gebhart/patrepeval huggingface dataset:
Different Ca<sub>V</sub>1.3 Channel Isoforms Control Distinct Components of the Synaptic Vesicle Cycle in Auditory Inner Hair Cells (2017)

The mechanisms orchestrating transient and sustained exocytosis in auditory inner hair cells (IHCs) remain largely unknown. These exocytotic responses are believed to mobilize sequentially a readily releasable pool of vesicles (RRP) underneath the synaptic ribbons and a slowly releasable pool of vesicles (SRP) at farther distance from them. They are both governed by Ca<sub>v</sub>1.3 channels and require otoferlin as Ca<sup>2+</sup> sensor, but whether they use the same Ca<sub>v</sub>1.3 isoforms is still unknown. Using whole-cell patch-clamp recordings in posthearing mice, we show that only a proportion (∼25%) of the total Ca<sup>2+</sup> current in IHCs displaying fast inactivation and resistance to 20 μm nifedipine, a l-type Ca<sup>2+</sup> channel blocker, is sufficient to trigger RRP but not SRP exocytosis. This Ca<sup>2+</sup> current is likely conducted by short C-terminal isoforms of Ca<sub>v</sub>1.3 channels, notably Ca<sub>v</sub>1.3<sub>42A</sub> and Ca<sub>v</sub>1.3<sub>43S</sub>, because their mRNA is highly expressed in wild-type IHCs but poorly expressed in <i>Otof</i><sup>-/-</sup> IHCs, the latter having Ca<sup>2+</sup> currents with considerably reduced inactivation. Nifedipine-resistant RRP exocytosis was poorly affected by 5 mm intracellular EGTA, suggesting that the Ca<sub>v</sub>1.3 short isoforms are closely associated with the release site at the synaptic ribbons. Conversely, our results suggest that Ca<sub>v</sub>1.3 long isoforms, which carry ∼75% of the total IHC Ca<sup>2+</sup> current with slow inactivation and confer high sensitivity to nifedipine and to internal EGTA, are essentially involved in recruiting SRP vesicles. Intracellular Ca<sup>2+</sup> imaging showed that Ca<sub>v</sub>1.3 long isoforms support a deep intracellular diffusion of Ca<sup>2+</sup><b>SIGNIFICANCE STATEMENT</b> Auditory inner hair cells (IHCs) encode sounds into nerve impulses through fast and indefatigable Ca<sup>2+</sup>-dependent exocytosis at their ribbon synapses. We show that this synaptic process involves long and short C-terminal isoforms of the Ca<sub>v</sub>1.3 Ca<sup>2+</sup> channel that differ in the kinetics of their Ca<sup>2+</sup>-dependent inactivation and their relative sensitivity to the l-type Ca<sup>2+</sup> channel blocker nifedipine. The short C-terminal isoforms, having fast inactivation and low sensitivity to nifedipine, mainly control the fast fusion of the readily releasable pool (RRP); that is, they encode the phasic exocytotic component. The long isoforms, with slow inactivation and great sensitivity to nifedipine, mainly regulate the vesicular replenishment of the RRP; that is, the sustained or tonic exocytosis.
ECCO: Equivalent Circuit Controlled Optimization (2022)

We propose an adaptive optimization algorithm for solving unconstrained scaled gradient flow problems that achieves fast convergence by controlling the optimization trajectory shape and the discretization step sizes. Under a broad class of scaling functions, we establish convergence of the proposed approach to critical points of smooth objective functions, while demonstrating its flexibility and robustness with respect to hyperparameter tuning. First, we prove convergence of component-wise scaled gradient flow to a critical point under regularity conditions. We show that this controlled gradient flow dynamics is equivalent to the transient response of an electrical circuit, allowing for circuit theory concepts to solve the problem. Based on this equivalence, we develop two optimization trajectory control schemes based on minimizing the charge stored in the circuit: a second order method that uses the true Hessian and an alternate first order method that approximates the optimization trajectory with only gradient information. While the control schemes are derived from circuit concepts, no circuit knowledge is needed to implement the algorithms. To find the value of the critical point, we propose a time step search routine for Forward Euler discretization that controls the local truncation error, a method adapted from circuit simulation ideas. In simulation we find that the trajectory control outperforms uncontrolled gradient flow, and the error-aware discretization out-performs line search with the Armijo condition. Our algorithms are evaluated on convex and non-convex test functions, including neural networks, with convergence speeds comparable to or exceeding Adam.
A physical model of axonal damage due to oxidative stress (2006)

