gebhart/patrepeval huggingface dataset:
Fetal antisense oligonucleotide therapy for congenital deafness and vestibular dysfunction (2020)

Disabling hearing loss impacts ∼466 million individuals worldwide with 34 million children affected. Gene and pharmacotherapeutic strategies to rescue auditory function in mouse models of human deafness are most effective when administered before hearing onset, after which therapeutic efficacy is significantly diminished or lost. We hypothesize that preemptive correction of a mutation in the fetal inner ear prior to maturation of the sensory epithelium will optimally restore sensory function. We previously demonstrated that transuterine microinjection of a splice-switching antisense oligonucleotide (ASO) into the amniotic cavity immediately surrounding the embryo on embryonic day 13-13.5 (E13-13.5) corrected pre-mRNA splicing in the juvenile Usher syndrome type 1c (Ush1c) mouse mutant. Here, we show that this strategy only marginally rescues hearing and partially rescues vestibular function. To improve therapeutic outcomes, we microinjected ASO directly into the E12.5 inner ear. A single intra-otic dose of ASO corrects harmonin RNA splicing, restores harmonin protein expression in sensory hair cell bundles, prevents hair cell loss, improves hearing sensitivity, and ameliorates vestibular dysfunction. Improvements in auditory and vestibular function were sustained well into adulthood. Our results demonstrate that an ASO pharmacotherapeutic administered to a developing organ system in utero preemptively corrects pre-mRNA splicing to abrogate the disease phenotype.
Color-image quantization with use of a fast binary splitting technique (1994)

We investigate an efficient color-image quantization technique that is based on an existing binary splitting algorithm [ IEEE Trans. Signal Process. 39, 2677 ( 1991)]. The algorithm sequentially splits the color space into polytopal regions and picks a palette color from each region. As originally proposed, the complexity of this algorithm is a function of the image size. We introduce a fast histogramming step so that the complexity will depend only on the number of distinct image colors. Data structures are employed that permit the storage of a full-color histogram at moderate memory cost. In addition, we apply a prequantization step that reduces the number of initial image colors while preserving image quality along visually important color coordinates. Finally, we incorporate a spatial-activity measure to reflect the increased sensitivity of the human observer to quantization errors in smooth image regions. This technique preserves the quantitative and qualitative performance of the original binary splitting algorithm while considerably reducing the computation time.
Data from ROS Induction Targets Persister Cancer Cells with Low Metabolic Activity in NRAS-Mutated Melanoma (2023)

&lt;div&gt;Abstract&lt;p&gt;Clinical management of melanomas with NRAS mutations is challenging. Targeting MAPK signaling is only beneficial to a small subset of patients due to resistance that arises through genetic, transcriptional, and metabolic adaptation. Identification of targetable vulnerabilities in NRAS-mutated melanoma could help improve patient treatment. Here, we used multiomics analyses to reveal that NRAS-mutated melanoma cells adopt a mesenchymal phenotype with a quiescent metabolic program to resist cellular stress induced by MEK inhibition. The metabolic alterations elevated baseline reactive oxygen species (ROS) levels, leading these cells to become highly sensitive to ROS induction. &lt;i&gt;In vivo&lt;/i&gt; xenograft experiments and single-cell RNA sequencing demonstrated that intratumor heterogeneity necessitates the combination of a ROS inducer and a MEK inhibitor to inhibit both tumor growth and metastasis. &lt;i&gt;Ex vivo&lt;/i&gt; pharmacoscopy of 62 human metastatic melanomas confirmed that MEK inhibitor–resistant tumors significantly benefited from the combination therapy. Finally, oxidative stress response and translational suppression corresponded with ROS-inducer sensitivity in 486 cancer cell lines, independent of cancer type. These findings link transcriptional plasticity to a metabolic phenotype that can be inhibited by ROS inducers in melanoma and other cancers.&lt;/p&gt;Significance:&lt;p&gt;Metabolic reprogramming in drug-resistant NRAS-mutated melanoma cells confers sensitivity to ROS induction, which suppresses tumor growth and metastasis in combination with MAPK pathway inhibitors.&lt;/p&gt;&lt;/div&gt;
Infrarenal aortic stenosis: long-term clinical and hemodynamic results of percutaneous transluminal angioplasty. (1998)

