gebhart/patrepeval huggingface dataset:
Exploiting criticality to reduce bottlenecks in distributed uniprocessors (2011)

Composable multicore systems merge multiple independent cores for running sequential single-threaded workloads. The performance scalability of these systems, however, is limited due to partitioning overheads. This paper addresses two of the key performance scalability limitations of composable multicore systems. We present a critical path analysis revealing that communication needed for cross-core register value delivery and fetch stalls due to misspeculation are the two worst bottlenecks that prevent efficient scaling to a large number of fused cores. To alleviate these bottlenecks, this paper proposes a fully distributed framework to exploit criticality in these architectures at different granularities. A coordinator core exploits different types of block-level communication criticality information to fine-tune critical instructions at decode and register forward pipeline stages of their executing cores. The framework exploits the fetch criticality information at a coarser granularity by reissuing all instructions in the blocks previously fetched into the merged cores. This general framework reduces competing bottlenecks in a synergic manner and achieves scalable performance/power efficiency for sequential programs when running across a large number of cores.
Mutation patterns in genes encoding interferon signaling and antigen presentation: A pan‐cancer survey with implications for the use of immune checkpoint inhibitors (2017)

Blockade of immune checkpoints has become a powerful tool in cancer medicine, which is effective across various solid cancer types and hematologic malignancies. While immunohistochemical detection of PD-L1 expression in tumor cells, immune cells, or both has been introduced as predictive biomarker in several clinical trials, shortcomings and limitations of this approach were quickly recognized. As a single biomarker is unlikely to adequately reflect the complex interplay between immune cells and cancer, various genetic determinants of therapy success, including microsatellite instability, mutational burden, and PD-L1 amplification, are being investigated. Very recent work indicates that mutations in B2M, JAK1, and JAK2 render melanoma resistant to immune checkpoint blockade, thus serving as negative response predictors. Using the TCGA dataset, we performed a pan-cancer analysis of potentially damaging mutations in key genes implicated in antigen presentation and interferon-gamma signaling and investigated associations with transcript levels of immune checkpoint genes, cytolytic activity, and mutational burden. For B2M, JAK1, and JAK2, we observed overall mutation frequencies of 1.8%, 2%, and 2.6%, respectively, and found significant associations with mutational burden. On pathway level, melanoma as well as bladder, gastric, and lung cancer were most frequently affected by putative resistance mutations with mutation rates of 27%-50% in the antigen presentation pathway and of 16%-21% in the interferon signaling pathway. Our analysis suggests that a significant number of tumors harbor mutations that may negatively interfere with immune checkpoint inhibition, or confer a higher likelihood of resistance for which a second hit is ultimately required. Since these mutations are prevalent in treatment-naïve tumors, genetic screening prior to therapy might complement current approaches at predicting response to immune checkpoint blockade.
Magnetic-field-assisted photothermal therapy of cancer cells using Fe-doped carbon nanoparticles (2012)

Photothermal therapy with assistance of nanoparticles offers a solution for the destruction of cancer cells without significant collateral damage to otherwise healthy cells. However, minimizing the required number of injected nanoparticles is a major challenge. Here, we introduce the use of magnetic carbon nanoparticles (MCNPs), localizing them in a desired region by applying an external magnetic-field, and irradiating the targeted cancer cells with a near-infrared laser beam. The MCNPs were prepared in benzene, using an electric plasma discharge, generated in the cavitation field of an ultrasonic horn. The CNPs were made ferromagnetic by use of Fe-electrodes to dope the CNPs, as confirmed by magnetometry. Transmission electron microscopy measurements showed the size distribution of these MCNPs to be in the range of 5 to 10 nm. For photothermal irradiation, a tunable continuous wave Ti: Sapphire laser beam was weakly focused on to the cell monolayer under an inverted fluorescence microscope. The response of different cell types to photothermal irradiation was investigated. Cell death in the presence of both MCNPs and laser beam was confirmed by morphological changes and propidium iodide fluorescence inclusion assay. The results of our study suggest that MCNP based photothermal therapy is a promising approach to remotely guide photothermal therapy.
Lysosomal Cysteine Proteases in Atherosclerosis (2004)

