gebhart/patrepeval huggingface dataset:
VERU-111: An Oral Tubulin Inhibitor That Suppresses Taxane-Sensitive and Taxane-Resistant Breast Cancer (2021)

Abstract Triple negative breast cancer (TNBC) patients have poorer overall prognosis relative to patients diagnosed with other molecular subtypes due to rapid onset of drug resistance to conventional chemotherapies and increased risk of visceral metastases. The microtubule inhibitor paclitaxel (Taxol, a taxane) is a frontline therapy for advanced breast cancer. We evaluated in TNBC models the preclinical safety and efficacy of a novel, potent, and orally bioavailable tubulin inhibitor, VERU-111, a tubulin inhibitor targeting the colchicine binding site. VERU-111 showed potent anti-proliferative and anti-migratory activity against several taxane-sensitive and taxane-resistant TNBC breast cancer cell lines. Based on these observations, taxane-resistant HER2+ cell lines were generated, and were also found to be responsive to VERU-111 treatment. In vivo, orally administered VERU-111 inhibited MDA-MB-231 tumor growth in a dose-dependent manner with antitumor potency similar to paclitaxel, and repressed metastases originating from the mammary fat pad or following tail vein injection. In contrast, in a MDA-MB-231 paclitaxel-resistant (TxR) subline, tumor growth was refractory to paclitaxel whereas VERU-111 significantly inhibited primary tumor growth and reduced lung and liver metastases. VERU-111 was then tested in a luciferase-labeled, multidrug resistant patient-derived xenograft (PDX) TNBC model. VERU-111 significantly inhibited HCI-10 PDX tumor growth and suppressed the expansion of axillary lymph node metastases present prior to initiation of therapy while suppressing lung, liver, bone and kidney metastases at study endpoint. Moreover, in contrast to paclitaxel, VERU-111 therapy did not cause a significant decrease in mouse body weight during treatment. Evaluation of efficacy of VERU-111 in taxane-sensitive and -resistant HER2+ xenograft models is in progress. Overall, we conclude that VERU-111 is a new generation orally bioavailable tubulin inhibitor that potently inhibits the growth of taxane-sensitive and taxane-resistant breast cancers with reduced adverse side effects relative to paclitaxel. Importantly, VERU-111 is well-tolerated in patients as evaluated in phase I/II clinical trials for advanced prostate cancer patients (NCT03752099). We propose that VERU-111 will be an effective second line therapy for patients with advanced breast cancer who progress on taxane-based therapeutic regimens.
NQO2 gene is associated with clozapine‐induced agranulocytosis (2003)

Clozapine is a dibenzodiazepine neuroleptic with atypical pharmacological and clinical profiles. Treatment with this drug may be complicated with agranulocytosis (AGR). It is likely that defective oxidative mechanism may be the cause of AGR. A candidate gene, dihydronicotinamide riboside (NRH) quinone oxidoreductase 2 (NQO2), which is involved in detoxification of drugs, was selected. This gene has been mapped to the short arm of chromosome six. The gene was studied by single-strand conformation polymorphism analysis and direct sequencing in 98 schizophrenic patients that were treated with clozapine. Eighteen of these patients developed AGR. Ten polymorphisms in the coding regions, in intron 1, and in the promoter region were found, two of which were novel. Comparisons of the polymorphisms in the first intron in AGR patients and controls suggested that this site might be connected with AGR. Quantitative reverse transcriptase-polymerase chain reaction analysis showed that the level of NQO2 mRNA is low in AGR patients compared with the control group. Such a reduction in message suggests that the NQO2 gene may be involved in the development of clozapine-induced AGR.
Towards an “assayome” for binary interactome mapping (2019)

ABSTRACT Complementary assays are required to comprehensively map complex biological entities such as genomes, proteomes and interactome networks. However, how various assays can be optimally combined to approach completeness while maintaining high precision often remains unclear. Here, we propose the concept of an “assayome” for binary protein-protein interaction (PPI) mapping as an optimal combination of assays and/or assay versions that maximizes detection of true positive interactions, while avoiding detection of random protein pairs. We engineered a novel NanoLuc two-hybrid (N2H) system that integrates 12 different versions differing by protein expression systems and tagging configurations. The resulting N2H assayome recovers as many PPIs as 10 distinct assays combined. Thus, to further improve PPI mapping, developing alternative versions of existing assays might be as productive as designing completely new assays. Our assayome concept should be applicable to systematic mapping of other biological landscapes.
Spectrally controlled source for interferometric measurements of multiple surface cavities (2018)

