pinecone/core-2020-05-10-deduplication huggingface dataset:
Dysfunction of voltage-gated K + Channels Kv1.1 in sciatic nerve causes spontaneous and stress-induced neuromuscular hyperexcitability

Episodic ataxia type 1 (EA1) is an autosomal dominant neurological disorder characterized by\ud
myokymia and attacks of ataxic gait precipitated by stress events. Several genetic mutations have\ud
been identified in the Shaker-like K+\ud
\ud
channel Kv1.1 (KCNA1) of EA1 individuals, including the\ud
V408A which results in remarkable channel dysfunction. By inserting heterozygous V408A\ud
mutation in one Kv1.1 allele, a mouse model of EA1 has been generated (Kv1.1\ud
\ud
V408A/+). Here, we\ud
hypothesized that dysfunction of Kv1.1 channels in sciatic nerve of Kv1.1V408A/+ ataxia mice leads to\ud
neuromuscular hyperexcitability and to abnormal susceptibility to different stressors. By using in\ud
vivo preparations of lateral gastrocnemius (LG) nerve–muscle from Kv1.1+/+ and Kv1.1V408A/+ mice,\ud
we show that the mutant animals exhibit spontaneous myokymic discharges consisting of repeated\ud
singlets, duplets or multiplets, despite sciatic nerve axotomy. Two-photon laser scanning\ud
microscopy from the sciatic nerve, ex vivo, revealed spontaneous Ca2+ signals that occurred\ud
abnormally only in preparations dissected from Kv1.1V408A/+ mice. The spontaneous bursting\ud
activity, as well as that evoked by motor nerve stimulation, was exacerbated by muscle fatigue,\ud
ischemia and low temperatures. These stressors also increased the amplitude of muscle compound\ud
action potential. Such abnormal neuromuscular transmission did not alter fiber type composition\ud
neuromuscular junction and vascularization of LG muscle analyzed by light and electron\ud
microscopy. These findings indicate that dysfunction of Kv1.1 channels results in sciatic nerve\ud
hyperexcitability and myokymia/neuromyotonia in Kv1.1V408A/+ ataxia mice. Moreover, this study\ud
sheds new light on the functional role played by K\ud
+\ud
channels segregated under the myelin sheath,\ud
\ud
which becomes crucial in certain situations of physiological stress.peer-reviewe
Heterotic reduction of Courant algebroid connections and Einstein–Hilbert actions

We discuss Levi-Civita connections on Courant algebroids. We define an appropriate generalization of the curvature tensor and compute the corresponding scalar curvatures in the exact and heterotic case, leading to generalized (bosonic) Einstein–Hilbert type of actions known from supergravity. In particular, we carefully analyze the process of the reduction for the generalized metric, connection, curvature tensor and the scalar curvature.The research
of B.J. was supported by grant GACRˇ P201/12/G028 and in part by the Action MP1405
QSPACE from COST. He would like to thank the Max Planck Institute for Mathematics, the
Erwin Schrödinger International Institute for Mathematical Physics in Vienna, and the Tohoku
Forum for Creativity for hospitality. The research of J.V. was supported by RVO: 67985840
and under Australian Research Council’s Discovery Projects funding scheme (project numbers
DP110100072 and DP150100008), he would like to thank the Mathematical Sciences Institute
and the Australian National University for a great hospitality and a very pleasant stay in Australia
Development and validation of a hospital frailty risk score focusing on older people in acute care settings using electronic hospital records; an observational study

