Systems level circuit model of C. elegans undulatory locomotion: mathematical modeling and molecular genetics

To establish the relationship between locomotory behavior and dynamics of neural circuits in the nematode C. elegans we combined molecular and theoretical approaches. In particular, we quantitatively analyzed the motion of C. elegans with defective synaptic GABA and acetylcholine transmission, defective muscle calcium signaling, and defective muscles and cuticle structures, and compared the data with our systems level circuit model. The major experimental findings are: (i) anterior-to-posterior gradients of body bending flex for almost all strains both for forward and backward motion, and for neuronal mutants, also analogous weak gradients of undulatory frequency, (ii) existence of some form of neuromuscular (stretch receptor) feedback, (iii) invariance of neuromuscular wavelength, (iv) biphasic dependence of frequency on synaptic signaling, and (v) decrease of frequency with increase of the muscle time constant. Based on (i) we hypothesize that the Central Pattern Generator (CPG) is located in the head both for forward and backward motion. Points (i) and (ii) are the starting assumptions for our theoretical model, whose dynamical patterns are qualitatively insensitive to the details of the CPG design if stretch receptor feedback is sufficiently strong and slow. The model reveals that stretch receptor coupling in the body wall is critical for generation of the neuromuscular wave. Our model agrees with our behavioral data(iii), (iv), and (v), and with other pertinent published data, e.g., that frequency is an increasing function of muscle gap-junction coupling.Comment: Neural control of C. elegans motion with genetic perturbation

A comparison of two gluteus maximus EMG maximum voluntary isometric contraction positions

Background. The purpose of this study was to compare the peak electromyography (EMG) of the most commonly-used position in the literature, the prone bent-leg (90°) hip extension against manual resistance applied to the distal thigh (PRONE), to a novel position, the standing glute squeeze (SQUEEZE). Methods. Surface EMG electrodes were placed on the upper and lower gluteus maximus of thirteen recreationally active females (age = 28.9 years; height = 164 cm; body mass = 58.2 kg), before three maximum voluntary isometric contraction (MVIC) trials for each position were obtained in a randomized, counterbalanced fashion. Results. No statistically significant (p \u3c 0.05) differences were observed between PRONE (upper: 91.94%; lower: 94.52%) and SQUEEZE (upper: 92.04%; lower: 85.12%) for both the upper and lower gluteus maximus. Neither the PRONE nor SQUEEZE was more effective between all subjects. Conclusions. In agreement with other studies, no single testing position is ideal for every participant. Therefore, it is recommended that investigators employ multiple MVIC positions, when possible, to ensure accuracy. Future research should investigate a variety of gluteus maximus MVIC positions in heterogeneous samples

Using present-day observations to detect when anthropogenic change forces surface ocean carbonate chemistry outside preindustrial bounds

© The Author(s), 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Biogeosciences 13 (2016): 5065-5083, doi:10.5194/bg-13-5065-2016.One of the major challenges to assessing the impact of ocean acidification on marine life is detecting and interpreting long-term change in the context of natural variability. This study addresses this need through a global synthesis of monthly pH and aragonite saturation state (Ωarag) climatologies for 12 open ocean, coastal, and coral reef locations using 3-hourly moored observations of surface seawater partial pressure of CO2 and pH collected together since as early as 2010. Mooring observations suggest open ocean subtropical and subarctic sites experience present-day surface pH and Ωarag conditions outside the bounds of preindustrial variability throughout most, if not all, of the year. In general, coastal mooring sites experience more natural variability and thus, more overlap with preindustrial conditions; however, present-day Ωarag conditions surpass biologically relevant thresholds associated with ocean acidification impacts on Mytilus californianus (Ωarag < 1.8) and Crassostrea gigas (Ωarag < 2.0) larvae in the California Current Ecosystem (CCE) and Mya arenaria larvae in the Gulf of Maine (Ωarag < 1.6). At the most variable mooring locations in coastal systems of the CCE, subseasonal conditions approached Ωarag =  1. Global and regional models and data syntheses of ship-based observations tended to underestimate seasonal variability compared to mooring observations. Efforts such as this to characterize all patterns of pH and Ωarag variability and change at key locations are fundamental to assessing present-day biological impacts of ocean acidification, further improving experimental design to interrogate organism response under real-world conditions, and improving predictive models and vulnerability assessments seeking to quantify the broader impacts of ocean acidification.The CO2 and ocean acidification observations were funded by NOAA’s Climate Observation Division (COD) in the Climate Program Office and NOAA’s Ocean Acidification Program. The maintenance of the Stratus and WHOTS Ocean Reference Stations were also supported by NOAA COD (NA09OAR4320129). Additional support for buoy equipment, maintenance, and/or ancillary measurements was provided by NOAA through the US Integrated Ocean Observing System office: for the La Parguera buoy under a Cooperative Agreement (NA11NOS0120035) with the Caribbean Coastal Ocean Observing System, for the Chá b˘a buoy under a Cooperative Agreement (NA11NOS0120036) with the Northwest Association of Networked Ocean Observing System, for the Gray’s Reef buoy under a Cooperative Agreement (NA11NOS0120033) with the Southeast Coastal Ocean Observing Regional Association, and for the Gulf of Main buoy under a Cooperative Agreement (NA11NOS0120034) with the Northeastern Regional Association of Coastal and Ocean Observing Systems

