gebhart/patrepeval huggingface dataset:
Genetic variants associated with platelet count are predictive of human disease and physiological markers (2021)

Platelets play an important role in hemostasis and other aspects of vascular biology. We conducted a meta-analysis of platelet count GWAS using data on 536,974 Europeans and identified 577 independent associations. To search for mechanisms through which these variants affect platelets, we applied cis-expression quantitative trait locus, DEPICT and IPA analyses and assessed genetic sharing between platelet count and various traits using polygenic risk scoring. We found genetic sharing between platelet count and counts of other blood cells (except red blood cells), in addition to several other quantitative traits, including markers of cardiovascular, liver and kidney functions, height, and weight. Platelet count polygenic risk score was predictive of myeloproliferative neoplasms, rheumatoid arthritis, ankylosing spondylitis, hypertension, and benign prostate hyperplasia. Taken together, these results advance understanding of diverse aspects of platelet biology and how they affect biological processes in health and disease.
Kinetics of Calcium Release by Immunoaffinity-purified Inositol 1,4,5-Trisphosphate Receptor in Reconstituted Lipid Vesicles (1995)

The kinetics of inositol 1,4,5-trisphosphate (IP3)-induced Ca2+ release of the immunoaffinity-purified IP3 receptor (IP3R), reconstituted into lipid vesicles, was investigated using the fluorescent Ca2+ indicator fluo-3. IP3R was purified from mouse cerebellar microsomal fraction by using an immunoaffinity column conjugated with an anti-IP3R type 1 (IP3R1) antibody. The immunoblotting analysis using monoclonal antibodies against each IP3R type showed that the purified IP3R is almost homogeneous, composed of IP3R1. Ca2+ efflux from the proteoliposomes was monitored as fluorescence changes of 10 microM fluo-3, whose concentration was high enough to buffer released Ca2+ and to keep deviations of extravesicular free Ca2+ concentration within 30 nM, excluding the possibility of Ca(2+)-mediated regulation of IP3-induced Ca2+ release. We also examined IP3-induced Ca2+ release using 1 microM fluo-3, where the deviations of free Ca2+ concentration were within 300 nM. At both fluo-3 concentrations, IP3-induced Ca2+ release showed similar kinetic properties, i.e. little Ca2+ regulation of Ca2+ release was observed in this system. IP3-induced Ca2+ release of the purified IP3R exhibited positive cooperativity; the Hill coefficient was 1.8 +/- 0.1. The half-maximal initial rate for Ca2+ release occurred at 100 nM IP3. At the submaximal concentrations of IP3, the purified IP3R showed quantal Ca2+ release, indicating that a single type of IP3R is capable of producing the phenomenon of quantal Ca2+ of release. The profiles of the IP3-induced Ca2+ release of the purified IP3R were found to be biexponential with the fast and slow rate constants (k(fast) = 0.3 approximately 0.7 s-1, k(slow) = 0.03 approximately 0.07 s-1), indicating that IP3R has two states to release CA2+. The amount of released Ca2+ by the slow phase was constant over the range of 10-5000 nM IP3 concentrations, whereas that by the fast phase increased in proportion to added IP3. This provides evidence to support the view that the fast phase of Ca2+ release is mediated by the low affinity state and the slow phase by the high affinity state of the IP3R. This also suggests that the fast component of Ca2+ release is responsible for the process of quantal Ca2+ release.
Chemistry of Glutamic Acid Analogues. Structure of an Isoxazolo[5,4-f]indolizine Derivative. (1985)

A partir de l'acetamido-1 [bromomethyl-5 methoxy-3 isoxazolyl-4]-2 ethanedicarboxylate-1,1 de diethyle, synthese de l'acetyl-6 methoxy-3 tetrahydro-4,5,6,7 isoxazolo [5,4-c] pyridinedicarboxylate-5,5 de diethyle et du (RS)-dioxo-5,7 methoxy-3 hexahydro-4,4a,5,6,7,9 isoxazolo [5,4-f] indolizinecarboxylate-4a d'ethyle; etude RX de ce compose
CC002/Unc females are mouse models of exercise-induced paradoxical fat response (2018)