Background: Older people are increasing users of healthcare globally; the aim of this study was to determine if older people with characteristics of frailty and at risk of adverse healthcare outcomes could be identified using routinely collected data. Methods: A three-step approach was used to develop and validate a Hospital Frailty Risk Score from ICD-10 diagnostic codes. First, we carried out a cluster analysis to identify a group of hospitalised older people (75 years+) with high resource use and diagnoses associated with frailty. Second, we created a Hospital Frailty Risk Score based on ICD-10 codes that characterised this group. Third, in separate cohorts, we tested how well the score predicted adverse outcomes, and whether it identified similar groups as other frailty tools. Findings: In the development cohort (n = 22,139), older people with frailty diagnoses formed a distinct group, and had higher non-elective hospital use. In a national validation cohort (n = 1,013,590), compared to patients with the lowest 40%, patients with the highest 20% of Hospital Frailty Risk Scores had increased odds of 30-day mortality (odds ratio 1·71, 95% confidence interval 1·68 to 1·75), long length of stay (OR 6·03, 95% CI 5·92 to 6·10) and 30-day readmission (OR 1·48, 95% CI 1·46 to 1·50). Model discrimination (c-statistic) between individuals for these three outcomes was 0·60, 0·68 and 0·56, respectively. The Hospital Frailty Risk Score exhibited fair or moderate overlap in the identification of frailty with the Fried or Rockwood frailty scales respectively. Interpretation: The Hospital Frailty Risk Score provides hospitals and health systems with a low cost, systematic way to screen for frailty, identifying a group of hospitalised patients at greater risk of adverse outcomes for whom a frailty-attuned approach might be useful. Funding: National Institute for Health Research.This study was funded by the National Institute for Health Research (NIHR; HSDR 12/5003/02). Open Access funded by Department of Health UK.Peer-reviewedPublisher Versio
Mechanism of Bacterial Interference with TLR4 Signaling by Brucella Toll/Interleukin-1 Receptor Domain-containing Protein TcpB

Upon activation of Toll-like receptors (TLRs), cytoplasmic Toll/interleukin-1 receptor (TIR) domains of the receptors undergo homo- or heterodimerization. This in turn leads to the recruitment of adaptor proteins, activation of transcription factors, and the secretion of pro-inflammatory cytokines. Recent studies have described the TIR domain-containing protein from Brucella melitensis, TcpB (BtpA/Btp1), to be involved in virulence and suppression of host innate immune responses. TcpB interferes with TLR4 and TLR2 signaling pathways by a mechanism that remains controversial. In this study, we show using co-immunoprecipitation analyses that TcpB interacts with MAL, MyD88, and TLR4 but interferes only with the MAL-TLR4 interaction. We present the crystal structure of the TcpB TIR domain, which reveals significant structural differences in the loop regions compared with other TIR domain structures. We demonstrate that TcpB forms a dimer in solution, and the crystal structure reveals the dimerization interface, which we validate by mutagenesis and biophysical studies. Our study advances the understanding of the molecular mechanisms of host immunosuppression by bacterial pathogens.Full Tex
Global sensitivity analysis of an end-to-end marine ecosystem model of the North Sea : factors affecting the biomass of fish and benthos

Comprehensive analysis of parameter and driver sensitivity is key to establishing the credibility of models of complex systems. This is especially so for models of natural systems where experimental manipulation of the real-world to provide controlled validation data is not possible. Models of marine ecosystems fall into this category, but despite the interest in these models for evaluating the effects of climate change and fishing on nutrient fluxes and the abundances of flora and fauna, none have yet been subjected to global sensitivity analysis. Here we present results of both local ‘one-at-a-time’ (OAT), and variance based global sensitivity analyses (GSA) of the fish and fishery aspects of StrathE2E, an end-to-end (nutrients to birds and mammals) ecosystem model of the North Sea. The sensitivity of the model was examined with respect to internal biological parameters, and external drivers related to climate and human activity. The OAT Morris method was first used to screen for factors most influential on model outputs. The Sobol GSA method was then used to calculate quantitative sensitivity indices. The results indicated that the fish and shellfish components of the model (demersal and pelagic fish, filter/deposit and scavenge/carnivore feeding benthos) were influenced by different sets of factors. Harvesting rates were directly influential on demersal and pelagic fish biomasses. Suspension/deposit feeding benthos were directly sensitive to changes in temperature, while the temperature acted indirectly on pelagic fish through the connectivity between model components of the food web. Biomass conversion efficiency was the most important factor for scavenge/carnivorous feeding benthos. The results indicate the primacy of fishing as the most important process affecting total fish biomass, together with varying responses to environmental factors which may be relevant in the context of climate change. The non-linear responses and parameter interactions identified by the analysis also highlight the necessity to use global rather than local methods for the sensitivity analysis of ecosystem models
NCoR1 is a conserved physiological modulator of muscle mass and oxidative function.

