The Prevalence and Magnitude of Impaired Cutaneous Sensation across the Hand in the Chronic Period Post-Stroke

Sensation is commonly impaired immediately post-stroke but little is known about the long-term changes in cutaneous sensation that have the capacity to adversely impact independence and motor-function. We investigated cutaneous sensory thresholds across the hand in the chronic post-stroke period. Cutaneous sensation was assessed in 42 community-dwelling stroke patients and compared to 36 healthy subjects. Sensation was tested with calibrated monofilaments at 6 sites on the hand that covered the median, ulnar and radial innervation territories and included both glabrous (hairless) and hairy skin. The motor-function of stroke patients was assessed with the Wolf Motor Function Test and the upper-limb motor Fugl-Meyer Assessment. Impaired cutaneous sensation was defined as monofilament thresholds >3 SD above the mean of healthy subjects and good sensation was ≤3 SD. Cutaneous sensation was impaired for 33% of patients and was 40–84% worse on the more-affected side compared to healthy subjects depending on the site (p<0.05). When the stroke patient data were pooled cutaneous sensation fell within the healthy range, although ∼1/3 of patients were classified with impaired sensation. Classification by motor-function revealed low levels of impaired sensation. The magnitude of sensory loss was only apparent when the sensory-function of stroke patients was classified as good or impaired. Sensation was most impaired on the dorsum of the hand where age-related changes in monofilament thresholds are minimal in healthy subjects. Although patients with both high and low motor-function had poor cutaneous sensation, overall patients with low motor-function had poorer cutaneous sensation than those with higher motor-function, and relationships were found between motor impairments and sensation at the fingertip and palm. These results emphasize the importance of identifying the presence and magnitude of cutaneous sensory impairments in the chronic period after stroke.     

In search of allosteric modulators of a7-nAChR by solvent density guided virtual screening

Nicotinic acetylcholine receptors (nAChR) are pentameric ligand gated ion channels whose activity can be modulated by endogenous neurotransmitters as well as by synthetic ligands that bind the same or distinct sites from the natural ligand. The subtype of α7 nAChR has been considered as a potenial therapeutic target for Alzheimer's disease, schizophrenia and other neurological and psychiatric disorders. Here we have developed a homology model of α7 nAChR based on two high resolution crystal structures with Brookhaven Protein Data Bank (PDB) codes 2QC1 and 2WN9 for threading on one monomer and then for building a pentamer, respectively. A number of small molecule binding sites are identified using Pocket Finder (J. An, M. Tortov, and R. Abagyan, Molecular & Cellular Proteomics, 4.6, 752-761 (2005)) of Internal Coordinate Mechanics (ICM). Remarkably, these computer-identified sites match perfectly with ordered solvent densities found in the high-resolution crystal structure of α1 nAChR, suggesting that the surface cavities in the α7 nAChR model are likely binding sites of small molecules. A high throughput virtual screening by flexible ligand docking of 5008 small molecule compounds was performed at three potential allosteric modulator (AM) binding sites of α7 nAChR using Molsoft ICM software (R. Abagyan, M. Tortov and D. Kuznetsov, J Comput Chem 15, 488-506, (1994)). Some experimentally verified allosteric modulators of α7 like CCMI comp-6, LY 7082101, 5-HI, TQS, PNU-120596, genistein, and NS-1738 ranked among top 100 compounds, while the rest of the compounds in the list could guide further search for new allosteric modulators.     

Structural analysis of chloroplast tail‐anchored membrane protein recognition by ArsA1

In mammals and yeast, tail‐anchored (TA) membrane proteins destined for the post‐translational pathway are safely delivered to the endoplasmic reticulum (ER) membrane by a well‐known targeting factor, TRC40/Get3. In contrast, the underlying mechanism for translocation of TA proteins in plants remains obscure. How this unique eukaryotic membrane‐trafficking system correctly distinguishes different subsets of TA proteins destined for various organelles, including mitochondria, chloroplasts and the ER, is a key question of long standing. Here, we present crystal structures of algal ArsA1 (the Get3 homolog) in a distinct nucleotide‐free open state and bound to adenylyl‐imidodiphosphate. This approximately 80‐kDa protein possesses a monomeric architecture, with two ATPase domains in a single polypeptide chain. It is capable of binding chloroplast (TOC34 and TOC159) and mitochondrial (TOM7) TA proteins based on features of its transmembrane domain as well as the regions immediately before and after the transmembrane domain. Several helices located above the TA‐binding groove comprise the interlocking hook‐like motif implicated by mutational analyses in TA substrate recognition. Our data provide insights into the molecular basis of the highly specific selectivity of interactions of algal ArsA1 with the correct sets of TA substrates before membrane targeting in plant cells.     