We present a new light source capable of locating interference fringes at an adjustable distance from the interferometer. The spectrum is electronically controlled in such a way that the fringes are limited to only one of the surfaces of the optics under test. With the new source it is straightforward, for example, to measure the parallel surfaces of thin glass plates and multiple surface cavities. Existing interferometers, as well as older systems, can be upgraded with this source. Traditional methods of interferometry are widely used and accepted for simple measurement configurations, but measurement accuracy can decrease rapidly with increasing measurement complexity. For example, coherent interferometry struggles to achieve accurate and repeatable results with the presence of any additional feedback surface in the measurement cavity due to temporally coherent back reflections. Conversely, incoherent interferometers can isolate single surfaces for measurement but require more complex interferometer system designs. As a result, many of these systems are limited in their dynamic range of measurable cavity sizes and present considerable difficulties in the alignment process, increasing total measurement time. Both methods are inherently restricted by the intrinsic properties of their respective source. Spectrally controlled interferometry (SCI) is a source driven method which inherits many advantages from both coherent and incoherent interferometry while evading typical limitations. The sources spectral properties are manipulated to produce a tunable coherence function in measurement space which allows control over the coherence envelope width, the fringe location, and the fringe phase. With this source realization, a host of measurement advantages which simplify measurement complexity and reduce total measurement time becomes available. One major application is the extinction of extraneous surface back reflections. Without any mechanical translation, realignment, or traditional piezoelectric transducers, front and back surfaces of planar optics can be isolated independently and complete phase shifting interferometric (PSI) measurements can be taken. Furthermore, because all control parameters are implemented at the source level, the spectrally controlled source is a good candidate for upgrading existing interferometer systems. In this paper, we present the theoretical background for this source and the implications of the method. Additionally, a multiple surface cavity measurement is provided as a means of demonstrating the spectrally controlled sources capability to isolate individual cavities from detrimental back reflections across a large dynamic range of measurable cavity sizes without mechanical realignment. A discussion of the implementation benefits and practical details will be included. Limitations and comparisons to alternative methods will be addressed, as well.
Computational Auditory Scene Analysis and its Application to Robot Audition (2008)

Robot capability of hearing sounds, in particular, a mixture of sounds, by its own microphones, that is, robot audition, is important in improving human robot interaction. This paper presents the robot audition open-source software, called "HARK" (HRI-JP Audition for Robots with Kyoto University), which consists of primitive functions in computational auditory scene analysis; sound source localization, separation, and recognition of separated sounds. Since separated sounds suffer from spectral distortion due to separation, the HARK generates a time-spectral map of reliability, called "missing feature mask", for features of separated sounds. Then separated sounds are recognized by the missing-feature theory (MFT) based ASR with missing feature masks. The HARK is implemented on the middleware called "FlowDesigner" to share intermediate audio data, which enables near real-time processing.
Estimation of Cry3Bb1 resistance allele frequency in field populations of western corn rootworm using a genetic marker (2021)

Following the discovery of western corn rootworm (WCR; Diabrotica virgifera virgifera) populations resistant to the Bacillus thuringiensis (Bt) protein Cry3Bb1, resistance was genetically mapped to a single locus on WCR chromosome 8 and linked SNP markers were shown to correlate with the frequency of resistance among field-collected populations from the US Corn Belt. The purpose of this paper is to further investigate the relationship between one of these resistance-linked markers and the causal resistance locus. Using data from laboratory bioassays and field experiments, we show that one allele of the resistance-linked marker increased in frequency in response to selection, but was not perfectly linked to the causal resistance allele. By coupling the response to selection data with a genetic model of the linkage between the marker and the causal allele, we developed a model that allowed marker allele frequencies to be mapped to causal allele frequencies. We then used this model to estimate the resistance allele frequency distribution in the US Corn Belt based on collections from 40 populations. These estimates suggest that chromosome 8 Cry3Bb1 resistance allele frequency was generally low (<10%) for 65% of the landscape, though an estimated 13% of landscape has relatively high (>25%) resistance allele frequency.
Oriented crystallization of a β-Quartz Solid Solution from a MgO/Al2O3/SiO2 glass in contact with tetragonal ZrO2 ceramics (2015)

Crystal nucleation and growth are studied at the air/glass and glass/ceramic interface of a MgO/Al<sub>2</sub>O<sub>3</sub>/SiO<sub>2</sub> glass in contact to a ZrO<sub>2</sub> ceramic. Mullite and additional crystal phases including a highly oriented layer of a β-quartz solid solution occur.
Precision Infection Prevention (PIP) as a New Standard of Practice Within Longitudinal Infection Prevention and Surveillance (2020)