Infrarenal aortic PTA proved to be safe and provided durable, long-term clinical improvement. In this group of relatively young patients, the clinical patency rate of PTA was equivalent to that of aortic surgery but with less morbidity.
T-VEMA: A Temperature- and Variation-Aware Electromigration Power Grid Analysis Tool (2014)

In this brief, a temperature- and variation-aware electromigration analysis (T-VEMA) tool for power grid wires is described. First, T-VEMA performs a two-stage interconnect thermal analysis on a full chip. Next, the tool extracts the effective jL product values and performs an electromigration (EM) lifetime calculation on ideally manufactured mortal wires on the basis of thermal effects. Finally, T-VEMA analyzes process variation effects on EM reliability at global and local levels and reports variation tolerances of EM-sensitive power grid wires.
Digital post-correction on dynamic nonlinearity in GaN HEMT track-and-hold sampling circuits (2017)

This paper introduces the recent development of GaN HEMT track-and-hold sampling circuits (THSCs) with a digital post-correction (DPC) technique for emerging applications. Compared to THSCs in silicon technologies, GaN THSCs achieve 20-30 dB higher signal-to-noise ratio (SNR) for a given bandwidth. Nevertheless, GaN THSCs suffer from dynamic nonlinearity due to charge trapping and introduce low-frequency dispersion, thus providing no more than 40-50 dB spurious-free dynamic range (SFDR). Conventional DPC techniques have been used to linearize CMOS data converters with weak memory effects, which is not effective for dynamic nonlinearity correction on GaN HEMT THSCs with deep memory effects. In order to provide dynamic nonlinearity correction on GaN HEMT THSCs for Nyquist bandwidth, the proposed DPC technique based on a truncated Volterra series eliminates DC offset before model parameter extraction and also uses a multi-section input signal for wideband model training. The DPC technique is applied to a 200-MS/s 98-dB SNR GaN THSC with 56.7-dB SFDR for a 12-MHz input and 48.4-dB SFDR for a 98-MHz input. After DPC, the SFDR improves to 77.9 dB at 12 MHz and 82.2 dB at 98 MHz, demonstrating 21.2 dB and 33.8 dB improvement respectively. The GaN THSC with DPC achieves 12.4-bit ENOB with a 98-MHz input, higher than prior CMOS sampling circuits reported to date.
5-Benzamidoisoquinolin-1-ones and 5-(ω-Carboxyalkyl)isoquinolin-1-ones as Isoform-Selective Inhibitors of Poly(ADP-ribose) Polymerase 2 (PARP-2) (2011)

PARP-2 is a member of the poly(ADP-ribose) polymerase family, with some activities similar to those of PARP-1 but with other distinct roles. Two series of isoquinolin-1-ones were designed, synthesized, and evaluated as selective inhibitors of PARP-2, using the structures of the catalytic sites of the isoforms. A new efficient synthesis of 5-aminoisoquinolin-1-one was developed, and acylation with acyl chlorides gave 5-acylaminoisoquinolin-1-ones. By examination of isoquinolin-1-ones with carboxylates tethered to the 5-position, Heck coupling of 5-iodoisoquinolin-1-one furnished the 5-CH═CHCO(2)H compound for reduction to the 5-propanoic acid. Alkylation of 5-aminoisoquinolin-1-one under mildly basic conditions, followed by hydrolysis, gave 5-(carboxymethylamino)isoquinolin-1-one, whereas it was alkylated at 2-N with methyl propenoate and strong base. Compounds were assayed in vitro for inhibition of PARP-1 and PARP-2, using FlashPlate and solution-phase assays, respectively. The 5-benzamidoisoquinolin-1-ones were more selective for inhibition of PARP-2, whereas the 5-(ω-carboxyalkyl)isoquinolin-1-ones were less so. 5-Benzamidoisoquinolin-1-one is the most PARP-2-selective compound (IC(50(PARP-1))/IC(50(PARP-2)) = 9.3) to date, in a comparative study.
Flow Cytometric Findings in Hemophagocytic Lymphohistiocytosis (2012)

