gebhart/patrepeval huggingface dataset:
High-quality DNA sequence capture of 524 disease candidate genes (2011)

The accurate and complete selection of candidate genomic regions from a DNA sample before sequencing is critical in molecular diagnostics. Several recently developed technologies await substantial improvements in performance, cost, and multiplex sample processing. Here we present the utility of long padlock probes (LPPs) for targeted exon capture followed by array-based sequencing. We found that on average 92% of 5,471 exons from 524 nuclear-encoded mitochondrial genes were successfully amplified from genomic DNA from 63 individuals. Only 144 exons did not amplify in any sample due to high GC content. One LPP was sufficient to capture sequences from <100-500 bp in length and only a single-tube capture reaction and one microarray was required per sample. Our approach was highly reproducible and quick (<8 h) and detected DNA variants at high accuracy (false discovery rate 1%, false negative rate 3%) on the basis of known sample SNPs and Sanger sequence verification. In a patient with clinical and biochemical presentation of ornithine transcarbamylase (OTC) deficiency, we identified copy-number differences in the OTC gene at exon-level resolution. This shows the ability of LPPs to accurately preserve a sample's genome information and provides a cost-effective strategy to identify both single nucleotide changes and structural variants in targeted resequencing.
AA2500 Testosterone Gel Normalizes Androgen Levels in Aging Males with Improvements in Body Composition and Sexual Function (2003)

Testosterone replacement in hypogonadal men improves body composition, mood, and sexual functioning. In this 90-d study, we compared the pharmacokinetics and treatment effectiveness of a topical testosterone gel (AA2500) at two concentrations, 50 mg/d and 100 mg/d, to a testosterone patch and placebo gel in 406 hypogonadal men. Pharmacokinetic profiles were obtained, body composition was measured, and mood and sexual function were monitored. AA2500 treatments resulted in dose-dependent improvements in all pharmacokinetic parameters, compared with testosterone patch and placebo. Mean average concentrations at d 90 T were 13.8, 17.1, 11.9, and 7.3 nmol/liter for 50 mg/d AA2500, 100 mg/d AA2500, testosterone patch, and placebo, respectively. At d 90, the 100 mg/d AA2500 treatment improved lean body mass by 1.7 kg and percentage of body fat by 1.2% to a significantly greater degree than either control treatment. Significant improvements in spontaneous erections, sexual desire, and sexual motivation were also evidenced with the 100 mg/d AA2500 dose in comparison with placebo. Testosterone gel was well tolerated; however, the testosterone patch resulted in a high rate of application site reactions. Overall, AA2500 is an effective, well tolerated treatment for hypogonadism.
Single modification at position 14 of siRNA strand abolishes its gene‐silencing activity by decreasing both RISC loading and target degradation (2013)

Normally siRNA has to be chemically stabilized in therapeutic applications. It is a challenge to obtain optimal stabilizing effects while maintaining full silencing activity due to a lack of understanding of how different chemical modifications would influence the efficacy of siRNA. In the current study, the effect of single 2'-sugar modifications was profiled across the length of the siRNA guide strand. This led to the surprising finding that a single 2'-OMe modification at position 14 of the siRNA guide strand substantially compromised its gene-silencing activity in a manner that was independent of the nucleotide identity at this site or the sequence context around it. We found that modification at position 14 of the siRNA guide strand reduced its RNA-induced silencing complex (RISC) loading tremendously, whereas the loading of the siRNA sense strand was only marginally affected. When comparing the silencing potency of 14th position-modified siRNA (transfected at 16.7 nM) and native control (transfected at 1 nM) at equivalent Ago2 loading levels, the silencing potency of modified siRNA was much lower, even lower than the level of native siRNA transfected at 0.1 nM. These data indicated that modification at position 14 of the siRNA guide strand abolishes its gene-silencing activity by decreasing both RISC loading and target degradation. Using a computational modeling approach, we demonstrated an intimate interaction between the 14th nucleotide of guide strand and the amino acid Q675 in the AGO protein, which is located in a highly conserved loop of PIWI domain. In addition to gaining insights into siRNA-AGO interactions, this study of structure-activity relationship further established a general principle for siRNA modification in siRNA drug development.
4,4-Disubstituted Piperidine High-Affinity NK1 Antagonists:  Structure−Activity Relationships and in Vivo Activity (1998)