Exercise results in beneficial health outcomes and protects against a variety of chronic diseases. However, U.S. exercise guidelines recommend identical exercise programs for everyone, despite individual variation in responses to these programs, including paradoxical fat gain. Experimental models of exercise-induced paradoxical outcomes may enable the dissection of underlying physiological mechanisms as well as the evaluation of potential interventions. Whereas several studies have identified individual mice exhibiting paradoxical fat gain following exercise, no systematic effort has been conducted to identify and characterize models of paradoxical response. Strains from the Collaborative Cross (CC) genetic reference population were used due to its high levels of genetic variation, its reproducible nature, and the observation that the CC is a rich source of novel disease models, to assess the impact genetic background has on exercise responses. We identified the strain CC002/Unc as an exercise-induced paradoxical fat response model in a controlled voluntary exercise study across multiple ages in female mice. We also found sex and genetic differences were consistent with this pattern in a study of forced exercise programs. These results provide a novel model for studies to determine the mechanisms behind paradoxical metabolic responses to exercise, and enable development of more rational personalized exercise recommendations based on factors such as age, sex, and genetic background.
Concurrent formation of furan-2,5- and furan-2,4-dicarboxylic acid: unexpected aspects of the Henkel reaction (2013)

The concurrent formation of furan-2,5- and furan-2,4-dicarboxylic acid under solvent free conditions via a disproportionation reaction is described. By reacting potassium-2-furoate at 260 °C in the presence of 22 mol% of (Lewis acidic) catalysts like CdI2 or ZnCl2, potassium-2-furoate is disproportionated to furan and furandicarboxylic acids. Besides furan and furan-2,5-dicarboxylic acid (2,5-FDCA) as the main products, furan-2,4-dicarboxylic acid (2,4-FDCA) is also formed as a by-product. Experimental evidence has been obtained that, under the reaction conditions applied, 2,5-FDCA and 2,4-FDCA are formed by separate reaction pathways. Selectivity towards the different FDCA isomers is affected by the type of catalyst used. Single-crystal X-ray analysis shows that 2,4-FDCA has a more ‘linear’ character compared to 2,5-FDCA and hence is structurally more comparable to terephthalic acid (TA), making it an interesting monomer for synthetic polyesters.
Experimental Validation of the COMPACT Code in Data Centers (2010)

This paper summarizes the comparison of predictions by a compact model of air flow and transport in data centers to temperature measurements of an operational data center. The simplified model and code package, referred to as COMPACT (Compact Model of Potential Flow and Convective Transport), is intended as an alternative to the use of time-intensive full CFD thermofluidic models as a first-order design tool, as well as a potential improvement to plant-based controllers. COMPACT is based on potential flow and combined with an application of convective energy equations, using sparse matrix solvers to seek flow and temperature solutions. Full-room solutions can be generated in 15 seconds on a commercially available laptop, and an accompanying graphical user interface has also been developed to allow quick configuration of data center designs and analysis of flow and temperature results. Experiments for validation of the model were conducted at the HP Labs data center in Palo Alto, CA, which is in a traditional configuration consisting of inlet floor tiles feeding cold air between two rows of multiple server racks. Subsequently, air exits either through ceiling tiles or direct room-return to CRAC units located on the side of the room. Temperatures were recorded at multiple points along entering and exiting flow faces within the room, as well as at various points in cold and hot aisles, and are presented and compared to model predictions to assess their accuracy. Areas of greater and lesser accuracy are analyzed and presented, in addition to conclusions as to the strengths and weaknesses of the model. For some cases, the average predicted temperature along in-flowing rack faces was within one degree of the average measured temperature. However, the differences in temperature are not evenly distributed. The most pronounced variations between the model and room measurements were located in areas above server racks where recirculation was shown to most likely occur. In these areas, the predicted temperature was higher than experimental values; this can likely be attributed to the absence of buoyancy effects in the simplified potential flow model. Adaptations of the model and its configuration standards for more accurate temperature distributions are proposed, as well as investigations into the effect on temperature comparisons to idealized model output by unaccounted heat sources or flow phenomena.
Scalable garbage collection for in-memory MVCC systems (2019)