Hemophagocytic lymphohistiocytosis (HLH) is an often fatal hyperinflammatory syndrome. HLH may be inherited, but it more commonly arises secondary to Epstein-Barr virus (EBV) or other infections, hematologic malignancies, or rheumatologic diseases. We identified 17 patients diagnosed with HLH who had flow cytometric analysis of peripheral blood or bone marrow performed at the time of diagnosis. Two patients had primary HLH, and the others had HLH secondary to EBV infection, hematologic malignancies, rheumatologic conditions, or tuberculosis. The marrow typically showed a reactive lymphocytosis and a marked left shift in myelopoiesis regardless of the etiology. Qualitative abnormalities were also found in several cases, including T-cell abnormalities in the majority of the EBV-associated HLH cases. While not specific, flow cytometric findings in HLH are different from the findings in uninvolved marrow samples, and care should be taken not to overinterpret immunophenotypic findings in these cases as indicative of a primary marrow disorder or lymphoma.
Bridging of macrocycles to bicycles. New synthetic technology for the construction of cis- and trans-fused oxopolycyclic systems (1986)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTBridging of macrocycles to bicycles. New synthetic technology for the construction of cis- and trans-fused oxopolycyclic systemsK. C. Nicolaou, C. K. Hwang, M. E. Duggan, K. Bal. Reddy, B. E. Marron, and D. G. McGarryCite this: J. Am. Chem. Soc. 1986, 108, 21, 6800–6802Publication Date (Print):October 1, 1986Publication History Published online1 May 2002Published inissue 1 October 1986https://pubs.acs.org/doi/10.1021/ja00281a056https://doi.org/10.1021/ja00281a056research-articleACS PublicationsRequest reuse permissionsArticle Views363Altmetric-Citations41LEARN 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 InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts
A DNA-Based Archival Storage System (2017)

Storing data in DNA molecules offers extreme density and durability advantages that can mitigate exponential growth in data storage needs. This article presents a DNA-based archival storage system, performs wet lab experiments to show its feasibility, and identifies technology trends that point to increasing practicality.
The Live Attenuated Dengue Serotype 1 Vaccine rDEN1&Delta;30 is Safe and Highly Immunogenic in Healthy Adult Volunteers (2006)

The rDEN1Delta30 vaccine is safe and induced a potent and durable antibody response against DEN1. It is a promising vaccine candidate for inclusion in a tetravalent dengue vaccine formulation.
Distinctive Metabolism of Flavonoid between Cultivated and Semiwild Soybean Unveiled through Metabolomics Approach (2016)

Soybeans are an important crop for agriculture and food, resulting in an increase in the range of its application. Recently, soybean leaves have been used not only for food products but also in the beauty industry. To provide useful and global metabolite information on the development of soy-based products, we investigated the metabolic evolution and cultivar-dependent metabolite variation in the leaves of cultivated (Glycine max) and semiwild (G. gracilis) soybean, through a (1)H NMR-based metabolomics approach, as they grew from V (vegetative) 1 to R (reproductive) 7 growth stages. The levels of primary metabolites, such as sucrose, amino acids, organic acids, and fatty acids, were decreased both in the G. gracilis and G. max leaves. However, the secondary metabolites, such as pinitol, rutin, and polyphenols, were increased while synthesis of glucose was elevated as the leaves grew. When metabolite variations between G. gracilis and G. max are compared, it was noteworthy that rutin and its precursor, quercetin-3-O-glucoside, were found only in G. gracilis but not in G. max. Furthermore, levels of pinitol, proline, β-alanine, and acetic acid, a metabolite related to adaptation toward environmental stress, were different between the two soybean cultivars. These results highlight their distinct metabolism for adaptation to environmental conditions and their intrinsic metabolic phenotype. This study therefore provides important information on the cultivar-dependent metabolites of soybean leaves for better understanding of plant physiology toward the development of soy-based products.
Phosphorylation of the 26 kDa TNF precursor in monocytic cells and in transfected HeLa cells. (1995)