Hereditary leukoencephalopathy with axonal spheroids: a spectrum of phenotypes from CNS vasculitis to parkinsonism in an adult onset leukodystrophy series

Background: Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS) is a hereditary, adult onset leukodystrophy which is characterised by the presence of axonal loss, axonal spheroids and variably present pigmented macrophages on pathological examination. It most frequently presents in adulthood with dementia and personality change. HDLS has recently been found to be caused by mutations in the colony stimulating factor-1 receptor (CSF1R) gene. Methods: In this study, we sequenced the CSF1R gene in a cohort of 48 patients from the UK, Greece and Ireland with adult onset leukodystrophy of unknown cause. Results: Five pathogenic mutations were found, including three novel mutations. The presentations ranged from suspected central nervous system (CNS) vasculitis to extrapyramidal to cognitive phenotypes. The case histories and imaging are presented here, in addition to neuropathological findings from two cases with novel mutations. Conclusion: We estimate that CSF1R mutations account for 10% of idiopathic adult onset leukodystrophies and that genetic testing for CSF1R mutations is essential in adult patients presenting with undefined CNS vasculitis or a leukodystrophy with prominent neuropsychiatric signs or dementia

Sympatric seals, satellite tracking and protected areas : habitat-based distribution estimates for conservation and management

Analysis was funded by the UK Government Department for Business, Energy and Industrial Strategy (BEIS; OESEA-16-76/OESEA-17-78) with support from the Natural Environment Research Council (NERC; INSITE Phase II NE/T010614/1 EcoSTAR), EU INTERREG (MarPAMM), and the Scottish Government (MMSS/002/15). DJFR’s contribution was funded by NERC National Capability Funding (NE/R015007/1). WJG was supported by INSITE Phase I (MAPS). Telemetry tags and their deployment were funded in the UK by BEIS (and previous incarnations), NERC, Marine Scotland, Scottish Government, NatureScot, SMRU, SMRU Instrumentation Group, Marine Current Turbines, Ørsted, the Met Office, the Zoological Society of London (ZSL), the Crown Estate, Highlands & Islands Enterprise, Moray Firth Renewables Limited (MORL), Beatrice Offshore Windfarm Limited (BOWL), SITA Trust, BBC Wildlife Fund and the Hampshire & Isle of Wight Wildlife Trust. Tags and their deployment in Ireland were funded by Inland Fisheries Ireland, the Department of Communications, Marine and Natural Resources, the Higher Education Authority of Ireland, the National Geographic Society, the Department of Agriculture, Food and the Marine, and the National Parks and Wildlife Service. UK aerial surveys conducted by SMRU were funded by NERC (NE/R015007/1), NatureScot, the Department for Agriculture, Environment and Rural Affairs (Northern Ireland), Marine Current Turbines, Marine Scotland, Natural England, and Scottish Power. Aerial surveys in Ireland were funded by the Department for Tourism, Culture, Arts, Gaeltacht, Sport and Media.Marine predator populations are crucial to the structure and functioning of ecosystems. Like many predator taxa, pinnipeds face an increasingly complex array of natural and anthropogenic threats. Understanding the relationship between at-sea processes and trends in abundance at land-based monitoring sites requires robust estimates of at-sea distribution, often on multi-region scales. Such an understanding is critical for effective conservation management, but estimates are often limited in spatial extent by spatial coverage of animal-borne tracking data. Grey (Halichoerus