Oxidative damage is implicated in the pathogenesis of neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's diseases, and in normal aging. Here, we model oxidative stress in neurons using photogenerated radicals in a simplified membrane-encapsulated microtubule system. Using fluorescence and differential interference contrast microscopies, we monitor photochemically induced microtubule breakdown on the supported region of membrane in encapsulating synthetic liposomes as a function of lipid composition and environment. Degradation of vesicle-encapsulated microtubules is caused by attack from free radicals formed upon UV excitation of the lipid-soluble fluorescent probe, 6-(9-anthroyloxy)stearic acid. Probe concentration was typically limited to a regime in which microtubule degradation was slow, and microtubule degradation was monitored by changes in the observed protrusion of the membrane surface. The kinetics of microtubule degradation are influenced by lipid saturation level, fluorescent probe concentration, and the presence of free-radical scavengers. This system is sufficient to reproduce some degenerative morphologies found in vivo.
Laser desorption lamp ionization source for ion trap mass spectrometry (2015)

A two-step laser desorption lamp ionization source coupled to an ion trap mass spectrometer (LDLI-ITMS) has been constructed and characterized. The pulsed infrared (IR) output of an Nd:YAG laser (1064 nm) is directed to a target inside a chamber evacuated to ~15 Pa causing desorption of molecules from the target's surface. The desorbed molecules are ionized by a vacuum ultraviolet (VUV) lamp (filled with xenon, major wavelength at 148 nm). The resulting ions are stored and detected in a three-dimensional quadrupole ion trap modified from a Finnigan Mat LCQ mass spectrometer operated at a pressure of ≥ 0.004 Pa. The limit of detection for desorbed coronene molecules is 1.5 pmol, which is about two orders of magnitude more sensitive than laser desorption laser ionization mass spectrometry using a fluorine excimer laser (157 nm) as the ionization source. The mass spectrum of four standard aromatic compounds (pyrene, coronene, rubrene and 1,4,8,11,15,18,22,25-octabutoxy-29H,31H-phthalocyanine (OPC)) shows that parent ions dominate. By increasing the infrared laser power, this instrument is capable of detecting inorganic compounds.
Low Latency Audio Video (2014)

The primary purpose of this study was to examine the potential of LOw LAtency (LOLA), a low latency audio visual technology designed to allow simultaneous music performance, as a distance learning tool for musical styles in which synchronous playing is an integral aspect of the learning process (e.g., jazz, folk styles). The secondary purpose was to describe participant perceptions of the effectiveness of three technologies used to teach music: LOLA, PolyCom, and Skype. To achieve these goals, we isolated a classical masterclass, jazz lesson, and old-time fiddle session and described trends for these lessons across the three technology platforms. Participants rated the overall effectiveness of LOLA ( M = 4.25) higher than PolyCom ( M = 3.06) and Skype ( M = 2.80). Participants shared their perception that LOLA was superior to other technologies for learning and teaching music. Implications for music teaching are discussed.
The maternal-fetal interface of successful pregnancies and impact of fetal sex using single cell sequencing (2019)

Summary The first trimester is a critical window of maternal-fetal communication for pregnancy. Therefore, we characterized crosstalk in ongoing human pregnancies at 11-13 weeks gestation. RNA-sequencing of matched maternal decidua and placenta identified 818 receptors and 3502 ligands, including 126 differentially expressed receptor-ligand pairs. Using single cell RNA-sequencing to further dissect placenta heterogeneity, we identified five major cell types (trophoblasts, stromal cells, hofbauer cells, antigen presenting cells and endothelial cells) with unique crosstalk at the maternal-fetal interface. We identified seven unique trophoblast subclusters, including new subtypes that transition into the terminal cell types, extra-villous trophoblasts and syncytiotrophoblasts. As fetal sex impacts pregnancy, we analyzed sex differences in each cell type and identified differences in immune cell function. TGFβ1, β-estradiol, and dihydrotestosterone emerge as upstream regulators of sexually dimorphic genes in a cell type specific manner. Thus, the fetal contribution at the maternal-fetal interface is cell and sex specific.
Factors Controlling Fluid Migration and Distribution in the Eagle Ford Shale (2014)