Atherosclerosis is an inflammatory disease characterized by extensive remodeling of the extracellular matrix architecture of the arterial wall. Although matrix metalloproteinases and serine proteases participate in these pathologic events, recent data from atherosclerotic patients and animals suggest the participation of lysosomal cysteine proteases in atherogenesis. Atherosclerotic lesions in humans overexpress the elastolytic and collagenolytic cathepsins S, K, and L but show relatively reduced expression of cystatin C, their endogenous inhibitor, suggesting a shift in the balance between cysteine proteases and their inhibitor that favors remodeling of the vascular wall. Extracts of human atheromatous tissue show greater elastolytic activity in vitro than do those from healthy donors. The cysteinyl protease inhibitor E64d limits this increased elastolysis, indicating involvement of cysteine proteases in elastin degradation during atherogenesis. Furthermore, inflammatory cytokines augment expression and secretion of active cysteine proteases from cultured monocyte-derived macrophages, vascular smooth muscle cells, and endothelial cells and increase degradation of extracellular elastin and collagen. Cathepsin S-deficient cells or those treated with E64d show significantly impaired elastolytic or collagenolytic activity. Additionally, recent in vivo studies of atherosclerosis-prone, LDL receptor-null mice lacking cathepsin S show participation of this enzyme in the initial infiltration of leukocytes, medial elastic lamina degradation, endothelial cell invasion, and neovascularization, illustrating an important role for cysteine proteases in arterial remodeling and atherogenesis.
Stearamidomethyl Ethers (1951)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTStearamidomethyl EthersJ. W. Weaver, H. A. Schuyten, J. G. Frick Jr., and J. David ReidCite this: J. Org. Chem. 1951, 16, 7, 1111–1116Publication Date (Print):July 1, 1951Publication History Published online1 May 2002Published inissue 1 July 1951https://doi.org/10.1021/jo50001a013RIGHTS & PERMISSIONSArticle Views159Altmetric-Citations12LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (331 KB) Get e-Alerts Get e-Alerts
The Effect of Negative External Cues on Self-Focus and Negative Recollections of an Interaction (2012)

Social anxiety is characterized by a fear of negative evaluation and avoidance of social situations. Clark and Wells (1995) suggest that socially anxious individuals tend to self-monitor, but Rapee and Heimberg (1997) posit that this may interact with another inclination to searchfor external threat cues, which could exacerbate social anxiety. In the current study, participants were randomly assigned to one of two conditions in a conversation task. Confederates gave critical and judgmental cues in the critical condition and neutral cues in the neutral condition Results show a trend toward significance for an interaction such that socially anxious participants in the critical condition engaged in self-focused attention m ore than the low social anxiety group, while social anxiety groups had similar levels of self-focused attention in the neutral condition. In the critical condition, socially anxious individuals reported significantly fewer positive thoughts about themselves than those in the low social anxiety group.
Inclined Sedimentation for Selective Retention of Viable Hybridomas in a Continuous Suspension Bioreactor (1990)

The continuous separation of nonviable hybridoma cells from viable hybridoma cells by using a narrow rectangular channel that is inclined from the vertical has been investigated experimentally. The effectiveness of the settler in selectively retaining viable hybridomas in the bioreactor while permitting the removal of nonviable hybridomas has been shown to depend on the flow rate through the settler. Intermediate flow rates through the settler have been found to provide the highest removal of nonviable hybridomas relative to viable hybridoma retention. At high dilution rates through the chemostat, over 95% of the viable cells could be partitioned to the bottom of the settler while over 50% of the nonviable cells are removed through the top of the settler. This successful separation is due to the significantly larger size of the viable hybridomas than the nonviable ones. A continuous perfusion experiment was performed in which an external inclined settler was used to retain virtually all of the viable hybridomas in the culture, while selectively removing from the culture approximately 20% of the nonviable cells that entered the settler. A stable viable cell concentration of 1.0 x 10(7) cells/mL was achieved, as was an antibody productivity of over 50 micrograms/(mL.day). These represent 3- and 6-fold increases, respectively, over the values obtained from a chemostat culture without cell retention.
Dendritic cells and scavenger macrophages in chronic inflammatory bowel disease. (1989)

We used enzyme (acid phosphatase [AP]) and immunohistochemical techniques and a set of monoclonal antibodies (CD11, CD5, CD4, CD19, CD8, OKIa), including two recently developed antibodies--for example, HECA-452 (specific for an adhesion molecule on high endothelial venules) and RFD1 (specific for 'active' human dendritic cells) to analyse the composition of the gut wall infiltrate of 10 well defined cases of chronic inflammatory bowel disease (CIBD) (six Crohn's disease (CD), four ulcerative colitis (UC]. Two polar forms in a spectrum of gut mononuclear phagocyte types (CD11+) were identified: at the one extreme scavenger macrophages with blunted projections (AP+, Heca-452-, RFD1-) and at the other extreme, dendritic cells with long dendritic cytoplasmic projections (AP-, Heca-452+, RFD1+). Dendritic cells were mainly found in highly organised lymphoid tissue present at the deeper layers in the gut wall (normal gut: underneath the muscularis mucosae and T-cell areas of lymph follicles [25-30 per follicle]; surrounding the broad zone of scavenger macrophages at the bottom of ulcers (CIBD) and fissures (CD) and in the lymphoid aggregates [25-30 dendritic cells per aggregate] adjacent to granulomas (CD]. These observations can be taken as evidence that exaggerated antigen handling and presentation and stimulation of the immune response takes place at these foci. The observation that scavenger macrophages were localised more superficial, as band like zones (normal gut: subepithelial; mainly surrounding ulcers (CIBD) and fissures (CD] can be taken as evidence that at these spots the ingestion and degradation of foreign material takes place.
An Empirical Review of Major Legislation Affecting Drug Development: Past Experiences, Effects, and Unintended Consequences (2011)