grypus) and harbour seals (Phoca vitulina) are sympatric predators in North Atlantic shelf seas. The United Kingdom (UK) and Ireland represents an important population centre for both species, and Special Areas of Conservation (SACs) are designated for their monitoring and protection. Here we use an extensive high-resolution GPS tracking dataset, unprecedented in both size (114 grey and 239 harbour seals) and spatial coverage, to model habitat preference and generate at-sea distribution estimates for the entire UK and Ireland populations of both species. We found regional differences in environmental drivers of distribution for both species which likely relate to regional variation in diet and population trends. Moreover, we provide SAC-specific estimates of at-sea distribution for use in marine spatial planning, demonstrating that hotspots of at-sea density in UK and Ireland-wide maps cannot always be apportioned to the nearest SAC. We show that for grey seals, colonial capital breeders, there is a mismatch between SACs (where impacts are likely to be detected) and areas where impacts are most likely to occur (at sea). We highlight an urgent need for further research to elucidate the links between at-sea distribution during the foraging season and population trends observed in SACs. More generally, we highlight that the potential for such a disconnect needs to be considered when designating and managing protected sites, particularly for species that aggregate to breed and exhibit partial migration (e.g. grey seals), or spatial variation in migration strategies. We demonstrate the use of strategic tracking efforts to predict distribution across multiple regions, but caution that such efforts should be mindful of the potential for differences in species-environment relationships despite similar accessible habitats.Publisher PDFPeer reviewe

Analysis of the History and Spread of HIV-1 in Uganda using phylodynamics

HIV prevalence has decreased in Uganda since the 1990s, but remains substantial within high-risk groups. Here, we reconstruct the history and spread of HIV subtypes A1 and D in Uganda and explore the transmission dynamics in high-risk populations. We analysed HIV pol sequences from female sex workers in Kampala (n = 42), Lake Victoria fisher-folk (n = 46) and a rural clinical cohort (n = 74), together with publicly available sequences from adjacent regions in Uganda (n = 412) and newly generated sequences from samples taken in Kampala in 1986 (n = 12). Of the sequences from the three Ugandan populations, 60 (37.1 %) were classified as subtype D, 54 (33.3 %) as subtype A1, 31 (19.1 %) as A1/D recombinants, six (3.7 %) as subtype C, one (0.6 %) as subtype G and 10 (6.2 %) as other recombinants. Among the A1/D recombinants we identified a new candidate circulating recombinant form. Phylodynamic and phylogeographic analyses using BEAST indicated that the Ugandan epidemics originated in 1960 (1950-1968) for subtype A1 and 1973 (1970-1977) for D, in rural south-western Uganda with subsequent spread to Kampala. They also showed extensive interconnection with adjacent countries. The sequence analysis shows both epidemics grew exponentially during the 1970s-1980s and decreased from 1992, which agrees with HIV prevalence reports in Uganda. Inclusion of sequences from the 1980s indicated the origin of both epidemics was more recent than expected and substantially narrowed the confidence intervals in comparison to previous estimates. We identified three transmission clusters and ten pairs, none of them including patients from different populations, suggesting active transmission within a structured transmission network