Previously reported studies from these laboratories described the design of a novel series of high-affinity NK1 antagonists based on the 4,4-disubstituted piperidine ring system. Further structure-activity studies have now established that for high NK1 affinity the benzyl ether side chain must be 3,5-disubstituted and highly lipophilic, the optimal side chain being the 3, 5-bis(trifluoromethyl)benzyl ether, 12 (hNK1 IC50 = 0.95 nM). Additional studies have shown that this class of NK1 antagonist tolerates a wider range of substituents on the piperidine nitrogen, including acyl (38) (hNK1 IC50 = 5.3 nM) and sulfonyl (39) (hNK1 IC50 = 5.7 nM) derivatives. Following preliminary pharmacokinetic analysis, two compounds (32 and 43) were selected for in vivo study in the resiniferotoxin-induced vascular leakage model, both showing excellent profiles (ID50 = 0.22 and 0.28 mg/kg, respectively).
A reliable method for intracranial electrode implantation and chronic electrical stimulation in the mouse brain (2013)

We suggest that the glue-based, screw-free method is reliable for chronic brain stimulation and high-quality electroencephalographic recordings in mice. The technical aspects described this study may help future studies in mouse models.
Intravenous Immunoglobulins in Multiple Sclerosis (1998)

The spectrum of diseases being treated with intravenous immunoglobulins (IVIg) appears to be ever broadening, including use in neurologic diseases. After a period of anectodal reports and smaller uncontrolled series, recently there have been several randomized, prospective, double-blind, placebo-controlled studies employing IVIg in patients with relapsing remitting (RR) multiple sclerosis (MS). Reduction in relapse rate and some evidence of decreased MRI activity has been reported, but to date no effect on disability or MRI lesion burden has been noted. Because of differences in methodologic design and patient populations, as well as the relatively small number of patients in some of these studies, a rigorous direct comparison of efficacy with the type I interferons and glatiramer acetate is not possible. Given these data and the high cost of IVIg, routine use of this mode of therapy cannot be recommended, certainly not as a first-line treatment. Larger studies would clearly be helpful. At present there is no evidence to support the use of IVIg in secondary progressive (SP) or primary progressive (PP) MS.
Correlation of in vivo collagen degradation rate with in vitro measurements (1975)

The rate of in vitro enzymatic degradation of various materials based on collagen has been determined by a novel mechanochemical method, and has been compared with the extent of degradation resulting from subcutaneous implantation in guinea pigs. In vitro data correlate well with in vivo data. It is suggested that the simple in vitro method described is an effective means of screening a large number of materials based on collagen for their ability to resist degradation during implantation in animals.
Novel and recurrent p14ARF mutations in Italian familial melanoma (2010)

CDKN2A and CDK4 are the only known high-penetrant genes conferring proneness to cutaneous melanoma. The CDKN2A locus consists of four exons and encodes several alternate transcripts, two of which are p16(INK4a) and p14(ARF), and originate from different open reading frames. Exon 1alpha is specific for p16(INK4a), while exon 1beta characterizes p14(ARF). Most CDKN2A mutations are located in exons 1alpha and 2, while exon 1beta variations have been identified in rare melanoma-prone pedigrees. In a previous study, we investigated 155 Italian melanoma cases, including 94 familial melanomas (FAMs) and 61 sporadic multiple primary melanomas (MPMs), for p16(INK4a)/CDK4 germline alterations and identified 15 p16(INK4a) and 1 CDK4 point mutations. In the present work, we extended our search to p14(ARF) mutations and CDKN2A deletions in the remaining samples. We identified the recurrent g.193+1G> A mutation in two FAM cases, while an additional pedigree displayed the previously undescribed variant g.161G> A. Multiplex ligation-dependent probe amplification (MLPA) screening for copy variations resulted negative in all cases. In Italy, the overall frequency of p14(ARF) mutations is 3.2% in FAM and 0% in sporadic MPM. Re-evaluation of our patients' cohort emphasizes that the chance of identifying CDKN2A/CDK4 mutations in FAM is mainly influenced by the number of affected family members and the presence of one or more MPM cases. Accordingly, mutation rate rises to 61% in selected cases. Further studies are expected in order to investigate CDKN2A rarer mutations, including atypical deletions and inherited epimutations.
Maximum Bond Strength of Dental Luting Cement to Amalgam Alloy (1989)