Using market exclusivity to promote pharmaceutical innovation can lead to positive outcomes, but the practice is also characterized by waste and collateral effects. Certain practices, such as mechanisms for reevaluation and closer ties of incentives programs to public health outcomes, can help address these problems.
Macroporous poly(L‐lactide) scaffold 1. Preparation of a macroporous scaffold by liquid–liquid phase separation of a PLLA–dioxane–water system (2002)

A biodegradable poly(L-lactic acid) (PLLA) macroporous scaffold with a regular and highly interconnected structure in the size range from 50 to 150 mu m was fabricated from a PLLA--dioxane--water ternary system with the use of the thermally induced phase separation (TIPS) process. The phase diagram of PLLA with molecular weight above 200,000 was measured. It was found that a small change in the water content in the solvent caused a large shift in the cloud-point temperature. The porous morphology of the scaffold was closely related to the quenching route and formulation parameters, including polymer concentration, quenching temperature, aging time, and solvent composition of the ternary system. The porous morphology development in the scaffold was recorded as a function of aging time by scanning electronic microscopy (SEM). For systems with lower polymer concentrations (<4.5 wt%), polymer sedimentation occurred in the later stages of phase separation. A slight increase in the water content of the solvent mixture caused the sedimentation boundary to expand to higher polymer concentration. For systems with higher polymer concentrations (> or = 4.5 wt%), the development of phase separation was restricted by gelation that resulted from the crystallization of the PLLA chains. This gelation effect was greater at high polymer concentrations and low quenching temperatures. The macroporous expected scaffold could be optimized from the slow development of phase separation during the long coarsening process.
Assessing and Grading Congestion in Acute Heart Failure: A Scientific Statement from the Acute Heart Failure Committee of the Heart Failure Association of the European Society of Cardiology and endorsed by the European Society of Intensive Care Medicine (2010)

Patients with acute heart failure (AHF) require urgent in-hospital treatment for relief of symptoms. The main reason for hospitalization is congestion, rather than low cardiac output. Although congestion is associated with a poor prognosis, many patients are discharged with persistent signs and symptoms of congestion and/or a high left ventricular filling pressure. Available data suggest that a pre-discharge clinical assessment of congestion is often not performed, and even when it is performed, it is not done systematically because no method to assess congestion prior to discharge has been validated. Grading congestion would be helpful for initiating and following response to therapy. We have reviewed a variety of strategies to assess congestion which should be considered in the care of patients admitted with HF. We propose a combination of available measurements of congestion. Key elements in the measurement of congestion include bedside assessment, laboratory analysis, and dynamic manoeuvres. These strategies expand by suggesting a routine assessment of congestion and a pre-discharge scoring system. A point system is used to quantify the degree of congestion. This score offers a new instrument to direct both current and investigational therapies designed to optimize volume status during and after hospitalization. In conclusion, this document reviews the available methods of evaluating congestion, provides suggestions on how to properly perform these measurements, and proposes a method to quantify the amount of congestion present.
Aripiprazole augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive–compulsive disorder: a 12-week open-label preliminary study (2009)

One of the most studied and well-documented strategies for treatment-resistant obsessive-compulsive disorder (OCD) is the addition of antipsychotic drugs to the ongoing serotonin reuptake inhibitor (SRI) treatment. To date, there has been a paucity of data regarding the use of aripiprazole in OCD patients who failed to respond to SRIs. The aim of the present pilot study was to investigate the efficacy of flexible doses of aripiprazole as augmenting agent in the treatment of resistant OCD patients. Patients meeting the inclusion criteria of treatment-resistant OCD entered a 12-week, open-label, flexible-dose trial of aripiprazole addition to SRIs. Aripiprazole was started at 5 mg/day and increased up to a maximum of 20 mg/day. Twelve patients fulfilled entry criteria; nine patients took at least one dose of study medication and eight of them completed the study. The mean daily dosage of aripiprazole in completers was 11.2+/-5.2 mg/day. Patients showed a significant improvement over the 12-week study period (paired t-test for mean Yale-Brown Obsessive Compulsive Scale total score at week 12 as compared with baseline - all patients: t = 4.860, d.f. = 8, P = 0.001). The most common adverse event reported was inner unrest reported by four (44.4%) patients. Our study supports the notion that adding aripiprazole to SRIs could be a valid strategy for treatment-resistant OCD patients, and points towards the need of randomized, double-blind studies.
CD8 T Cell Exhaustion in Chronic Infection and Cancer: Opportunities for Interventions (2018)

