gebhart/patrepeval huggingface dataset:
Pharmacology of the CIC-1 chloride channel. (2010)

Clinical studies reported side effects of muscular spasms and muscle stiffness following the administration of clofibrate, a drug once used to treat hyperlipidaemia in patients. Experiments with clofibrate and its analogues in animal models showed it produced these myotonic symptoms in muscle by reducing the chloride conductance of the muscle membrane.&#13;\nThe effects of 2-(4-chlorophenoxy)propionic acid, an analogue of clofibric acid, was assessed on the rat ClC-1 channel (rClC-1). Racemic 2-(4-chlorophenoxy)propionic acid shifted the voltage dependence of rClC-1 activation to more depolarising potentials, a mechanism accounting for myotonic symptoms previously reported. Experiments with resolved enantiomers revealed that the effects recorded were due exclusively to S-(–) 2-(4- chlorophenoxy)propionic acid. The R-(+) enantiomer was ineffective at the concentrations tested. Further experiments with the compound at differing Cl- concentrations in the extracellular solution suggested that S-(–) 2-(4-chlorophenoxy)propionic acid altered the gating of ClC-1 by decreasing the affinity of the binding site where Cl- normally acts to ‘gate’ the channel.&#13;\nSimilarities in the effects reported for most dominant mutations in the CLCN1 gene that lead to myotonia congenita and 2-(4-chlorophenoxy)propionic acid prompted experiments that introduced these point mutations in the human ClC-1 (hClC-1) gene to compare their mode of action to that of the drug. These mutations, F307S and A313T, predominantly altered the slow, or common, gate of the channel. Conversely, the effect of&#13;\n2-(4-chlorophenoxy)propionic acid was predominantly on the fast gating process of hClC-1. A macroscopically similar effect therefore, can be produced by two different modes of action. Results suggested that both drug and mutations exert their action by affecting the transition of the channel from its closed to open state subsequent to Cl- binding.&#13;\nInvestigation of the interaction between rClC-1 gating and a further 25 compounds structurally related to clofibric acid identified a number of compounds effective at shifting the open probability of fast gating to depolarising potentials. Fewer were identified that influence slow gating. Some compounds affected both gating processes, however, none were identified which influenced slow gating alone. Ability to displace the voltage dependent activation of the fast gate appeared to depend largely on the lipophilicity of the molecules tested, indicating the importance of hydrophobic interactions between drug and channel protein.
Main staff members page for the Laboratory of Muscle Stem Cells and Gene Regulation (2007)

This page has the name, title, phone, e-mail, and address of the staff members for the Laboratory of Muscle Stem Cells and Gene Regulation
H-wise Independence. (2019)

For a hypergraph H on the vertex set {1,...,n}, a distribution D = (D_1,...,D_n) over {0,1}^n is H-wise independent if every restriction of D to indices which form an edge in H is uniform. This generalizes the notion of k-wise independence obtained by taking H to be the complete n vertex k-uniform hypergraph. This generalization was studied by Schulman (STOC 1992), who presented constructions of H-wise independent distributions that are linear, i.e., the samples are strings of inner products (over F2) of a fixed set of vectors with a uniformly chosen random vector. Let l(H) denote the minimum possible size of a sample space of a uniform H-wise independent distribution. The l parameter is well understood for the special case of k-wise independence. In this work we study the notion of H-wise independence and the l parameter for general graphs and hypergraphs. For graphs, we show how the l parameter relates to standard graph parameters (e.g., clique number, chromatic number, Lovasz theta function, minrank). We derive algorithmic and hardness results for this parameter as well as an explicit construction of graphs G for which l(G) is exponentially smaller than the size of the sample space of any linear G-wise independent distribution. For hypergraphs, we study the problem of testing whether a given distribution is H-wise independent, generalizing results of Alon et al. (STOC 2007).
Biceps Transfer Using Subdeltoid Arthroscopy (2007)