Tumor necrosis factor (TNF) functions both as a soluble molecule and as a cell surface 26 kDa transmembrane protein, from which the soluble form is proteolytically derived. The 26 kDa TNF molecules isolated from 32P labeled HeLa cells that had been transfected with the cDNA of a partially cleavable TNF mutant were found labeled. Phosphorylated 26 kDa TNF molecules could also be isolated from human LPS stimulated monocytic Mono Mac 6. Phosphoaminoacid analysis revealed that the labeled phosphate is bound to serine residues. No label was found incorporated in soluble 17 kDa TNF, indicating that the phosphorylated residue(s) of membrane-associated TNF occur in the cytoplasmic portion of the molecule. Phosphorylation of the intracellular domain of the 26 kDa TNF molecules may play a role in the regulation of expression or proteolytic processing of TNF, modulate TNF bioactivity, or take part in intracellular signaling by cell-surface TNF.
Coherent Automotive Radar Networks: The Next Generation of Radar-Based Imaging and Mapping (2021)

Imaging radar is a key perception technology for automotive and industrial applications. A lot of progress has been made with high channel count systems, deploying, for example, 12 transmit and 16 receive channels with cascaded monolithic microwave integrated circuit solutions. Nevertheless, fully automated driving requires even higher angular resolution for drive-under/drive-over decisions and exact predictions of object trajectories in dense urban driving scenarios. Both problems can be solved by increasing the antenna size and building larger radars. However, there is a physical limit to what can be placed on the front of a car, and manufacturing very large arrays is quite difficult. Thus, coherent automotive radar networks are a way to achieve high spatial resolution and obtain the complete velocity vector of an object from a single measurement. This solution is commercially attractive, as the sensor can remain relatively small, and complexity can be moved from the physical hardware to algorithms and processing. Two different test setups, each comprised of two multiple-input multiple-output radar units in the 76-77 GHz band, are presented in this article. To obtain azimuth and additional elevation information, the setups use a 1D and a 2D antenna array, respectively. Processing-based coherent evaluation is employed to create an additional radar image with doubled azimuth resolution and improved signal-to-noise ratio and to enable the estimation of vectorial target velocities. These benefits are presented and compared with optical reference images in traffic scenarios.
In vitro-in vivo relationship for amorphous solid dispersions using a double membrane dissolution-permeation setup (2023)

The use of amorphous solid dispersions (ASDs) is one commonly applied formulation strategy to improve the oral bioavailability of poorly water-soluble drugs by overcoming dissolution rate and/or solubility limitations. While bioavailability enhancement of ASDs is well documented, it has often been a challenge to establish a predictive model describing in vitro-in vivo relationship (IVIVR). In this study, it is hypothesized that drug absorption might be overestimated by in vitro dissolution-permeation (D/P)-setups, when drug in suspension has the possibility of directly interacting with the permeation barrier. This is supported by the overprediction of drug absorption from neat crystalline efavirenz compared to four ASDs in a D/P-setup based on the parallel artificial membrane permeability assay (PAMPA). However, linear IVIVR (R<sup>2</sup> = 0.97) is established in a modified D/P-setup in which the addition of a hydrophilic PVDF-filter acts as a physical boundary between the donor compartment and the PAMPA-membrane. Based on microscopic visualization, the improved predictability of the modified D/P-setup is due to the avoidance of direct dissolution of drug particles in the lipid components of the PAMPA-membrane. In general, this principle might aid in providing a more reliable evaluation of formulations of poorly water-soluble drugs before initiating animal models.
Building Career Paths for Ph.D., Basic and Translational Scientists in Clinical Departments in the United States: An Official American Thoracic Society Workshop Report (2023)