To support Hybrid Transaction and Analytical Processing (HTAP), database systems generally rely on Multi-Version Concurrency Control (MVCC). While MVCC elegantly enables lightweight isolation of readers and writers, it also generates outdated tuple versions, which, eventually, have to be reclaimed. Surprisingly, we have found that in HTAP workloads, this reclamation of old versions, i.e., garbage collection, often becomes the performance bottleneck. It turns out that in the presence of long-running queries, state-of-the-art garbage collectors are too coarse-grained. As a consequence, the number of versions grows quickly slowing down the entire system. Moreover, the standard background cleaning approach makes the system vulnerable to sudden spikes in workloads. In this work, we propose a novel garbage collection (GC) approach that prunes obsolete versions eagerly. Its seamless integration into the transaction processing keeps the GC overhead minimal and ensures good scalability. We show that our approach handles mixed workloads well and also speeds up pure OLTP workloads like TPC-C compared to existing state-of-the-art approaches.
Cylindrical spinner and speed controller for magic angle spinning nuclear magnetic resonance (1984)

A new design for a cylindrical spinner suitable for magic angle spinning nuclear magnetic resonance (NMR) is described. The rotor has a large sample volume (0.66 cm3) and is capable of spinning speeds from 500 Hz to 5 kHz at drive gas pressures below 50 lb/in.2. The rotor is completely supported by gas bearings. Axial positioning is provided by the rotor’s T shape, leaving the bottom surface available for a photoelectric tachometer. The coil is wrapped on a form machined into the outer surface of the stator, producing a high filling factor. Also described is an instrument which controls the spinning speed of such a rotor to ±0.6 Hz around a set speed in the range of 3–4 kHz. The rotor’s speed is determined by means of a photoelectric tachometer. The instrument then compares this measured speed to the desired value and adjusts the gas flow to the rotor to correct any difference.
Structural Assignments of Sulfur-Containing Compounds in Crude Oil Using Ion Mobility Spectrometry-Mass Spectrometry (2016)

Through proof-of-concept experiments, a preliminary structural characterization of isomeric and isobaric sulfur-containing compounds in petroleum is presented. Silver attachment to sulfur atom has been used for ionization enhancement of these compounds, which are less accessible by positive-ion electrospray ionization mass spectrometry (ESI-MS). Here, ion mobility spectrometry (IMS) is combined with the enhanced ionization approach and MS to characterize sulfur compounds in crude oil. The silver isotopes, being of nearly equal abundance and having a similar effect upon ion mobilities, provide a fingerprint for assignments of sulfur-containing ions in two-dimensional (2D) plots of mass-to-charge (m/z) vs drift time (tD). Fourier transform ion cyclotron resonance (FT-ICR) MS has been employed for the determination of molecular formulas for these ions. Collision-induced dissociation (CID) data are utilized to complement collision cross section (CCS) comparisons for candidate structures obtained from high mass measurements. With regard to method workflow, molecular formulas are first proposed from high mass accuracy data. Next, the structures associated with the formulas are compared to the CID data for consistency. Finally, theoretical CCS values are calculated for the remaining structures and compared with experimental tD profiles. Without the ability to exhaustively compare a large number of standards, the work provides a tentative compound assessment of petroleum samples. Although several isomeric compounds should exhibit similar CCS values, this work demonstrates how compounds may be discarded based on the complementary measurements. Future directions to improve the overall approach are discussed.
Immuno-therapy in the treatment of cancer: implications for efficacy and economic evaluations (2016)

In the last few years, immuno-oncology has partially modified the paradigm of cancer treatment, due to the observation of long-term survivors among patients with advanced tumors and with a predicted limited life expectancy, if treated with immunotherapeutic agents. This paper illustrates the opinion of an expert panel (Scientific Board on Immuno-oncology and Cancer Treatment) regarding the clinical and economic assessments of immunologic anticancer treatments. The agreement on the document was reached through a Consensus Conference. Overall survival and/or survival rates at specific time-points are the ideal parameters to evaluate the efficacy and effectiveness of immunotherapies. Since benefits affect different patients at different times across cancer indications of immunotherapies, short-term (on most of targeted patients) and long-term effects on smaller groups should be considered. When market access decisions are taken, the benefit profile of immunotherapies has important implications for their economic assessment. Robust long-term extrapolation of expected survival rates should be carried out when cost-efficacy (effectiveness) of immunotherapies is estimated; mean instead of median incremental survival rate is a more appropriate measure; real-world data collection should be strengthened and used to eventually revise decisions taken on price and reimbursement.
A NeuroD1 AAV-Based Gene Therapy for Functional Brain Repair after Ischemic Injury through In Vivo Astrocyte-to-Neuron Conversion (2019)