The diagnosis and treatment of biceps tendon pathology remain controversial. These patients may be more resistant to conservative treatment than those patients with standard subacromial impingement. When conservative treatment fails, surgical options should be explored. Tenotomy and tenodesis of the biceps tendon have been described, although persistent pain, deformity, and muscle cramping have been frequently reported. We describe a novel technique of biceps tenodesis by arthroscopic transfer of the long head of the biceps tendon to the anterior aspect of the lateral conjoint tendon using the subdeltoid space. The soft tissue transfer closely reproduces the native axis of pull of the biceps. It also allows soft tissue healing, which creates the normal "bungee" effect of the superior labrum/biceps anchor complex. This technique also allows the surgeon direct visualization during tenodesis to help prevent overtensioning of the tendon. Because of the early success of the procedure, we continue to use this technique with increasing frequency in appropriately indicated patients to access the anterior aspect of the shoulder extraarticularly.
A quantitative measurement of peritoneal drainage in malignant ascites (1977)

With a two-compartment model, a method is described for quantitative determination of peritoneal drainage rates in malignant ascites. Data on twenty-four patients are presented and comparison is made with the qualitative assessment of the integrity of diaphragmatic and mediastinal lymphatics on the basis of lymphoscintigrams. It is concluded that flow rates less than 50 ml/hour are usually associated with abnormalities of the diaphragmatic and mediastinal lymphatics, indicating that tumor permeation of these structures is a significant contributing factor to persistent, intractable ascites in patients with malignant diseases.
An investigation on partial discharge time-behavior in epoxy resin cavities (2016)

This paper provides some insights on aging due to PD activity occurring in insulation cavities. In particular, it is observed that the variation of PD amplitude may drastically decrease or increase during aging, thus challenging the interpretation of PD magnitude and repetition rate as diagnostic quantities. Explanations are proposed, based on a series of chemical-physical measurements, as Raman spectroscopy and SEM observations. At the beginning, aging leads to the formation of crystals on the cavity walls, which decrease PD activity, while for longer aging times also pitting and electrical treeing is observed. This would lead to speculate about the diagnostic validity of spot off-line measurements.
Microstructural optimisation of materials for SOFC applications using PMMA microspheres (2006)

A novel and facile route to control the porosity of materials for Solid Oxide Fuel Cells (SOFCs) applications has been developed through the simple combination of oxide powders, polyvinyl alcohol and poly(methyl methacrylate) (PMMA) microspheres. This method allows the microstructure to be optimised improving the performances of SOFC electrode materials.
On the Blind Estimation of Chip Time of Time-Hopping Signals Through Minimization of a Multimodal Cost Function (2010)

In this correspondence, we focus on blind estimation of the chip duration of time-hopping signals by introducing a cost function based on time-of-arrival (ToA) folding over multiple observation sets. An optimization algorithm that takes advantage of the highly oscillatory behavior in the nearby of the global minimum is proposed and a performance bound for the chip time estimate is derived. The pertinence of our approach is shown through numerical results, considering alternative methods like periodogram and separable least squares line search. The proposed technique enables a good tradeoff between statistical accuracy and computational complexity.
Electronic magnetostriction of Bi1-xSbxalloys (1985)

The magnetostriction of Bi1-xSbx narrow-gap semimetals and semiconductors has been measured at 4.2K as a function of magnetic field for values of x<10 at.%. The field-induced strain is due to the change in the free carrier densities and energies, in turn due to the Landau level quantisation: the crystal size changes to minimise the sum of the elastic and electronic free energies. A quantitative model, involving a compilation of the literature on the band structure of these alloys, is developed and compared with the authors' data.
Under the influence: Proof‐of‐concept chemical probe discovery in academia (2008)

The Scripps Research Institute Molecular Screening Center is a Molecular Libraries Screening Center Network (MLSCN) facility that spans the Scripps campuses in La Jolla, California and Jupiter in Palm Beach County, Florida. Scripps has brought together an integrated combination of infrastructure, people and technologies that support the identification of proof‐of‐concept small molecules in the academic setting. By this we mean chemical probes of adequate potency, selectivity, physical properties and stability to show robust activities in cell‐based assays and in vivo, allowing pre‐competitive advancement to fields of breaking biology. Chemical probes developed for POC studies the sphingolipid receptors in physiology and pathology will be presented.
Using Loss to Narrow Plasmon Linewidths (2020)

