The R403Q Myosin Mutation Implicated in Familial Hypertrophic Cardiomyopathy Causes Disorder at the Actomyosin Interface

Mutations in virtually all of the proteins comprising the cardiac muscle sarcomere have been implicated in causing Familial Hypertrophic Cardiomyopathy (FHC). Mutations in the beta-myosin heavy chain (MHC) remain among the most common causes of FHC, with the widely studied R403Q mutation resulting in an especially severe clinical prognosis. In vitro functional studies of cardiac myosin containing the R403Q mutation have revealed significant changes in enzymatic and mechanical properties compared to wild-type myosin. It has been proposed that these molecular changes must trigger events that ultimately lead to the clinical phenotype.Here we examine the structural consequences of the R403Q mutation in a recombinant smooth muscle myosin subfragment (S1), whose kinetic features have much in common with slow beta-MHC. We obtained three-dimensional reconstructions of wild-type and R403Q smooth muscle S1 bound to actin filaments in the presence (ADP) and absence (apo) of nucleotide by electron cryomicroscopy and image analysis. We observed that the mutant S1 was attached to actin at highly variable angles compared to wild-type reconstructions, suggesting a severe disruption of the actin-myosin interaction at the interface.These results provide structural evidence that disarray at the molecular level may be linked to the histopathological myocyte disarray characteristic of the diseased state

Molecular Basis for the Dual Function of Eps8 on Actin Dynamics: Bundling and Capping

The unusual dual functions of the actin-binding protein EPS8 as an actin capping and actin bundling factor are mapped to distinct structural features of the protein and to distinct physiological activities in vivo

Illuminating hydrological processes at the soil-vegetation-atmosphere interface with water stable isotopes

Funded by DFG research project “From Catchments as Organised Systems to Models based on Functional Units” (FOR 1Peer reviewedPublisher PDFPublisher PD

Short-Course, High-Dose Rifampicin Achieves Wolbachia Depletion Predictive of Curative Outcomes in Preclinical Models of Lymphatic Filariasis and Onchocerciasis

Lymphatic filariasis (LF) and onchocerciasis are priority neglected tropical diseases targeted for elimination. The only safe drug treatment with substantial curative activity against the filarial nematodes responsible for LF (Brugia malayi, Wuchereria bancrofti) or onchocerciasis (Onchocerca volvulus) is doxycycline. The target of doxycycline is the essential endosymbiont, Wolbachia. Four to six weeks doxycycline therapy achieves >90% depletion of Wolbachia in worm tissues leading to blockade of embryogenesis, adult sterility and premature death 18–24 months post-treatment. Long treatment length and contraindications in children and pregnancy are obstacles to implementing doxycycline as a public health strategy. Here we determine, via preclinical infection models of Brugia malayi or Onchocerca ochengi that elevated exposures of orally-administered rifampicin can lead to Wolbachia depletions from filariae more rapidly than those achieved by doxycycline. Dose escalation of rifampicin achieves >90% Wolbachia depletion in time periods of 7 days in B. malayi and 14 days in O. ochengi. Using pharmacokinetic-pharmacodynamic modelling and mouse-human bridging analysis, we conclude that clinically relevant dose elevations of rifampicin, which have recently been determined as safe in humans, could be administered as short courses to filariasis target populations with potential to reduce anti-Wolbachia curative therapy times to between one and two weeks

Filarial Parasites Develop Faster and Reproduce Earlier in Response to Host Immune Effectors That Determine Filarial Life Expectancy

During larval development, filarial nematodes adjust their lifelong reproductive strategy to the presence of anti-parasitic immune cells that determine host resistance and experimental vaccine efficacy

Interactive Responses of a Thalamic Neuron to Formalin Induced Lasting Pain in Behaving Mice

Thalamocortical (TC) neurons are known to relay incoming sensory information to the cortex via firing in tonic or burst mode. However, it is still unclear how respective firing modes of a single thalamic relay neuron contribute to pain perception under consciousness. Some studies report that bursting could increase pain in hyperalgesic conditions while others suggest the contrary. However, since previous studies were done under either neuropathic pain conditions or often under anesthesia, the mechanism of thalamic pain modulation under awake conditions is not well understood. We therefore characterized the thalamic firing patterns of behaving mice in response to nociceptive pain induced by inflammation. Our results demonstrated that nociceptive pain responses were positively correlated with tonic firing and negatively correlated with burst firing of individual TC neurons. Furthermore, burst properties such as intra-burst-interval (IntraBI) also turned out to be reliably correlated with the changes of nociceptive pain responses. In addition, brain stimulation experiments revealed that only bursts with specific bursting patterns could significantly abolish behavioral nociceptive responses. The results indicate that specific patterns of bursting activity in thalamocortical relay neurons play a critical role in controlling long-lasting inflammatory pain in awake and behaving mice

Molecular systematics of the marine Dothideomycetes

Phylogenetic analyses of four nuclear genes, namely the large and small subunits of the nuclear ribosomal RNA, transcription elongation factor 1-alpha and the second largest RNA polymerase II subunit, established that the ecological group of marine bitunicate ascomycetes has representatives in the orders Capnodiales, Hysteriales, Jahnulales, Mytilinidiales, Patellariales and Pleosporales. Most of the fungi sequenced were intertidal mangrove taxa and belong to members of 12 families in the Pleosporales: Aigialaceae, Didymellaceae, Leptosphaeriaceae, Lenthitheciaceae, Lophiostomataceae, Massarinaceae, Montagnulaceae, Morosphaeriaceae, Phaeosphaeriaceae, Pleosporaceae, Testudinaceae and Trematosphaeriaceae. Two new families are described: Aigialaceae and Morosphaeriaceae, and three new genera proposed: Halomassarina, Morosphaeria and Rimora. Few marine species are reported from the Dothideomycetidae (e.g. Mycosphaerellaceae, Capnodiales), a group poorly studied at the molecular level. New marine lineages include the Testudinaceae and Manglicola guatemalensis in the Jahnulales. Significantly, most marine Dothideomycetes are intertidal tropical species with only a few from temperate regions on salt marsh plants (Spartina species and Juncus roemerianus), and rarely totally submerged (e.g. Halotthia posidoniae and Pontoporeia biturbinata on the seagrasses Posidonia oceanica and Cymodocea nodosum). Specific attention is given to the adaptation of the Dothideomycetes to the marine milieu, new lineages of marine fungi and their host specificity

An MBO scheme for minimizing the graph Ohta-Kawasaki functional

We study a graph based version of the Ohta-Kawasaki functional, which was originally introduced in a continuum setting to model pattern formation in diblock copolymer melts and has been studied extensively as a paradigmatic example of a variational model for pattern formation. Graph based problems inspired by partial differential equations (PDEs) and varational methods have been the subject of many recent papers in the mathematical literature, because of their applications in areas such as image processing and data classification. This paper extends the area of PDE inspired graph based problems to pattern forming models, while continuing in the tradition of recent papers in the field. We introduce a mass conserving Merriman-Bence-Osher (MBO) scheme for minimizing the graph Ohta-Kawasaki functional with a mass constraint. We present three main results: (1) the Lyapunov functionals associated with this MBO scheme Γ-converge to the Ohta-Kawasaki functional (which includes the standard graph based MBO scheme and total variation as a special case); (2) there is a class of graphs on which the Ohta-Kawasaki MBO scheme corresponds to a standard MBO scheme on a transformed graph and for which generalized comparison principles hold; (3) this MBO scheme allows for the numerical computation of (approximate) minimizers of the graph Ohta-Kawasaki functional with a mass constraint