing instruments would extend and improve WaSH services. The lessons outlined justify no-regrets investment by government during recovery from the current pandemic to improve day-to-day lives and as preparedness for future pandemics

Structure-Based Design of Non-Natural Amino Acid Inhibitors of Amyloid Fibrillation

Many globular and natively disordered proteins can convert into amyloid fibers. These fibers are associated with numerous pathologies1 as well as with normal cellular functions2,3, and frequently form during protein denaturation4,5. Inhibitors of pathological amyloid fibers could serve as leads for therapeutics, provided the inhibitors were specific enough to avoid interfering with normal processes. Here we show that computer-aided, structure-based design can yield highly specific peptide inhibitors of amyloid formation. Using known atomic structures of segments of amyloid fibers as templates, we have designed and characterized an all D-amino acid inhibitor of fibrillation of the tau protein found in Alzheimer’s disease, and a non-natural L-amino acid inhibitor of an amyloid fiber that enhances sexual transmission of HIV. Our results indicate that peptides from structure-based designs can disrupt the fibrillation of full-length proteins, including those like tau that lack fully ordered native structures.We thank M.I. Ivanova, J. Corn, T. Kortemme, D. Anderson, M.R. Sawaya, M. Phillips, S. Sambashivan, J. Park, M. Landau, Q. Zhang, R. Clubb, F. Guo, T. Yeates, J. Nowick, J. Zheng, and M.J. Thompson for discussions, HHMI, NIH, NSF, the GATES foundation, and the Joint Center for Translational Medicine for support, R. Peterson for help with NMR experiments, E. Mandelkow for providing tau constructs, R. Riek for providing amyloid beta, J. Stroud for amyloid beta preparation. Support for JK was from the Damon Runyon Cancer Research Foundation, for HWC by the Ruth L. Kirschstein National Research Service Award, for JM from the programme for junior-professors by the ministry of science, Baden-Württemberg, and for SAS by a UCLA-IGERT bioinformatics traineeship

Intracellular Bacteria Encode Inhibitory SNARE-Like Proteins

Pathogens use diverse molecular machines to penetrate host cells and manipulate intracellular vesicular trafficking. Viruses employ glycoproteins, functionally and structurally similar to the SNARE proteins, to induce eukaryotic membrane fusion. Intracellular pathogens, on the other hand, need to block fusion of their infectious phagosomes with various endocytic compartments to escape from the degradative pathway. The molecular details concerning the mechanisms underlying this process are lacking. Using both an in vitro liposome fusion assay and a cellular assay, we showed that SNARE-like bacterial proteins block membrane fusion in eukaryotic cells by directly inhibiting SNARE-mediated membrane fusion. More specifically, we showed that IncA and IcmG/DotF, two SNARE-like proteins respectively expressed by Chlamydia and Legionella, inhibit the endocytic SNARE machinery. Furthermore, we identified that the SNARE-like motif present in these bacterial proteins encodes the inhibitory function. This finding suggests that SNARE-like motifs are capable of specifically manipulating membrane fusion in a wide variety of biological environments. Ultimately, this motif may have been selected during evolution because it is an efficient structural motif for modifying eukaryotic membrane fusion and thus contribute to pathogen survival