Using the split squat to potentiate bilateral and unilateral jump performance

The purpose of this study was to examine if a split squat conditioning exercise with no or light loads could potentiate unilateral and bilateral jump performance. Twelve semi-professional rugby players (age: 22.3 +/- 1.4 years; height: 1.84 +/- 0.05 m, mass: 92.4 +/- 9.6 kg) from the English National League 1 performed a series of unilateral and bilateral countermovement jumps (CMJ) and broad jumps (BJ) over the course of two testing days. Both testing days involved performing baseline jumps before completing two sets of ten repetitions of a split squat, this completed with either bodyweight (testing session 1) or a 30kg weighted vest (testing session 2). A five-minute recovery period was permitted both following the warm up and following the completion of the split squat exercise. Significantly larger bilateral jump scores were reported following completion of the bodyweight split squat: CMJ (p = 0.001, ES = 0.44, [mean difference 2.517]), BJ (p = 0.001, ES = 0.37, [mean difference 3.817]), and the weighted vest split squat; CMJ (p = 0.001, ES = 0.8, [mean difference 4.383]), BJ (p = 0.001, ES = 0.68, [mean difference 6.817]). The findings of this study demonstrate that no or light loads of a split squat conditioning exercise are able to potentiate bilateral jump performance in semi-professional rugby players without the need for expensive weight room equipment. As such, this may provide coaches with a viable option of enhancing bilateral jump performance as part of a warm up or on-field conditioning practice

Chromosome 10q26-driven age-related macular degeneration is associated with reduced levels of HTRA1 in human retinal pigment epithelium

Genome-wide association studies have identified the chromosome 10q26 (Chr10) locus, which contains the age-related maculopathy susceptibility 2 (ARMS2) and high temperature requirement A serine peptidase 1 (HTRA1) genes, as the strongest genetic risk factor for age-related macular degeneration (AMD) [L.G. Fritsche et al., Annu. Rev. Genomics Hum. Genet. 15, 151–171, (2014)]. To date, it has been difficult to assign causality to any specific single nucleotide polymorphism (SNP), haplotype, or gene within this region because of high linkage disequilibrium among the disease-associated variants [J. Jakobsdottir et al. Am. J. Hum. Genet. 77, 389–407 (2005); A. Rivera et al. Hum. Mol. Genet. 14, 3227–3236 (2005)]. Here, we show that HTRA1 messenger RNA (mRNA) is reduced in retinal pigment epithelium (RPE) but not in neural retina or choroid tissues derived from human donors with homozygous risk at the 10q26 locus. This tissue-specific decrease is mediated by the presence of a noncoding, cis-regulatory element overlapping the ARMS2 intron, which contains a potential Lhx2 transcription factor binding site that is disrupted by risk variant rs36212733. HtrA1 protein increases with age in the RPE–Bruch’s membrane (BM) interface in Chr10 nonrisk donors but fails to increase in donors with homozygous risk at the 10q26 locus. We propose that HtrA1, an extracellular chaperone and serine protease, functions to maintain the optimal integrity of the RPE–BM interface during the aging process and that reduced expression of HTRA1 mRNA and protein in Chr10 risk donors impairs this protective function, leading to increased risk of AMD pathogenesis. HtrA1 augmentation, not inhibition, in high-risk patients should be considered as a potential therapy for AMD

ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF-and IFN?-driven immunopathology

Despite tremendous progress in the understanding of COVID-19, mechanistic insight into immunological, disease-driving factors remains limited. We generated maVie16, a mouse-adapted SARS-CoV-2, by serial passaging of a human isolate. In silico modeling revealed how only three Spike mutations of maVie16 enhanced interaction with murine ACE2. maVie16 induced profound pathology in BALB/c and C57BL/6 mice, and the resulting mouse COVID-19 (mCOVID-19) replicated critical aspects of human disease, including early lymphopenia, pulmonary immune cell infiltration, pneumonia, and specific adaptive immunity. Inhibition of the proinflammatory cyto-kines IFN? and TNF substantially reduced immunopathology. Importantly, genetic ACE2-deficiency completely prevented mCOVID-19 development. Finally, inhalation therapy with recombinant ACE2 fully protected mice from mCOVID-19, revealing a novel and efficient treatment. Thus, we here present maVie16 as a new tool to model COVID-19 for the discovery of new therapies and show that disease severity is determined by cytokine-driven immunopathology and critically dependent on ACE2 in vivo. © Gawish et al