Transcriptional coregulators control the activity of many transcription factors and are thought to have wide-ranging effects on gene expression patterns. We show here that muscle-specific loss of nuclear receptor corepressor 1 (NCoR1) in mice leads to enhanced exercise endurance due to an increase of both muscle mass and of mitochondrial number and activity. The activation of selected transcription factors that control muscle function, such as MEF2, PPARβ/δ, and ERRs, underpins these phenotypic alterations. NCoR1 levels are decreased in conditions that require fat oxidation, resetting transcriptional programs to boost oxidative metabolism. Knockdown of gei-8, the sole C. elegans NCoR homolog, also robustly increased muscle mitochondria and respiration, suggesting conservation of NCoR1 function. Collectively, our data suggest that NCoR1 plays an adaptive role in muscle physiology and that interference with NCoR1 action could be used to improve muscle function
Plasmacytoid Dendritic Cells Are Productively Infected and Activated through TLR-7 Early after Arenavirus Infection.

The antiviral response is largely mediated by dendritic cells (DCs), including conventional (c) DCs that function as antigen-presenting cells, and plasmacytoid (p) DCs that produce type I interferons, making them an attractive target for viruses. We find that the Old World arenaviruses lymphocytic choriomeningitis virus clone 13 (LCMV Cl13) and Lassa virus bind pDCs to a greater extent than cDCs. Consistently, LCMV Cl13 targets pDCs early after in vivo infection of its natural murine host and establishes a productive and robust replication cycle. pDCs coproduce type I interferons and proinflammatory cytokines, with the former being induced in both infected and uninfected pDCs, demonstrating a dissociation from intrinsic virus replication. TLR7 globally mediates pDC responses, limits pDC viral load, and promotes rapid innate and adaptive immune cell activation. These early events likely help dictate the outcome of infections with arenaviruses and other DC-replicating viruses and shed light on potential therapeutic targets
A survey of urban climate change experiments in 100 cities.

Cities are key sites where climate change is being addressed. Previous research has largely overlooked the multiplicity of climate change responses emerging outside formal contexts of decision-making and led by actors other than municipal governments. Moreover, existing research has largely focused on case studies of climate change mitigation in developed economies. The objective of this paper is to uncover the heterogeneous mix of actors, settings, governance arrangements and technologies involved in the governance of climate change in cities in different parts of the world.\ud
\ud
The paper focuses on urban climate change governance as a process of experimentation. Climate change experiments are presented here as interventions to try out new ideas and methods in the context of future uncertainties. They serve to understand how interventions work in practice, in new contexts where they are thought of as innovative. To study experimentation, the paper presents evidence from the analysis of a database of 627 urban climate change experiments in a sample of 100 global cities.\ud
\ud
The analysis suggests that, since 2005, experimentation is a feature of urban responses to climate change across different world regions and multiple sectors. Although experimentation does not appear to be related to particular kinds of urban economic and social conditions, some of its core features are visible. For example, experimentation tends to focus on energy. Also, both social and technical forms of experimentation are visible, but technical experimentation is more common in urban infrastructure systems. While municipal governments have a critical role in climate change experimentation, they often act alongside other actors and in a variety of forms of partnership. These findings point at experimentation as a key tool to open up new political spaces for governing climate change in the city
Pharmaceuticalisation and ethical review in South Asia : issues of scope and authority for practitioners and policy makers.

Ethical review by expert committee continues to be the first line of defence when it comes to protecting human subjects recruited into clinical trials. Drawing on a large scale study of biomedical experimentation across South Asia, and specifically on interviews with 24 ethical review committee [ERC] members across India, Sri Lanka and Nepal, this article identifies some of the tensions that emerge for ERC members as the capacity to conduct credible ethical review of clinical trials is developed across the region. The article draws attention to fundamental issues of scope and authority in the operation of ethical review. On the one hand, ERC members experience a powerful pull towards harmonisation and a strong alignment with international standards deemed necessary for the global pharmaceutical assemblage to consolidate and extend. On the other hand, they must deal with what is in effect the double jeopardy of ethical review in developing world contexts. ERC members must undertake review but are frequently made aware of their responsibility to protect interests that go beyond the ‘human subject’ and into the realms of development and national interest [for example, in relation to literacy and informed consent]. These dilemmas are indicative of broader questions about where ethical review sits in institutional terms and how it might develop to best ensure improved human subject protection given growth of industry-led research
On the Yang-Mills two-loop effective action with wordline methods