Although dental amalgam is used frequently under artificial crowns for restoration of severely damaged teeth, there is little information available on the bond between luting cements and this alloy. This study was designed for determination of the strength of the bond between a dental amalgam alloy and three crown-luting cements. Cylinders of dental amalgam were joined in pairs, with use of a zinc-phosphate, a glass-ionomer, and an acrylic-adhesive resin cement. The tensile-fracture stress of 45 samples of each cement was measured with a universal testing machine, and subjected to a Weibull analysis. The fractured surfaces were examined under low magnification with use of a light microscope, and at low and high magnifications with use of a scanning electron microscope, for evaluation of the appearance of the fractured joints. The Weibull analysis demonstrated that the adhesive resin cement provided a stronger and more predictable bond than either the zinc-phosphate or the glass-ionomer cement. The appearance of the fractured surfaces gave no indication of the strength of the joints, a feature that is common to brittle materials. The results suggest that crowns placed on teeth offering a large amalgam-alloy surface could be retained more predictably with an adhesive resin cement.
Intrusion Investigations with Data-Hiding for Computer Log-File Forensics (2010)

In most of companies or organizations, logs play important role in information security. However, the common security mechanism only backup logs, it is not able to find out traces of intruders because the hacker who is able to intrudes the security mechanism of organization would try to alter logs or destroy important intrusion evidences making it impossible to preserve evidence using traditional log security strategies. Thus, logs are not considered as evidence to prove the damage. In that case, digital evidence lacks in terms of completeness which makes it difficult to perform computer forensics operations. In order to maintain the completeness and reliability of evidence for later forensic procedures and intrusion detection, the study applies concepts of steganography to logs forensics, for which even intrusion altered records will be kept as well. Comparing to traditional security strategies, this study proposes a better logging mechanism to ensure the completeness of logs. Furthermore, the study will assist in intrusion detection through alteration behavior, and help in forensic operations.
Breast tumour angiogenesis (2007)

The central importance of tumour neovascularization has been emphasized by clinical trials using antiangiogenic therapy in breast cancer. This review gives a background to breast tumour neovascularization in in situ and invasive breast cancer, outlines the mechanisms by which this is achieved and discusses the influence of the microenvironment, focusing on hypoxia. The regulation of angiogenesis and the antivascular agents that are used in an antiangiogenic dosing schedule, both novel and conventional, are also summarized.
The Notch Ligand Delta-Like 4 Regulates Multiple Stages of Early Hemato-Vascular Development (2012)

This study highlights a previously unnoticed role for Dll4 in the quantitative regulation of early hemato-vascular precursors, further indicating that it is also involved on the timely emergence of mesoderm in early embryogenesis.
A homogenous frameshift mutation in LRAT causes retinitis punctata albescens. (2012)

To determine the genetic defect and to describe the clinical characteristics in patients with retinitis punctata albescens (RPA) and fundus albipunctatus (FAP).Case series/observational study.We included 13 patients affected by RPA or FAP.Thirteen patients were collected from 8 families with a retinal dystrophy characterized by tiny, yellow-white dots on funduscopy, typical for FAP or RPA. All patients underwent full ophthalmologic examinations, including visual field assessment. Fundus photography, and electroretinography were performed in 12 patients, and optical coherence tomography and fundus autofluorescence were performed in 4 patients. DNA samples of all patients were screened for mutations in RLBP1 and for mutations in RDH5 in patients who did not carry mutations in RLBP1. DNA samples of 2 sibling pairs of nonconsanguineous families who carried mutations neither in RLBP1 nor in RDH5 were analyzed by genome-wide homozygosity mapping. Sequence analysis was performed of LRAT, a candidate gene in a shared homozygous region.We assessed DNA sequence variants, best-corrected visual acuity, fundus appearance, visual field measurements, electroretinogram responses, optical coherence tomography, and fundus autofluorescence.A homozygous frameshift mutation was identified in LRAT in 4 patients with RPA. Mutations in RLBP1 were identified in 7 patients with RPA and in 1 patient with FAP and cone dystrophy. One patient had compound heterozygous mutations in RDH5 and suffered from FAP with mild maculopathy.A genetic defect was identified in LRAT as a novel cause of RPA. LRAT is therefore the fourth gene involved in the visual cycle that may cause a white-dot retinopathy. We also revealed that mutations in RLBP1 may lead to FAP with cone dystrophy.
Prostate cancer. An overview of an increasing dilemma (1993)