Lossy materials can be used in nanoplasmonic systems to narrow plasmon linewidths, which is desirable for biosensing applications. A scattering cross section linewidth of about 30 nm is found for gold nanoparticles in the lossy P3HT.
Electrochemical properties of core-shell TiC–TiO2nanoparticle films immobilized at ITO electrode surfaces (2006)

Titanium carbide (TiC) nanoparticles are readily deposited onto tin-doped indium oxide (ITO) electrodes in the form of thin porous films. The nanoparticle deposits are electrically highly conducting and electrochemically active. In aqueous media (at pH 7) and at applied potentials positive of 0.3 V vs. SCE partial anodic surface oxidation and formation (at least in part) of novel core-shell TiC-TiO2 nanoparticles is observed. Significant thermal oxidation of TiC nanoparticles by heating in air occurs at a temperature of 250 degrees C and leads first to core-shell TiC-TiO2 nanoparticles, next at ca. 350 degrees C to TiO2 (anatase), and finally at temperatures higher than 750 degrees C to TiO2 (rutile). Electrochemically and thermally partially oxidized TiC nanoparticles still remain very active and for some redox systems electrocatalytically active. Scanning and transmission electron microscopy (SEM and TEM), temperature dependent XRD, quartz crystal microbalance, and voltammetric measurements are reported. The electrocatalytic properties of the core-shell TiC-TiO2 nanoparticulate films are surveyed for the oxidation of hydroquinone, ascorbic acid, and dopamine in aqueous buffer media. In TiC-TiO2 core-shell nanoparticle films TiO2 surface reactivity can be combined with TiC conductivity.
Specification of Subunit Assembly by the Hydrophilic Amino-Terminal Domain of the Shaker Potassium Channel (1992)

The functional heterogeneity of potassium channels in eukaryotic cells arises not only from the multiple potassium channel genes and splice variants but also from the combinatorial mixing of different potassium channel polypeptides to form heteromultimeric channels with distinct properties. One structural element that determines the compatibility of different potassium channel polypeptides in subunit assembly has now been localized to the hydrophilic amino-terminal domain. A Drosophila Shaker B (ShB) potassium channel truncated polypeptide that contains only the hydrophilic amino-terminal domain can form a homomultimer; the minimal requirement for the homophilic interaction has been localized to a fragment of 114 amino acids. Substitution of the amino-terminal domain of a distantly related mammalian potassium channel polypeptide (DRK1) with that of ShB permits the chimeric DRK1 polypeptide to coassemble with ShB.
Ten mysteries of about:config (2005)

If you're catching Firefox fever, but the browser isn't quite right, you might just find the tweak you need in this secret configuration tool.
17 Tb/s (161&#x00D7;114 Gb/s) PolMux-RZ-8PSK transmission over 662 km of ultra-low loss fiber using C-band EDFA amplification and digital coherent detection (2008)

Employing PolMux-RZ-8PSK modulation and coherent detection, we demonstrate 25 GHz-spaced, 161×114 Gb/s DWDM transmission through eight spans of ultra-low-loss fiber (average span length/loss of 82.75 km/14.6 dB) with a record capacity of 17 Tb/s (spectral efficiency 4.2 b/s/Hz) within the C-band EDFA bandwidth (4.025 THz).
Hierarchical Porous Carbon—PLLA and PLGA Hybrid Nanoparticles for Intranasal Delivery of Galantamine for Alzheimer’s Disease Therapy (2020)