Background: Infection prevention and control (IPC) workflows are often retrospective and manual. New tools, however, have entered the field to facilitate rapid prospective monitoring of infections in hospitals. Although artificial intelligence (AI)–enabled platforms facilitate timely, on-demand integration of clinical data feeds with pathogen whole-genome sequencing (WGS), a standardized workflow to fully harness the power of such tools is lacking. We report a novel, evidence-based workflow that promotes quicker infection surveillance via AI-assisted clinical and WGS data analysis. The algorithm suggests clusters based on a combination of similar minimum inhibitory concentration (MIC) data, timing of sample collection, and shared location stays between patients. It helps to proactively guide IPC professionals during investigation of infectious outbreaks and surveillance of multidrug-resistant organisms and healthcare-acquired infections. Methods: Our team established a 1-year workgroup comprised of IPC practitioners, clinical experts, and scientists in the field. We held weekly roundtables to study lessons learned in an ongoing surveillance effort at a tertiary care hospital—utilizing Philips IntelliSpace Epidemiology (ISEpi), an AI-powered system—to understand how such a tool can enhance practice. Based on real-time case discussions and evidence from the literature, a workflow guidance tool and checklist were codified. Results: In our workflow, data-informed clusters posed by ISEpi underwent triage and expert follow-up analysis to assess: (1) likelihood of transmission(s); (2) potential vector(s) identity; (3) need to request WGS; and (4) intervention(s) to be pursued, if warranted. In a representative sample (spanning October 17, 2019, to November 7, 2019) of 67 total isolates suggested for inclusion in 19 unique cluster investigations, we determined that 9 investigations merited follow-up. Collectively, these 9 investigations involved 21 patients and required 115 minutes to review in ISEpi and an additional 70 minutes of review outside of ISEpi. After review, 6 investigations were deemed unlikely to represent a transmission; the other 3 had potential to represent transmission for which interventions would be performed. Conclusions: This study offers an important framework for adaptation of existing infection control workflow strategies to leverage the utility of rapidly integrated clinical and WGS data. This workflow can also facilitate time-sensitive decisions regarding sequencing of specific pathogens given the preponderance of available clinical data supporting investigations. In this regard, our work sets a new standard of practice: precision infection prevention (PIP). Ongoing effort is aimed at development of AI-powered capabilities for enterprise-level quality and safety improvement initiatives. Funding: Philips Healthcare provided support for this study. Disclosures: Alan Doty and Juan Jose Carmona report salary from Philips Healthcare.
Planktonic blue‐green algae: Production, sedimentation, and decomposition in Lake Mendota, Wisconsin (1980)

During two annual phytoplankton cycles (1976, 1977), growth, primary production, and sedimentation were measured in Lake Mendota. Blue‐green algal blooms developed after lake stratification in a succession of dominant genera. Aphanizomenon and Anabaena normally dominated early populations with Microcystis becoming more important by midsummer. Periodic declines in blue‐green algal standing crop could be accounted for by a combination of epilimnetic decomposition and sedimentation. For Aphanizomenon and Anabaena, decomposition appeared to be primarily important, whereas sedimentation accounted for more of the decline of Microcystis. Estimates for annual sediment accumulation obtained by correcting the observed sedimentation rates for resuspension agreed fairly well with values calculated from coring data. For the period of blue‐green algal dominance, about 57–67% of the organic carbon was lost from particles during sedimentation due to decomposition. Further decomposition occurred at the sediment surface so that only about 11% of the original organic material was more or less permanently buried. Amounts of blue‐green algal volume, particulate chlorophyll, and particulate phosphorus measured in the traps also indicated that significant decomposition had occurred during sedimentation.
Excess of glucocorticoid induces myocardial remodeling and alteration of calcium signaling in cardiomyocytes (2011)

Ventricular dysfunction is one of the important side effects of the anti-inflammatory agent, glucocorticoid (GC). The present study was undertaken to examine whether abnormal calcium signaling is responsible for cardiac dysfunction due to an excess of GC hormone. The synthetic GC drug, dexamethasone (DEX), significantly (P<0.001, n=20) increased heart weight to body weight ratio, left ventricular remodeling, and fibrosis. The microarray analysis showed altered expression of several genes encoding calcium cycling/ion channel proteins in DEX-treated rat heart. The altered expression of some of the genes was validated by real-time PCR and western blotting analyses. The expression of the L-type calcium channels and calsequestrin was increased, whereas sarcoendoplasmic reticulum calcium transport ATPase 2a (SERCA2a) and junctin mRNAs were significantly reduced in DEX-treated rat left ventricular tissues. In neonatal rat ventricular cardiomyocytes, DEX also increased the level of mRNAs of atrial- and brain natriuretic peptides, L-type calcium channels, and calsequestrin after 24 h of treatment, which were mostly restored by mifepristone. The caffeine-induced calcium release was prolonged by DEX compared to the sharp release in control cardiomyocytes. Taken together, these data show that impaired calcium kinetics may be responsible for cardiac malfunction by DEX. The results are important in understanding the pathophysiology of the heart in patients treated with excess GC.
ChemInform Abstract: Highly Regioselective Palladium‐Catalyzed Direct Arylation of Oxazole at C‐2 or C‐5 with Aryl Bromides, Chlorides, and Triflates. (2010)