Antigen-specific CD8 T cells are central to the control of chronic infections and cancer, but persistent antigen stimulation results in T cell exhaustion. Exhausted CD8 T cells have decreased effector function and proliferative capacity, partly caused by overexpression of inhibitory receptors such as programmed cell death (PD)-1. Blockade of the PD-1 pathway has opened a new therapeutic avenue for reinvigorating T cell responses, with positive outcomes especially for patients with cancer. Other strategies to restore function in exhausted CD8 T cells are currently under evaluation-many in combination with PD-1-targeted therapy. Exhausted CD8 T cells comprise heterogeneous cell populations with unique differentiation and functional states. A subset of stem cell-like PD-1<sup>+</sup> CD8 T cells responsible for the proliferative burst after PD-1 therapy has been recently described. A greater understanding of T cell exhaustion is imperative to establish rational immunotherapeutic interventions.
Fully Biodegradable Airway Stents Using Amino Alcohol‐Based Poly(ester amide) Elastomers (2013)

Airway stents are often used to maintain patency of the tracheal and bronchial passages in patients suffering from central airway obstruction caused by malignant tumors, scarring, and injury. Like most conventional medical implants, they are designed to perform their functions for a limited period of time, after which surgical removal is often required. Two primary types of airway stents are in general use, metal mesh devices and elastomeric tubes; both are constructed using permanent materials, and must be removed when no longer needed, leading to potential complications. This paper describes the development of process technologies for bioresorbable prototype elastomeric airway stents that would dissolve completely after a predetermined period of time or by an enzymatic triggering mechanism. These airway stents are constructed from biodegradable elastomers with high mechanical strength, flexibility and optical transparency. This work combines microfabrication technology with bioresorbable polymers, with the ultimate goal of a fully biodegradable airway stent ultimately capable of improving patient safety and treatment outcomes.
Regulatory consequences of neuronal ELAV-like protein binding to coding and non-coding RNAs in human brain (2016)

Neuronal ELAV-like (nELAVL) RNA binding proteins have been linked to numerous neurological disorders. We performed crosslinking-immunoprecipitation and RNAseq on human brain, and identified nELAVL binding sites on 8681 transcripts. Using knockout mice and RNAi in human neuroblastoma cells, we showed that nELAVL intronic and 3' UTR binding regulates human RNA splicing and abundance. We validated hundreds of nELAVL targets among which were important neuronal and disease-associated transcripts, including Alzheimer's disease (AD) transcripts. We therefore investigated RNA regulation in AD brain, and observed differential splicing of 150 transcripts, which in some cases correlated with differential nELAVL binding. Unexpectedly, the most significant change of nELAVL binding was evident on non-coding Y RNAs. nELAVL/Y RNA complexes were specifically remodeled in AD and after acute UV stress in neuroblastoma cells. We propose that the increased nELAVL/Y RNA association during stress may lead to nELAVL sequestration, redistribution of nELAVL target binding, and altered neuronal RNA splicing.
Optical modelocking at 10 GHz using a highly nonlineargermanosilicate optical fibre (1995)

The authors report the optical modelocking of an erbium fibre ring laser at 10 GHz using only 20 m of a highly nonlinear germania-doped silica fibre that has been developed for use in all-optical processing applications.
Efficiency of High- and Low-Voltage Pulse Combinations for Gene Electrotransfer in Muscle, Liver, Tumor, and Skin (2008)

Gene electrotransfer is gaining momentum as an efficient methodology for nonviral gene transfer. In skeletal muscle, data suggest that electric pulses play two roles: structurally permeabilizing the muscle fibers and electrophoretically supporting the migration of DNA toward or across the permeabilized membrane. To investigate this further, combinations of permeabilizing short high-voltage pulses (HV; hundreds of V/cm) and mainly electrophoretic long low-voltage pulses (LV; tens of V/cm) were investigated in muscle, liver, tumor, and skin in rodent models. The following observations were made: (1) Striking differences between the various tissues were found, likely related to cell size and tissue organization; (2) gene expression is increased, if there was a time interval between the HV pulse and the LV pulse; (3) the HV pulse was required for high electrotransfer to muscle, tumor, and skin, but not to liver; and (4) efficient gene electrotransfer was achieved with HV field strengths below the detectability thresholds for permeabilization; and (5) the lag time interval between the HV and LV pulses decreased sensitivity to the HV pulses, enabling a wider HV amplitude range. In conclusion, HV plus LV pulses represent an efficient and safe option for future clinical trials and we suggest recommendations for gene transfer to various types of tissues.