In the present study, poly(l-lactic acid) (PLLA) and poly(lactide-co-glycolide) (PLGA) hybrid nanoparticles were developed for intranasal delivery of galantamine, a drug used in severe to moderate cases of Alzheimer’s disease. Galantamine (GAL) was adsorbed first in hierarchical porous carbon (HPC). Formulations were characterized by FT-IR, which showed hydrogen bond formation between GAL and HPC. Furthermore, GAL became amorphous after adsorption, as confirmed by XRD and differential scanning calorimetry (DSC) studies. GAL was quantified to be 21.5% w/w by TGA study. Adsorbed GAL was nanoencapsulated in PLLA and PLGA, and prepared nanoparticles were characterized by several techniques. Their sizes varied between 182 and 394 nm, with an exception that was observed in nanoparticles that were prepared by PLLA and adsorbed GAL that was found to be 1302 nm in size. DSC thermographs showed that GAL was present in its crystalline state in nanoparticles before its adsorption to HPC, while it remained in its amorphous phase after its adsorption in the prepared nanoparticles. It was found that the polymers controlled the release of GAL both when it was encapsulated alone and when it was adsorbed on HPC. Lastly, PLGA hybrid nanoparticles were intranasally-administered in healthy, adult, male Wistar rats. Administration led to successful delivery to the hippocampus, the brain area that is primarily and severely harmed in Alzheimer’s disease, just a few hours after a single dose.
Abstract 67: Phase I Safety, Pharmacokinetic, and Pharmacodynamic Results for ALN-PCS, a Novel RNAi Therapeutic for the Treatment of Hypercholesterolemia (2012)

Proprotein convertases subtilisin/kexin type 9 (PCSK9) is a member of the proprotein convertase (PC) family of subtilisin-like serine endoproteases that regulates low density lipoprotein receptor (LDLR) levels and function. Murine models and human genetic studies indicate that loss of PCSK9 protein increases LDLR levels while excess PCSK9 decreases LDLR levels. These changes in LDLR protein levels coincide with reciprocal changes in circulating levels of plasma LDL cholesterol (LDL-C). We have developed a highly potent RNA interference (RNAi) therapeutic, ALN-PCS, targeting both intra and extracellular PCSK9 for inhibition through an RNAi mechanism. Pre-clinical data in non-human primate models, indicate that a single intravenous dose of ALN-PCS results in rapid, dose dependent, and significant lowering of liver PCSK9 transcript, plasma PCSK9 protein and subsequently serum LDL-C and ApoB levels, without impacting serum HDL-C. Here we report on interim data from an ongoing Phase 1 trial of ALN-PCS being conducted as a randomized, single-blind, placebo-controlled, single-ascending dose study in healthy volunteer subjects with elevated baseline LDL-C (&gt;116mg/dL) who are not on any lipid lowering therapy. The primary objective of the study is to evaluate the safety and tolerability of a single dose of ALN-PCS, with subjects being enrolled into sequential cohorts of increasing doses. Secondary objectives of the study include characterization of plasma and urine pharmacokinetics of ALN-PCS, assessment of pharmacodynamic effects of the drug on plasma PCSK9 protein levels, and evaluation of clinical efficacy as measured by LDL-C levels. Data from 20 subjects enrolled in five sequential dose cohorts ranging from 0.015 to 0.250 mg/kg in a 3:1 randomization of drug to placebo will be presented. ALN-PCS was safe and well tolerated in this study and there have been no serious adverse events related to study drug administration to date. There have been no drug-related discontinuations from the study and no liver enzyme elevations. A mild, transient rash that resolved spontaneously was observed in three subjects that received ALN-PCS, and in two that received placebo. To date, administration of ALN-PCS resulted in a rapid, dose-dependent, and durable silencing of PCSK9 protein levels in plasma of up to 66% relative to baseline, with a statistically significant mean reduction of 60% at day four in the current high dose group of 0.250 mg/kg (p&lt;0.001). In addition, administration of ALN-PCS resulted in dose-dependent reductions in LDL-C of up to 50% relative to baseline, with a statistically significant mean reduction of 39% at day four (p&lt;0.05) at the 0.250 mg/kg dose level. There was no significant decrease in high-density lipoprotein (HDL). Dosing of further cohorts at the current top dose (0.25 mg/kg) and at a higher dose is planned. Additional data will be presented as available.
Nanaerobic growth enables direct visualization of dynamic cellular processes in human gut symbionts (2020)