KSRP is critical in governing hepatic lipid metabolism through controlling Per2 expression

Hepatic lipid metabolism is controlled by integrated metabolic pathways. Excess accumulation of hepatic TG is a hallmark of nonalcoholic fatty liver disease, which is associated with obesity and insulin resistance. Here, we show that KH-type splicing regulatory protein (KSRP) ablation reduces hepatic TG levels and diet-induced hepatosteatosis. Expression of period 2 (Per2) is increased during the dark period, and circadian oscillations of several core clock genes are altered with a delayed phase in Ksrp^−/− livers. Diurnal expression of some lipid metabolism genes is also disturbed with reduced expression of genes involved in de novo lipogenesis. Using primary hepatocytes, we demonstrate that KSRP promotes decay of Per2 mRNA through an RNA-protein interaction and show that increased Per2 expression is responsible for the phase delay in cycling of several clock genes in the absence of KSRP. Similar to Ksrp^−/− livers, both expression of lipogenic genes and intracellular TG levels are also reduced in Ksrp^−/− hepatocytes due to increased Per2 expression. Using heterologous mRNA reporters, we show that the AU-rich element-containing 3′ untranslated region of Per2 is responsible for KSRP-dependent mRNA decay. These findings implicate that KSRP is an important regulator of circadian expression of lipid metabolism genes in the liver likely through controlling Per2 mRNA stability.     

Photo-movement of coral larvae influences vertical positioning in the ocean

Coral Reefs - Behaviour can have profound consequences for the dispersal potential of an organism. In the marine environment, larvae rely heavily on oceanic currents to migrate from one area to...     

Direct transmission of the 18q- syndrome from mother to daughter

A 34-year-old mother presented moderate mental retardation, short stature, microcephaly, and characteristic facial dysmorphism. Her 12-year-old daughter manifested moderate mental retardation, short stature, microcephaly, dysplastic external ear canals, hearing impairment, and characteristic facial dysmorphism. Cytogenetic analysis of the family revealed a normal karyotype, 46,XY, in the father, and a 46,XX,del(18)(q22.2) karyotype in both mother and daughter. Molecular marker analysis determined direct transmission of the distal 18q deletion from mother to daughter. The present case provides evidence of fertility of the affected females and a mother-to-daughter direct transmission in the familial 18q- syndrome. Identification of affected females with the 18q- syndrome should include genetic counseling of possible direct transmission and consideration of birth control or prenatal genetic testing at reproductive age.     

AMG531 stimulates megakaryopoiesis in vitro by binding to Mpl

Thrombopoietin (TPO) plays a pivotal role in megakaryopoiesis. TPO initiates its biological effects by binding to its receptor Mpl. A recombinant protein consisting of a carrier Fc domain linked to multiple Mpl-binding domains was constructed, and is called AMG531. To define the biological activity of AMG531, we examined the ability of AMG531 to support CFU-Meg growth and to promote megakaryocyte maturation in vitro. AMG531 stimulates CFU-Meg growth in a dose-dependent manner, and acts in concert with erythropoietin, stem cell factor, interleukin-3, and interleukin-6 to enhance CFU-Meg growth, similar to parallel experiments with TPO. AMG531-stimulated serum-free liquid cultures support the development of mature polyploid megakaryocytes with a predominant DNA content of 32 N and 64 N, identical to that of parallel TPO-stimulated cultures. Competitive binding experiments show that AMG531 effectively competes with 125I-TPO for binding to BaF3-Mpl cells or normal platelets. Treatment of BaF3-Mpl cells with AMG531 or with TPO resulted in rapid tyrosine phosphorylation of Mpl, JAK2, and STAT5. These results indicate that AMG531 is a potent stimulant of megakarypoiesis in vitro, and provide support for its further characterization in vivo.