Abstract Production of shale and tight oil is the cornerstone of the United States race for energy independence. According to the U.S. Energy Information Administration (EIA) nearly 90% of the oil production growth comes from six tight oil plays. The Eagle Ford is one of these plays and accounts for 33% of the oil production growth with a contribution of 1.3 million barrels per day. A geological challenge in the Eagle Ford shale is the unconventional fluids distribution: shallower in the structure there is black oil, deeper and to the south condensate appears, and at the bottom dry gas can be found. Differences in burial depth, temperature, and vitrinite reflectance are used to explain this unique distribution. A similar fluid distribution occurs in other reservoirs (e.g. Duvernay shale in Canada). The above observations led to the key objective of this paper: to identify the main factors that control fluid migration (due to buoyancy of gas in oil) from one zone to another. This was done by constructing a conceptual cross sectional simulation model with NW to SE orientation that allowed the study of fluid migration and distribution throughout one million years while maintaining computational time within reasonable limits. The input data used for the model were gathered from published work in the geoscience and petroleum engineering literature. Results show that although there is some gas migration through fractures to the top of the structure, fluids in the matrix remained with approximately the same original distribution. This fluid migration through fractures could be responsible for higher initial gas production in some oil wells in the top of the structure. Results show that ultralow permeability, low porosity, and low natural fracturing are the main restrictions for fluid migration in the Eagle Ford shale.
Evaluation of the In vivo Radiosensitizing Activity of Etanidazole Using Tumor-bearing Chick Embryo (2011)

Chick embryos have been used as alternative experimental animals in various research fields, including virology, immunology, toxicology, oncology, and embryology. Until now, there have been no in vivo models using chick embryo to evaluate radiosensitizing activity. Here, the in vivo radiosensitizing activity of etanidazole, a well-known hypoxic cell radiosensitizer, was evaluated using tumor-bearing chick embryo. On the basis of tumor growth, drug administration and X-ray irradiation were performed on day 15 chick embryo, with the endpoint being day 18 chick embryo. In day 15 chick embryo, an X-ray irradiation dose of equal or less than 10 Gy did not cause significant tumor growth suppression. Intravenous administration of equal or less than 1.0 mg of etanidazole did not cause tumor growth suppression. Neither doses of equal or less than 8 Gy of irradiation nor 1.0 mg of etanidazole caused fatality of the chick embryo. On the basis of these results, we evaluated the radiosensitizing effect of a combination treatment with 8 Gy of irradiation and 1.0 mg of etanidazole. As noted above, 1.0 mg of etanidazole alone and 8 Gy of irradiation alone did not show tumor growth suppression. In contrast, a combination treatment with 8 Gy of irradiation and 1.0 mg of etanidazole showed 35% of significant tumor growth suppression. Thus, we succeeded in evaluating the in vivo radiosensitizing activity of etanidazole using tumor-bearing chick embryo. These results suggest that the use of tumor-bearing chick embryo may be part of a promising system for evaluating radiosensitizing activity.
Comparison of Immunoreactivity of Staphylococcal Enterotoxin B Mutants for Use as Toxin Surrogates (2012)