Abstract Mechanistic studies of anaerobic gut bacteria have been hindered by the lack of a fluorescent protein system to track and visualize proteins and dynamic cellular processes in actively growing bacteria. Although underappreciated, many gut “anaerobes” are able to respire using oxygen as the terminal electron acceptor. The oxygen continually released from gut epithelial cells creates an oxygen gradient from the mucus layer to the anaerobic lumen (1), with oxygen available to bacteria growing at the mucus layer. Using a combination of analyses, we show that Bacteroides species are metabolically and energetically robust and do not mount stress responses in the presence of 0.10 - 0.14% oxygen, defined as nanaerobic conditions (2). Taking advantage of this metabolic capability, we show that nanaerobic growth provides sufficient oxygen for the maturation of oxygen-requiring fluorescent proteins in Bacteroides species. Type strains of four different Bacteroides species show bright GFP fluorescence when grown nanaerobically versus anaerobically. We compared four different red fluorescent proteins and found that mKate2 yields high fluorescence intensity in our assay. We show that GFP-tagged proteins can be localized in nanaerobically growing bacteria. In addition, we used time-lapse fluorescence microscopy to image dynamic Type VI secretion system processes in metabolically active B. fragilis . The ability to visualize fluorescently-labeled Bacteroides and fluorescently-linked proteins in actively growing nanaerobic gut symbionts ushers in a new age of imaging analyses in these bacteria. Significance Despite many recent technological advances to study the human gut microbiota, we still lack a facile system to image dynamic cellular processes in most abundant gut species due to the requirement of oxygen for chromophore maturation of commonly used fluorescent proteins. Here, we took advantage of the ability of anaerobes of the gut microbiota to respire aerobically and grow robustly at 0.10– 0.14% oxygen. This physiologic concentration of oxygen is sufficient for fluorescent proteins to mature, allowing for visualization of biological processes never before imaged in these bacteria. This advance will allow for numerous types of analyses in actively-growing “nanaerobic” gut bacteria including subcellular protein localizations, single-cell analyses, biofilm imaging, and protein interactions with other microbes and the host.
Identification of B Cell Defects Using Age-Defined Reference Ranges for In Vivo and In Vitro B Cell Differentiation (2013)

Primary immunodeficiencies consist to a large extent of B cell defects, as indicated by inadequate Ab levels or response upon immunization. Many B cell defects have not yet been well characterized. Our objective was to create reliable in vivo and in vitro assays to routinely analyze human B cell differentiation, proliferation, and Ig production and to define reference ranges for different age categories. The in vitro assays were applied to classify the developmental and/or functional B cell defects in patients previously diagnosed with common variable immunodeficiency. Apart from standard immunophenotyping of circulating human B cell subsets, an in vitro CFSE dilution assay was used for the assessment of proliferative capacity comparing T cell-dependent and T cell-independent B cell activation. Plasmablast/plasma cell differentiation was assessed by staining for CD20, CD38, and CD138, and measurement of in vitro Ig secretion. At young age, B cells proliferate upon in vitro activation, but neither differentiate nor produce IgG. These latter functions reached adult levels at 5 and 10 y of age for T cell-dependent versus T cell-independent stimulations, respectively. The capacity of B cells to differentiate into plasmablasts and to produce IgG appeared to be contained within the switched memory B cell pool. Using these assays, we could categorize common variable immunodeficiency patients into subgroups and identified a class-switch recombination defect caused by an UNG mutation in one of the patients. We defined age-related reference ranges for human B cell differentiation. Our findings indicate that in vivo B cell functionality can be tested in vitro and helps to diagnose suspected B cell defects.
Mitochondrial Hearing Impairment (2003)

The last decade has led to the identification of several mitochondrial DNA mutations associated with hearing loss. Since the only known function of the human mitochondrial chromosome is to participate in the production of chemical energy through oxidative phosphorylation, it was not unexpected that mitochondrial mutations interfering with energy production could cause systemic neuromuscular disorders, which have as one of their features hearing impairment. Surprisingly however, inherited mitochondrial mutations have also been found to be a cause of non-syndromic hearing loss and to predispose to aminoglycoside- induced hearing loss, while acquired mitochondrial mutations have been proposed as one of the causes of presbycusis. After a brief review of mitochondrial genetics, we will outline the different mitochondrial mutations associated with hearing loss, describe the audiological features, and discuss the clinical relevance of diagnosing these mutations. Clinical expression of these mitochondrial mutations is dependent on environmental exposures and nuclear-encoded modifier genes. Preventive and therapeutic strategies will depend on identification and avoidance of the environmental exposures, and the identification of the nuclear-encoded modifier genes. Experimental approaches to identify these modifier genes will be presented.