Currently, it is becoming clear that the prostate gland may be the major site for medical problems in the American man. Abnormalities in prostate growth and infection in human prostate glands produce some of the most common, costly, and devastating disease occurring in men. This became apparent in the National Kidney and Urological Disease Advisory Report of 1990.' It was reported that the annual treatment in 1985 of all prostate diseases in the United States required 4.4 million physician visits per year and 836,000 admissions to hospitals with 39,215 deaths resulting, a cost in excess of $3 billion dollars per year (Table Benign prostatic hyperplasia (BPH) occurs in almost 80% of men by the age of 80 years, and it is estimated that 18 million men have evidence of this tumor, and 25% will require prostate surgery during their lives to alleviate urinary obstruction. The treatment of BPH in American men requires more than 400,000 surgical procedures each year, and in addition, many more will have symptoms of BPH. BPH-related problems make this disorder the second leading cost of Medicare reimbursement.
Aggregation Effects on Oxygen Binding of Sickle Cell Hemoglobin (1978)

Deoxygenation of concentrated solutions (0.33 gram per milliliter) of sickle cell hemoglobin show (i) a "crisis point" where the oxygen binding curve is unusually steep (Hill coefficient of 5 to 6), and (ii) a simultaneous increase in light scattering. Nearly identical oxygen binding curves are obtained upon oxygenation and deoxygenation of these solutions. The influence of aggregation is to shift the curve toward higher pressures.
Research of Chinese Continuous Digital Speech Input System Based on HTK (2012)

HTK is a speech signal processing toolkit developed by CUED based on C language.It is widely used for speech signal recognition,speech synthesis,character recognition and so on.This paper describes the process and principles of speech recognition and related concepts.Then,the basic principles and software architecture of HTK are introduced.The entire process of speech recognition task is completed with HTK.Finally,a chinese continuous speech input system was built and discuss how to select a series of acoustic unit model parameter.
Relative roles of TGF‐β1 and Wnt in the systemic regulation and aging of satellite cell responses (2009)

Muscle stem (satellite) cells are relatively resistant to cell-autonomous aging. Instead, their endogenous signaling profile and regenerative capacity is strongly influenced by the aged P-Smad3, differentiated niche, and by the aged circulation. With respect to muscle fibers, we previously established that a shift from active Notch to excessive transforming growth factor-beta (TGF-beta) induces CDK inhibitors in satellite cells, thereby interfering with productive myogenic responses. In contrast, the systemic inhibitor of muscle repair, elevated in old sera, was suggested to be Wnt. Here, we examined the age-dependent myogenic activity of sera TGF-beta1, and its potential cross-talk with systemic Wnt. We found that sera TGF-beta1 becomes elevated within aged humans and mice, while systemic Wnt remained undetectable in these species. Wnt also failed to inhibit satellite cell myogenicity, while TGF-beta1 suppressed regenerative potential in a biphasic fashion. Intriguingly, young levels of TGF-beta1 were inhibitory and young sera suppressed myogenesis if TGF-beta1 was activated. Our data suggest that platelet-derived sera TGF-beta1 levels, or endocrine TGF-beta1 levels, do not explain the age-dependent inhibition of muscle regeneration by this cytokine. In vivo, TGF-beta neutralizing antibody, or a soluble decoy, failed to reduce systemic TGF-beta1 and rescue myogenesis in old mice. However, muscle regeneration was improved by the systemic delivery of a TGF-beta receptor kinase inhibitor, which attenuated TGF-beta signaling in skeletal muscle. Summarily, these findings argue against the endocrine path of a TGF-beta1-dependent block on muscle regeneration, identify physiological modalities of age-imposed changes in TGF-beta1, and introduce new therapeutic strategies for the broad restoration of aged organ repair.
CP-violating asymmetries inB0decays toK+K−KS(L)0andKS0KS0KS(L)0 (2005)