The development and testing of detection methodologies for biothreat agents are by their very nature complicated by the necessity to handle hazardous materials. Toxoids prepared by thermal or chemical inactivation are often used in place of the native toxin; however, the process of detoxification can decrease the agent's ability to be detected at similar concentrations. One method to overcome this limitation is the use of toxin mutants which have altered amino acid sequences sufficient to abrogate or greatly reduce their toxic activity. While this method of toxoid preparation is much more controlled, there is still no guarantee that the resulting product will be equal in detectability to the native toxin. In this work, we have evaluated the utility of two recombinantly expressed Staphylococcal Enterotoxin B (SEB) mutants, a single point mutant (Y89A), and a mutant with three amino acids changed (L45R, Y89A, Y94A), to act as surrogates for SEB in immunoassays. We evaluated the affinity of a number of anti-SEB monoclonal antibodies (mAb) and an anti-SEB single domain antibody (sdAb) for SEB and its surrogates. One of the mAb's affinity was decreased by a factor of 3000 for the triple mutant, and another mAb's affinity for the triple mutant was decreased by 11-fold while the others bound the mutants nearly as well as they did the native toxin. MAGPIX sandwich immunoassays were used to evaluate the ability of all combinations of the recognition reagents to detect the SEB mutants in comparison to SEB and a chemically inactivated SEB. These results show that recombinant mutants of SEB can serve as much more useful surrogates for this hazardous material relative to the chemically inactivated toxin; however, even the point mutant impacted limits of detection, illustrating the need to evaluate the utility of toxin mutants on a case-by-case basis depending on the immunoreagents being employed.
Supplementary Table 2 from A Targeted RNAi Screen of the Breast Cancer Genome Identifies &lt;i&gt;KIF14&lt;/i&gt; and &lt;i&gt;TLN1&lt;/i&gt; as Genes That Modulate Docetaxel Chemosensitivity in Triple-Negative Breast Cancer (2023)

&lt;p&gt;PDF File - 77K, Descriptive statistics of IC50 determinations of MDA-MB-231 cells to docetaxel.&lt;/p&gt;
SLAP: Small Labeling Pair for Single‐Molecule Super‐Resolution Imaging (2015)

Abstract Protein labeling with synthetic fluorescent probes is a key technology in chemical biology and biomedical research. A sensitive and efficient modular labeling approach (SLAP) was developed on the basis of a synthetic small‐molecule recognition unit (Ni‐ tris NTA) and the genetically encoded minimal protein His 6‐10 ‐tag. High‐density protein tracing by SLAP was demonstrated. This technique allows super‐resolution fluorescence imaging and fulfills the necessary sampling criteria for single‐molecule localization‐based imaging techniques. It avoids masking by large probes, for example, antibodies, and supplies sensitive, precise, and robust size analysis of protein clusters (nanodomains).
Discovery of <i>N</i>-((3<i>R</i>,4<i>R</i>)-4-Fluoro-1-(6-((3-methoxy-1-methyl-1<i>H</i>-pyrazol-4-yl)amino)-9-methyl-9<i>H</i>-purin-2-yl)pyrrolidine-3-yl)acrylamide (PF-06747775) through Structure-Based Drug Design: A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivity over Wild-Type EGFR (2017)

Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR mutant NSCLC patients before resistance mechanisms render these inhibitors ineffective. Secondary oncogenic EGFR mutations account for approximately 50% of relapses, the most common being the gatekeeper T790M substitution that renders existing therapies ineffective. The discovery of PF-06459988 (1), an irreversible pyrrolopyrimidine inhibitor of EGFR T790M mutants, was recently disclosed.1 Herein, we describe our continued efforts to achieve potency across EGFR oncogenic mutations and improved kinome selectivity, resulting in the discovery of clinical candidate PF-06747775 (21), which provides potent EGFR activity against the four common mutants (exon 19 deletion (Del), L858R, and double mutants T790M/L858R and T790M/Del), selectivity over wild-type EGFR, and desirable ADME properties. Compound 21 is currently being evaluated in phase-I clinical trials of mutant EGFR driven NSCLC.
A call to arms: Unifying the fight against resistance (2018)

This Editorial discusses the state of research on drug resistance in the fields of cancer, infectious disease, and agriculture. Reaching across the aisle for a more cross-collaborative approach may lead to exciting breakthroughs toward tackling the challenges of drug resistance in each field.
A comprehensive analysis of RHOA mutation positive and negative angioimmunoblastic T-cell�lymphomas by targeted deep sequencing, expression profiling and single cell digital image analysis (2020)