Abstract Treatment of oxazole with aryl halides and triflates in the presence of Pd(OAc) 2 and POS or APO results in efficient and selective formation of C‐5 arylated oxazoles.
Characterization of System Services and Their Performance Impact in Multi-core Nodes (2011)

The performance of parallel applications on large scale systems is shown to disproportionately degrade due to interference from system services. This interference from system services is also known as jitter. However, there is limited understanding of sources and patterns of jitter on multi-core systems. In this paper, we identify and characterize jitter sources in terms of their amplitude and execution interval distributions on multi-core IBM Power systems with UNIX-based general purpose operating systems: AIX and Linux. Our analysis shows that there are various kinds of jitter sources and their execution varies drastically between different cores and between hardware threads within each core for practical reasons. This in-depth knowledge of jitter events is leveraged to devise effective approaches to mitigate the jitter impact on application performance in large scale systems. Moreover, such knowledge would provide useful insights to a new generation of operating system designs such as multikernel or satellite kernel for multicore systems.
Cationic Four- and Five-Coordinate Nickel(II) Complexes:  Insights into the Nickel(II)-Catalyzed Copolymerization of Ethylene and Carbon Monoxide (2000)

Using the dppp-derived Ni(II) catalyst system 2, several four- and five-coordinate intermediates relevant to the alternating copolymerization of ethylene and carbon monoxide have been characterized. In addition, the activation barriers for the migratory insertion steps corresponding to chain growth have been determined to be at or below ca. 10 kcal/mol, indicating that a strongly stabilized catalyst resting state is most likely responsible for the low activity of 2 for copolymerization.
Selected Approaches for Rational Drug Design and High Throughput Screening to Identify Anti-Cancer Molecules (2012)

Structure-based modeling combined with rational drug design, and high throughput screening approaches offer significant potential for identifying and developing lead compounds with therapeutic potential. The present review focuses on these two approaches using explicit examples based on specific derivatives of Gossypol generated through rational design and applications of a cancer-specificpromoter derived from Progression Elevated Gene-3. The Gossypol derivative Sabutoclax (BI-97C1) displays potent anti-tumor activity against a diverse spectrum of human tumors. The model of the docked structure of Gossypol bound to Bcl-XL provided a virtual structure-activity-relationship where appropriate modifications were predicted on a rational basis. These structure-based studies led to the isolation of Sabutoclax, an optically pure isomer of Apogossypol displaying superior efficacy and reduced toxicity. These studies illustrate the power of combining structure-based modeling with rational design to predict appropriate derivatives of lead compounds to be empirically tested and evaluated for bioactivity. Another approach to cancer drug discovery utilizes a cancer-specific promoter as readouts of the transformed state. The promoter region of Progression Elevated Gene-3 is such a promoter with cancer-specific activity. The specificity of this promoter has been exploited as a means of constructing cancer terminator viruses that selectively kill cancer cells and as a systemic imaging modality that specifically visualizes in vivo cancer growth with no background from normal tissues. Screening of small molecule inhibitors that suppress the Progression Elevated Gene-3-promoter may provide relevant lead compounds for cancer therapy that can be combined with further structure-based approaches leading to the development of novel compounds for cancer therapy.
Mutations of the AMH Type II Receptor in Two Extended Families with Persistent Müllerian Duct Syndrome: Lack of Phenotype/Genotype Correlation (2012)

Our goal was to compare phenotype and genotype in two extended Middle-Eastern families affected by persistent Müllerian duct syndrome due to mutations of the type II anti-Müllerian hormone receptor (AMHR-II). The first, consanguineous, family consisted of 6 boys and 2 girls, the second consisted of 4 girls and 2 boys. In family I, 4 boys and 1 girl were homozygous for a stop mutation in the 9th exon of AMHR-II, removing part of the intracellular domain of the protein. In family II, 1 girl and 1 boy were homozygous for a transversion changing conserved histidine 254 into a glutamine. Both homozygous girls were normal. In the homozygous males, the degree of development of Müllerian derivatives was variable. The uterus was well developed in 2 boys of family I and in the patient from family II; however, in 1 subject from family I, Müllerian derivatives were undetectable. Taken together, the diversity of clinical symptoms within the same sibship and the lack of correlation between the development of the Müllerian derivatives and the severity of the molecular defects suggest highly variable penetrance of the abnormal alleles and/or the existence of other genetic or epigenetic modifiers of gene expression.