Decay rates and time-dependent and direct $CP$ asymmetries in the decays ${B}^{0}\ensuremath{\rightarrow}{K}^{+}{K}^{\ensuremath{-}}{K}_{S(L)}$ and ${K}_{S}{K}_{S}{K}_{S(L)}$ are studied. Resonant and nonresonant contributions to the three-body decays are carefully investigated. Nonresonant effects on two-body and three-body matrix elements are constrained by QCD counting rules. The predicted branching ratios are consistent with the data within the theoretical and experimental errors, though the theoretical central values are somewhat smaller than the experimental ones. Owing to the presence of color-allowed tree amplitudes in ${B}^{0}\ensuremath{\rightarrow}{K}^{+}{K}^{\ensuremath{-}}{K}_{S(L)}$, this penguin-dominated mode may be subject to a potentially significant tree pollution and the deviation of the mixing-induced $CP$ asymmetry from that measured in $B\ensuremath{\rightarrow}J/\ensuremath{\psi}{K}_{S}$, namely, $\ensuremath{\Delta}\mathrm{sin}﻿2{\ensuremath{\beta}}_{{K}^{+}{K}^{\ensuremath{-}}{K}_{S(L)}}\ensuremath{\equiv}\mathrm{sin}﻿2{\ensuremath{\beta}}_{{K}^{+}{K}^{\ensuremath{-}}{K}_{S(L)}}\ensuremath{-}\mathrm{sin}﻿2{\ensuremath{\beta}}_{J/\ensuremath{\psi}{K}_{S}}$, can be as large as $\mathcal{O}(0.10)$. In contrast, the ${K}_{S}{K}_{S}{K}_{S(L)}$ modes appear theoretically very clean in our picture with negligible theoretical errors in $\ensuremath{\Delta}\mathrm{sin}﻿2{\ensuremath{\beta}}_{{K}_{S}{K}_{S}{K}_{S(L)}}$. Direct $CP$ asymmetries in ${K}^{+}{K}^{\ensuremath{-}}{K}_{S(L)}$ and ${K}_{S}{K}_{S}{K}_{S(L)}$ modes are found to be very small.
Multicistronic lentiviral vectors containing the FMDV 2A cleavage factor demonstrate robust expression of encoded genes at limiting MOI (2006)

The small and efficient 2A sequence can be used alone or in combination with an IRES for the construction of multicistronic lentiviral vectors which can express encoded transgenes at functionally relevant levels in cells containing an average of one pro-viral insert.
Low-complexity and high-performance soft MIMO detection based on distributed M-algorithm through trellis-diagram (2010)

This paper presents a novel low-complexity multiple-input multiple-output (MIMO) detection scheme using a distributed M-algorithm (DM) to achieve high performance soft MIMO detection. To reduce the searching complexity, we build a MIMO trellis graph and split the searching operations among different nodes, where each node will apply the M-algorithm. Instead of keeping a global candidate list as the traditional detector does, this algorithm keeps multiple small candidate lists to generate soft information. Since the DM algorithm can achieve good BER performance with a small M, the sorting cost of the DM algorithm is lower than that of the conventional K-best MIMO algorithm. The proposed algorithm is very suitable for high speed parallel processing.
Individual Microbes Shape Various Parts of the Immune System (2015)

The gastrointestinal tract, home to a vast number of bacteria, requires finely-tuned regulatory and effector immune mechanisms to maintain homeostasis and tolerance. In a large-scale screen, we studied the impacts of single microbes on major immune populations, whole intestinal tissue homeostasis and metabolism. Bacteria interacted with the host at multiple levels including cytokine responses, accumulation of various T cells, alterations in composition of mononuclear phagocytes and induction of epithelial cell genes as measured by transcriptome analysis of whole intestinal tissue. Interestingly, taxonomically unrelated bacteria elicited similar immune phenotypes and metabolic effects. A more focused analysis of the induction of regulatory mechanisms revealed a microbiota-dependent, context-specific transcriptional control of Foxp3+ regulatory T cells and of IL17 producing T cells. These facets were both regulated by Rorγ, a transcription factor known for its antagonistic effects on Foxp3. Paradoxically, Rorγ expression induced by bacteria in colonic Foxp3+ regulatory T cells was necessary for function of these cells especially in the context of IL17 and IFNγ-mediated colitis. Overall, this large-scale screen provides a comprehensive study of how individual bacterial species shape many aspects of the host immunity and metabolism, and exemplifies a microbiota-dependent, context-specific mechanism that potentiates function in Foxp3+ regulatory T cells.