Adult mammalian brains have largely lost neuroregeneration capability except for a few niches. Previous studies have converted glial cells into neurons, but the total number of neurons generated is limited and the therapeutic potential is unclear. Here, we demonstrate that NeuroD1-mediated in situ astrocyte-to-neuron conversion can regenerate a large number of functional new neurons after ischemic injury. Specifically, using NeuroD1 adeno-associated virus (AAV)-based gene therapy, we were able to regenerate one third of the total lost neurons caused by ischemic injury and simultaneously protect another one third of injured neurons, leading to a significant neuronal recovery. RNA sequencing and immunostaining confirmed neuronal recovery after cell conversion at both the mRNA level and protein level. Brain slice recordings found that the astrocyte-converted neurons showed robust action potentials and synaptic responses at 2 months after NeuroD1 expression. Anterograde and retrograde tracing revealed long-range axonal projections from astrocyte-converted neurons to their target regions in a time-dependent manner. Behavioral analyses showed a significant improvement of both motor and cognitive functions after cell conversion. Together, these results demonstrate that in vivo cell conversion technology through NeuroD1-based gene therapy can regenerate a large number of functional new neurons to restore lost neuronal functions after injury.
Wax ester fermentation in &lt;i&gt;E&lt;/i&gt;. &lt;i&gt;gracilis&lt;/i&gt;. (2016)

&lt;p&gt;Under anaerobic conditions, mitochondrial wax ester fermentation proceeds through two routes: the C2-donor route supplies acetyl-CoA via the pyruvate:NADP&lt;sup&gt;+&lt;/sup&gt; oxidoreductase (PNO) reaction, and the C3-donor route includes anaerobic fumarate respiration to produce propionyl-CoA. The &lt;sup&gt;13&lt;/sup&gt;C-isotope from &lt;sup&gt;13&lt;/sup&gt;CO&lt;sub&gt;2&lt;/sub&gt; (red circle) is incorporated into phosphoenolpyruvate (PEP) by the PEPCK reaction, and it is retained in propionyl-CoA that is used as the C3-donor in wax ester fermentation. The metabolic flow functioning under anaerobic conditions is indicated by green arrows [&lt;a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0162827#pone.0162827.ref008" target="_blank"&gt;8&lt;/a&gt;, &lt;a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0162827#pone.0162827.ref015" target="_blank"&gt;15&lt;/a&gt;, &lt;a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0162827#pone.0162827.ref029" target="_blank"&gt;29&lt;/a&gt;, &lt;a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0162827#pone.0162827.ref031" target="_blank"&gt;31&lt;/a&gt;]. Another possible route for the carboxylation reaction is indicated by broken green arrows: α-ketoglutarate (α-KG) is carboxylated to yield citrate which ultimately serves as the precursor to produce oxaloacetate (OAA) in cytoplasm. &lt;b&gt;Abbreviations for key enzymes:&lt;/b&gt; ACL, ATP citrate lyase; FUM, fumarase; FRD, fumarate reductase; IDH*, isocitrate dehydrogenase; KAT, ketoacyl-CoA thiolase; α-KGDH, α-ketoglutarate decarboxylase; MDH, malate dehydrogenase; ME, malic enzyme; MMC, methylmalonyl-CoA mutase; PK, pyruvate kinase; PNO, pyruvate:NADP&lt;sup&gt;+&lt;/sup&gt; oxidoreductase; PrCC, propionyl-CoA carboxylase; SSDH, succynyl semialdehyde dehydrogenase; RQ, rhodoquinone; SCS, succinyl-CoA synthetase. Abbreviations for metabolic intermediates: Cit, citrate; Fum, fumarate; Isocit, isocitorate; Mal, malate; OAA, oxaloacetate; Pyr, pyruvate; Suc, succinate; SucSA, succinate semialdehyde. *IDH has not been known in &lt;i&gt;Euglena&lt;/i&gt; to produce isocitrate from α-KG.&lt;/p&gt;
Tivantinib plus erlotinib versus placebo plus erlotinib in Asian patients with previously treated nonsquamous NSCLC with wild-type <i>EGFR:</i> First report of a phase III ATTENTION trial. (2014)