Angioimmunoblastic T‑cell lymphoma (AITL) is a uniquely aggressive mature T‑cell neoplasm. In recent years, recurrent genetic mutations in ras homolog family member A (RHOA), tet methylcytosine dioxygenase 2 (TET2), DNA methyltransferase 3 alpha (DNMT3A) and isocitrate dehydrogenase [NADP(+)] 2 (IDH2) have been identified as associated with AITL. However, a deep molecular study assessing both DNA mutations and RNA expression profile combined with digital image analysis is lacking. The present study aimed to evaluate the significance of molecular and morphologic features by high resolution digital image analysis in several cases of AITL. To do so, a total of 18 separate tissues from 10 patients with AITL were collected and analyzed. The results identified recurrent mutations in RHOA, TET2, DNMT3A, and IDH2, and demonstrated increased DNA mutations in coding, promoter and CCCTC binding factor (CTCF) binding sites in RHOA mutated AITLs vs. RHOA non‑mutated cases, as well as increased overall survival in RHOA mutated patients. In addition, single cell computational digital image analysis morphologically characterized RHOA mutated AITL cells as distinct from cells from RHOA mutation negative patients. Computational analysis of single cell morphological parameters revealed that RHOA mutated cells have decreased eccentricity (more circular) compared with RHOA non‑mutated AITL cells. In conclusion, the results from the present study expand our understanding of AITL and demonstrate that there are specific cell biological and morphological manifestations of RHOA mutations in cases of AITL.
Temperature of Peptide Ions Generated by Matrix-Assisted Laser Desorption Ionization and Their Dissociation Kinetic Parameters (2009)

Product ion yields in postsource decay and photodissociation at 193 and 266 nm were measured for some peptide ions without a basic amino acid residue ([Y(6) + H](+), [F(5) + H](+), and [YPFVEPI + H](+)) generated by matrix-assisted laser desorption ionization (MALDI). Data indicated statistical nature for the dissociation processes. Assuming that peptide ions formed by MALDI are in thermal equilibrium at temperature T and that their dissociation rate constants are specified by the critical energy (E(0)) and entropy (DeltaS(double dagger)), a method based on kinetic analysis was devised to determine these parameters simultaneously. The matrix used was found to affect the effective temperature of peptide ions, 2,5-dihydroxybenzoic acid (400-430 K) < sinapinic acid (440 K) < alpha-cyano-4-hydroxycinnamic acid (460-510 K), in agreement with previous perceptions. E(0) of around 0.6 eV and DeltaS(double dagger) of -24 eu were smaller than previous quantum chemical results for small model peptide ions.
Differentially Private Combinatorial Optimization (2010)

Consider the following problem: given a metric space, some of whose points are “clients,” select a set of at most k facility locations to minimize the average distance from the clients to their nearest facility. This is just the well-studied k-median problem, for which many approximation algorithms and hardness results are known. Note that the objective function encourages opening facilities in areas where there are many clients, and given a solution, it is often possible to get a good idea of where the clients are located. This raises the following quandary: what if the locations of the clients are sensitive information that we would like to keep private? Is it even possible to design good algorithms for this problem that preserve the privacy of the clients? In this paper, we initiate a systematic study of algorithms for discrete optimization problems in the framework of differential privacy (which formalizes the idea of protecting the privacy of individual input elements). We show that many such problems indeed have good approximation algorithms that preserve differential privacy; this is even in cases where it is impossible to preserve cryptographic definitions of privacy while computing any non-trivial approximation to even the value of an optimal solution, let alone the entire solution. Apart from the k-median problem, we consider the problems of vertex and set cover, min-cut, k-median, facility location, and Steiner tree, and give approximation algorithms and lower bounds for these problems. We also consider the recently introduced submodular maximization problem, “Combinatorial Public Projects” (CPP), shown by Papadimitriou et al. [28] to be inapproximable to subpolynomial multiplicative factors by any efficient and truthful algorithm. We give a differentially private (and hence approximately truthful) algorithm that achieves a logarithmic additive approximation.
Salivary duct carcinoma: Treatment, outcomes, and patterns of failure (2015)

Distant recurrence is common. Presence of pN2b/N2c disease is associated with reduced OS. Local recurrence frequently involves the facial nerves. © 2015 Wiley Periodicals, Inc. Head Neck 38: E820-E826, 2016.
New paradigms in acid-base physiology (1999)

*Associate Professor, Director of Intensive Care Research, Department of Intensive Care, Austin and Repatriation Medical Centre, Victoria, Australia; †Director *Department of Nephrology, St. Bortolo Hospital, Vicenza, Italy Correspondence to Rinaldo Bellomo, MD, Department of Intensive Care, Austin and Repatriation Medical Centre, Heidelberg, Melbourne, Victoria 3084, Australia; e-mail: [email protected]
Be‐Ba and Zn‐Hg (2006)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.