We derive the two-loop effective action for covariantly constant field
strength of pure Yang-Mills theory in the presence of an infrared scale. The
computation is done in the framework of the worldline formalism, based on a
generalization procedure of constructing multiloop effective actions in terms
of the bosonic worldline path integral. The two-loop beta-function is correctly
reproduced. This is the first derivation in the worldline formulation, and
serves as a nontrivial check on the consistency of the multiloop generalization
procedure in the worldline formalism.Comment: 8 pages, 4 figure
Analysis of Pseudoxanthoma Elasticum-Causing Missense Mutants of ABCC6 In Vivo; Pharmacological Correction of the Mislocalized Proteins

Mutations in the ABCC6 gene cause soft-tissue calcification in pseudoxanthoma elasticum (PXE) and, in some patients, generalized arterial calcification of infancy (GACI). PXE is characterized by late onset and progressive mineralization of elastic fibers in dermal, ocular, and cardiovascular tissues. GACI patients present a more severe, often prenatal arterial calcification. We have tested 10 frequent disease-causing ABCC6 missense mutants for the transport activity by using Sf9 (Spodoptera frugiperda) cells, characterized the subcellular localization in MDCKII (Madin-Darby canine kidney (cell line)) cells and in mouse liver, and tested the phenotypic rescue in zebrafish. We aimed at identifying mutants with preserved transport activity but with improper plasma membrane localization for rescue by the chemical chaperone 4-phenylbutyrate (4-PBA). Seven of the mutants were transport-competent but mislocalized in mouse liver. The observed divergence in cellular localization of mutants in MDCKII cells versus mouse liver underlined the limitations of this 2D in vitro cell system. The functionality of ABCC6 mutants was tested in zebrafish, and minimal rescue of the morpholino-induced phenotype was found. However, 4-PBA, a drug approved for clinical use, restored the plasma membrane localization of four ABCC6 mutants (R1114P, S1121W, Q1347H, and R1314W), suggesting that allele-specific therapy may be useful for selected patients with PXE and GACI.Journal of Investigative Dermatology advance online publication, 19 December 2013; doi:10.1038/jid.2013.482
Dimension, matroids, and dense pairs of first-order structures

A structure M is pregeometric if the algebraic closure is a pregeometry in
all M' elementarily equivalent to M. We define a generalisation: structures
with an existential matroid. The main examples are superstable groups of U-rank
a power of omega and d-minimal expansion of fields. Ultraproducts of
pregeometric structures expanding a field, while not pregeometric in general,
do have an unique existential matroid.
  Generalising previous results by van den Dries, we define dense elementary
pairs of structures expanding a field and with an existential matroid, and we
show that the corresponding theories have natural completions, whose models
also have a unique existential matroid. We extend the above result to dense
tuples of structures.Comment: Version 2.8. 61 page
Evaporation of the planet HD189733b observed in HI Lyman-alpha

We observed three transits of the extrasolar planet HD189733b in HI
Lyman-alpha and in a few other lines in the ultraviolet with HST/ACS, in the
search for atmospheric signatures. We detect a transit signature in the
Lyman-alpha light curve with a transit depth of 5.05 +/- 0.75 %. This depth
exceeds the occultation depth produced by the planetary disk alone at the
3.5-sigma level (statistical). Other stellar emission lines are less bright,
and, taken individually, they do not show the transit signature, while the
whole spectra redward of the Lyman-alpha line has enough photons to show a
transit signature consistent with the absorption by the planetary disk alone.
The transit depth's upper limits in the emission lines are 11.1% for OI at
1305A and 5.5% for CII at 1335A. The presence of an extended exosphere of
atomic hydrogen around HD189733b producing 5% absorption of the full unresolved
Lyman-alpha line flux shows that the planet is losing gas. The Lyman-alpha
light curve is well-fitted by a numerical simulation of escaping hydrogen in
which the planetary atoms are pushed by the stellar radiation pressure. We
constrain the escape rate of atomic hydrogen to be between 10^9 and 10^{11} g/s
and the ionizing extreme UV flux between 2 and 40 times the solar value
(1-sigma), with larger escape rates corresponding to larger EUV flux. The best
fit is obtained for dM/dt=10^{10} g/s and an EUV flux F_{EUV}=20 times the
solar value. HD189733b is the second extrasolar planet for which atmospheric
evaporation has been detected.Comment: Accepted for publication in A&
SPT-CL J0546-5345: A Massive z > 1 Galaxy Cluster Selected Via the
  Sunyaev-Zel'dovich Effect with the South Pole Telescope