8044 Background: A randomized phase II study suggested that adding a c-Met inhibitor tivantinib (T) to an EGFR-TKI erlotinib (E) may prolong PFS in non-squamous NSCLC patients (pts) with 1-2 prior chemotherapy. Furthermore, the subset analysis suggested that survival benefit was more prominent in pts with wild-type EGFR (WT-EGFR) than in those with EGFR mutation. Therefore we conducted the phase III ATTENTION trial to compare overall survival (OS) between T+E vs. placebo (P)+E, in Asian pts with pretreated NSCLC with WT-EGFR. Methods: Four-hundred-and sixty Asian (Japan, Korea, and Taiwan) pts who had been treated with 1-2 chemotherapy for non-squamous NSCLC with WT-EGFR were planned to be randomized between T+E and P+E. The doses of T were 360mg BID and 240mg BID, for CYP2C19 extensive metabolizers (EM) and poor metabolizers (PM), respectively, whereas that of E was 150 mg QD for both EM and PM. The primary endpoint was OS, and secondary endpoints included PFS, ORR, and safety. Exploratory analysis tested biomarkers including c-Met expression and KRAS mutation. Results: New enrollment was stopped when 307 pts had been randomized, following the Safety Review Committee’s recommendation based on an observed imbalance in interstitial lung disease (ILD) between the groups. Accordingly,153 and 154 pts were treated with T+E and P+E, respectively. Patient backgrounds including CYP2C19 genotype were well balanced. Results are summarized below. Typical ≥Gr.3 adverse events in T+E were anemia (13.2 %), neutropenia (10.5 %), and leukopenia (6.6 %). Fourteen pts (including 3 deaths) and 6 pts (0 deaths) developed ILD in T+E and P+E, respectively. Conclusions: Although this trial lacked a statistical power due to the prematurely termination owing to toxicity concern, our results indicated some sign for benefit for adding T to E in this population. OS was numerically prolonged but this did not reach statistical significance. Exploratory biomarker analysis may identify subsets in which benefit and risk from this treatment is well balanced. Clinical trial information: NCT01377376. Median OS Median PFS ORR T+E 12.9 mo 2.9 mo 8.4% P+E 11.2 mo 2.0 mo 6.5% HR 0.891 0.719 P value 0.427 0.019
Impact of Exogenous Testosterone on Reproduction in Transgender Men (2020)

Studies show that a subset of transgender men desire children; however, there is a paucity of literature on the effect of gender-affirming testosterone therapy on reproductive function. In this manuscript, we will review the process of gender-affirming hormone therapy for transgender men and what is known about ovarian and uterine consequences of testosterone exposure in transgender men; draw parallels with existing animal models of androgen exposure; summarize the existing literature on parenting experiences and desires in transgender people; discuss considerations for assisted reproductive technologies and fertility preservation; and identify gaps in the literature and opportunities for further research.
Diverse prognostic value of the <scp>GTn</scp> promoter polymorphism in squamous cell and adeno carcinoma of the oesophagus (2016)

The basal transcription of heme oxygenase-1 (HO-1) regulation is dependent upon a GT repeat germ line polymorphism (GTn) in the promoter of the HO-1 gene. We determined the prognostic value of HO-1 promoter polymorphism on the natural postoperative course of complete resected oesophageal cancer. Genomic DNA from 297 patients was amplified by polymerase chain reaction and sequenced. The results were correlated with clinicopathological parameters, disseminated tumour cells in bone marrow (DTC) and clinical outcome. Depending on short allele with <25 and long allele with ≥25, GTn repeats three genotypes (SS, SL and LL) were defined. A diverse role of GTn was evident in squamous cell carcinoma (SCC) and adenocarcinoma (AC). In SCC, the SS genotype presented less advanced tumours with lower rate DTC in bone marrow and relapse compared with L-allele carriers. In contrast, AC patients with the SS genotype displayed a complete opposing tumour characteristic. The disease-free (DFS) and overall survival (OS) in SCC patients was markedly reduced in LL genotypes (p < 0.001). In AC contrarily the SS genotype patients displayed the worst DFS and OS (p < 0.001). GTn is a strong prognostic factor with diverse prognostic value for recurrence and survival in AC and SCC.