<b>Rationale:</b> To identify barriers and opportunities for Ph.D., basic and translational scientists to be fully integrated into clinical units. <b>Objectives:</b> In 2022, an <i>ad hoc</i> committee of the American Thoracic Society developed a project proposal and workshop to identify opportunities and barriers for scientists who do not practice medicine to develop successful careers and achieve tenure-track faculty positions in clinical departments and divisions within academic medical centers (AMCs) in the United States. <b>Methods:</b> This document focuses on results from a survey of adult and pediatric pulmonary, critical care, and sleep medicine division chiefs as well as a survey of workshop participants, including faculty in departmental and school leadership roles in both basic science and clinical units within U.S. AMCs. <b>Results:</b> We conclude that full integration of non-clinically practicing basic and translational scientists into the clinical units, in addition to their traditional placements in basic science units, best serves the tripartite mission of AMCs to provide care, perform research, and educate the next generation. Evidence suggests clinical units do employ Ph.D. scientists in large numbers, but these faculty are often hired into non-tenure track positions, which do not provide the salary support, start-up funds, research independence, or space often associated with hiring in basic science units within the same institution. These barriers to success of Ph.D. faculty in clinical units are largely financial. <b>Conclusions:</b> Our recommendation is for AMCs to consider and explore some of our proposed strategies to accomplish the goal of integrating basic and translational scientists into clinical units in a meaningful way.
Development of an antibody fused with an antimicrobial peptide targeting Pseudomonas aeruginosa: a new approach to prevent and treat bacterial infections (2022)

Abstract The increase of emerging drug resistant Gram-negative bacterial infections is of global concern. In addition, there is growing recognition that compromising the microbiota, through the use of broad spectrum antibiotics, may affect patient health in the long term. Therefore, there is the need to develop new -cidal strategies to combat Gram-negative infections that would consider these specific issues. In this study, we report and characterize one such approach, the antibody-drug conjugates (ADCs) that combine (i) targeting a specific pathogenic organism through a monoclonal antibody with (ii) the high killing activity of antimicrobial peptides. We focused on a major pathogenic Gram-negative bacterium associated with antibacterial resistance: Pseudomonas aeruginosa and designed an ADC by fusing an antimicrobial peptide at the C-terminal end of the V H and/or V L -chain of a monoclonal antibody, VSX, that targets the core of P. aeruginosa lipopolysaccharide (LPS). This ADC demonstrated appropriately minimal levels of toxicity to mammalian cells and rapidly kills P. aeruginosa strains through several mechanisms while protecting mice from P. aeruginosa lung infection when administered therapeutically. Furthermore, we found that the ADC was synergistic with several classes of antibiotics. This approach described in this study may result in a widely useful strategy to target specific pathogenic microorganisms without augmenting further antibiotic resistance. Author Summary The increasing of emerging drug resistant bacterial infections is a worldwide issue and infections caused by antibiotic resistant Gram-negative pathogens are particularly concerning. In addition, there is now growing recognition that disruption of the microbiota, through the use of broad spectrum antibiotics, may affect patient health in the long term. Therefore, there is the need to develop new -cidal strategies to combat Gram-negative infections while preserving the microbiota and also avoid enhancement of antibiotic resistance. We report and characterize here one such approach by using a specific monoclonal antibody associated with the potent killing activity of antimicrobial peptides in the form of an antibody-drug conjugate (ADC). The selected pathogenic bacterium was Pseudomonas aeruginosa, that presents numerous markers for both innate and acquired antibiotic resistance. The ADC lacked significant cytotoxicity against mammalian cells and was shown to be effective both in vitro and in vivo against P. aeruginosa .
Clinical presentation of anorexia nervosa in males: 24 new cases (1994)

As part of a larger prognostic study of anorexia nervosa, clinical features at presentation of 24 males with anorexia are described, and compared with a female group matched for date of admission. Data were extracted from the original case records and follow-up interview. The study confirms the view that males display the classical syndrome of anorexia nervosa, but differs from previous studies in several respects. Age at onset (mean 18.6 years) and at presentation (mean 20.2 years) is later, with a mean duration of illness at presentation of only 1.6 years. A premorbid tendency to obesity is confirmed; maximum weight loss during the illness amounted to 42% matched population mean weight (MPMW), and weight at presentation was 78.5% MPMW, somewhat higher than the female group. In keeping with earlier studies, binging and vomiting were noted commonly, in around half of sufferers, but laxative abuse was less frequent and excessive exercising more frequent in males. Depressive and obsessional symptoms are common in both groups, and a strong family history of affective disorders and alcohol abuse was noted in over one third.
B2B: Prostate Cancer (2021)

The first talk was led by Dr. Alexander Wyatt, who presented the state of the art of liquid biopsy in urologic oncology [...]