We report the spectroscopic confirmation of SPT-CL J0546-5345 at <z> = 1.067.
To date this is the most distant cluster to be spectroscopically confirmed from
the 2008 South Pole Telescope (SPT) catalog, and indeed the first z > 1 cluster
discovered by the Sunyaev-Zel'dovich Effect (SZE). We identify 21 secure
spectroscopic members within 0.9 Mpc of the SPT cluster position, 18 of which
are quiescent, early-type galaxies. From these quiescent galaxies we obtain a
velocity dispersion of 1179^{+232}_{-167} km/s, ranking SPT-CL J0546-5345 as
the most dynamically massive cluster yet discovered at z > 1. Assuming that
SPT-CL J0546-5345 is virialized, this implies a dynamical mass of M_200 =
1.0^{+0.6}_{-0.4} x 10^{15} Msun, in agreement with the X-ray and SZE mass
measurements. Combining masses from several independent measures leads to a
best-estimate mass of M_200 = (7.95 +/- 0.92) x 10^{14} Msun. The spectroscopic
confirmation of SPT-CL J0546-5345, discovered in the wide-angle, mass-selected
SPT cluster survey, marks the onset of the high redshift SZE-selected galaxy
cluster era.Comment: ApJ, in pres
Topological expansion of beta-ensemble model and quantum algebraic
  geometry in the sectorwise approach

We solve the loop equations of the $\beta$-ensemble model analogously to the
solution found for the Hermitian matrices $\beta=1$. For \beta=1$, the solution
was expressed using the algebraic spectral curve of equation $y^2=U(x)$. For
arbitrary $\beta$, the spectral curve converts into a Schr\"odinger equation
$((\hbar\partial)^2-U(x))\psi(x)=0$ with $\hbar\propto
(\sqrt\beta-1/\sqrt\beta)/N$. This paper is similar to the sister paper~I, in
particular, all the main ingredients specific for the algebraic solution of the
problem remain the same, but here we present the second approach to finding a
solution of loop equations using sectorwise definition of resolvents. Being
technically more involved, it allows defining consistently the B-cycle
structure of the obtained quantum algebraic curve (a D-module of the form
$y^2-U(x)$, where $[y,x]=\hbar$) and to construct explicitly the correlation
functions and the corresponding symplectic invariants $F_h$, or the terms of
the free energy, in 1/N^2$-expansion at arbitrary $\hbar$. The set of "flat"
coordinates comprises the potential times $t_k$ and the occupation numbers
\widetilde{\epsilon}_\alpha$. We define and investigate the properties of the
A- and B-cycles, forms of 1st, 2nd and 3rd kind, and the Riemann bilinear
identities. We use these identities to find explicitly the singular part of
$\mathcal F_0$ that depends exclusively on $\widetilde{\epsilon}_\alpha$.Comment: 58 pages, 7 figure
Two-Baryon Potentials and H-Dibaryon from 3-flavor Lattice QCD
  Simulations

Baryon-baryon potentials are obtained from 3-flavor QCD simulations with the
lattice volume L ~ 4 fm, the lattice spacing a ~ 0.12 fm, and the
pseudo-scalar-meson mass M_ps =469 - 1171 MeV. The NN scattering phase shift
and the mass of H-dibaryon in the flavor SU(3) limit are extracted from the
resultant potentials by solving the Schrodinger equation. The NN phase shift in
the SU(3) limit is shown to have qualitatively similar behavior as the
experimental data. A bound H-dibaryon in the SU(3) limit is found to exist in
the flavor-singlet J^P=0^+ channel with the binding energy of about 26 MeV for
the lightest quark mass M_ps = 469 MeV. Effect of flavor SU(3) symmetry
breaking on the H-dibaryon is estimated by solving the coupled-channel
Schrodinger equation for Lambda Lambda - N Xi - Sigma Sigma with the physical
baryon masses and the potential matrix obtained in the SU(3) limit: a resonant
H-dibaryon is found between Lambda Lambda and N Xi thresholds in this
treatment.Comment: 22 pages, 11 figures, Version accepted to publish on Nucl. Phys.