Both left ventricular (LV) and left atrial (LA) dysfunction and remodelling contribute to adverse outcomes in heart failure with reduced ejection fraction (HFrEF). Danicamtiv is a novel, cardiac myosin activator that enhances cardiomyocyte contraction.

The seasonality of litter insect abundance and its relationship with rainfall was analyzed in a wet evergreen forest on the windward side of south Western Ghats. Monthly litter samples were collected using Berlese funnels during 4 seasons of a year: southwest monsoon season June—August), northeast monsoon season (September—November), summer (March -May) and pre-summer season (December—February). Insect fauna as a whole showed no seasonal variation in abundance, however, some individual insect orders showed significant seasonal variation. Overall insect fauna and individual orders were distributed independently relative to rainfall. All insect orders with the exception of Psocoptera were present during all four seasons. Coleoptera (42%) was the dominant group in all seasons followed by Formicidae (12.3%), insect larvae (10.1%), Collembola (9.2%) and Thysanoptera (8.9%). Exceptionally high abundance of Ptiliidae contributed to the unprecedented abundance of litter Coleoptera. The aseasonality of litter insect fauna as a whole is attributed to year-round availability of rainfall and the absence of severe summer conditions.

The diversity of litter ant assemblages in evergreen, deciduous and Shola evergreen (Shola) forest vegetation types of the Wayanad region of the Western Ghats was assessed employing conventional and taxonomic diversity indices. Non-dependence on quantitative data and the ability to relate the phylogenetic structure of assemblages with ecological conditions of the habitat, and to ascertain priorities for conservation of habitats, makes non-parametric taxonomic diversity measures, such as variation in taxonomic distinctness Λ+ and average taxonomic distinctness Δ+, highly useful tools for assessment of litter ant biodiversity.Although Δ+ values saturated leading to closer values for the 3 litter ant assemblages, Λ+ proved to be a more dependable index. Evenness in taxonomic spread was high in ant assemblages in deciduous forests and low in evergreen forests compared to the regional master list. Low Λ+ of ant assemblage in deciduous forests indicates that among the 3 forest vegetation types, deciduous forests provided the most favorable habitat conditions for litter ants. Low evenness, as is indicated by Λ+ in evergreen forests, was attributed to the presence of a group of taxonomically closely related ant assemblage more adapted to prevail in moist and wet ecological conditions.

B: Alterations in the length dependent activation (LDA) of left ventricular (LV) muscle fibres, the mechanistic driver of the Frank-Starling Law of the heart, are thought to mediate impaired LV function in heart failure (HF). However, little is known about LDA's role in the left atria (LA). Given the concomitant presence of LA dysfunction in HF, the purpose of this study was to compare/assess LDA on LA and LV muscle, as well to evaluate the effects of a novel small-molecule acto-myosin activator, danicamtiv (formerly known as MYK-491). M: LA and LV myofibrils from healthy Yucatan mini-pigs were used to determine biomechanical function with ATPase assays, with and without danicamtiv. Skinned LA and LV muscle fibres from these same animals were prepared to study contractile force, Ca2+ sensitivity, active/passive stiffness, and responsiveness to increasing sarcomere length (2.0 and 2.3). These parameters were also evaluated in the presence of danicamtiv. R: LA myofibrils had significantly faster ATPase and Pi release rates compared to LV, consistent with their respective alpha/beta myosin-isoform content. Despite increased metabolic rate, LA fibres generated less maximum isometric tension (12.3±1.96 vs 35.2±3.07 mN/mm2) and had a lower pCa50 than LV fibres (5.66±0.02 vs 5.82±0.02), demonstrating reduced force-generating capability and Ca2+ sensitivity. Stretch of LV fibres resulted in a gain in tension over a range of pCas (pCa6.4, 6.2, 6.0, and 5.8, all p<0.05). However, in LA, LDA-induced gain was not significant at submaximal pCas (pCa6.4, 6.2, 6.0, all p>0.05). Stretch had no effect on active stiffness, but increased passive stiffness in both muscle types. Stretched LA fibres showed grater passive stiffness compared to LV (196.7±21.5 vs. 138.5±22.3 kN/m3). A stiffer myofilament would in part explain the blunted ability of the LA to generate force in response to stretch. Danicamtiv activated both LA and LV myofibrils, increasing ATPase and Pi release rates, and increased Ca2+ sensitivity in fibres (ΔpCa; LV, 0.320±0.032; LA, 0.149±0.028, p<0.01). Unlike with stretch, danicamtiv had no effect on passive stiffness, yet altered the active stiffness/tension (S/T) relationship in both fiber types, but, differentially. In LV, danicamtiv increased the number of available heads (Y0; 129.9±26.3 vs 10.1±4.2 kN/m3, p<0.001) with no significant effect on slope. In the LA, Y0 was largely unchanged with a significant increase in the slope of the S/T relationship (slope: 34.0±2.9 vs. 20.0±1.9 au, p<0.01). Together, these data suggest an increased number of force producing cross-bridges, without altering passive stiffness. C: These data confirm the functional differences between LA and LV muscle fibres and demonstrate a blunted ability of LA tissue to recruit force when stretched. The acto-myosin activator danicamtiv increased biochemical activity, Ca2+ sensitivity, and the active S/T relationship in LA and LV fibres without altering passive strain. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): MyoKardia Inc.

and are implicated in many neurological disorders. Available x-ray structures of prokaryotic and eukaryotic Cys-loop receptors provide tremendous insights into the binding of agonists, the subsequent opening of the ion channel, and the mechanism of channel activation [1][2][3][4][5][6][7][8] . Yet the mechanism of inactivation by antagonists remains unknown. Here we present a 3.0 Å x-ray structure of the human glycine receptor a3 homopentamer in complex with a high affinity, high specificity antagonist strychnine. Our structure allows us to explore in great detail the molecular recognition of antagonists. Comparisons with previous structures reveal a mechanism of inactivating Cys-loop receptors by antagonist binding.This work has been published in Nature Sep 28.