gebhart/patrepeval huggingface dataset:
The P Domain of Norovirus Capsid Protein Forms a Subviral Particle That Binds to Histo-Blood Group Antigen Receptors (2005)

Norovirus is the most important cause of nonbacterial acute gastroenteritis. We have shown previously that the isolated P domain containing the hinge forms a dimer and binds to histo-blood group antigen (HBGA) receptors with a low affinity (M. Tan, R. S. Hegde, and X. Jiang, J. Virol. 78:6233-6242, 2004). Here, we reported that the P domain of VA387 without the hinge forms a small particle with a significantly increased receptor binding affinity. An end-linked oligopeptide containing one or more cysteines promoted P-particle formation by forming intermolecular disulfide bridges. The binding sensitivity of the P particle to HBGAs was enhanced >700-fold compared to the P dimer, which was comparable to that of virus-like particles. The binding specificity of the P particle was further confirmed by strong binding to the Caco-2 cells, a human colon carcinoma cell line. This binding enhancement was observed in the P particles of both norovirus GI and GII strains. The P particle is estimated to contain 12 P dimers, in which the P2 subdomain builds up the outer layer, while the P1 subdomain forms the internal core. Taken together, our data indicate that the P domain is involved not only in dimerization but also in polymerization of the protein during the capsid assembling. The enhanced receptor binding of the P particle reflects the intrinsic feature of the viral capsid. The easy production of the P particle and its strong binding to HBGAs suggest that the P particle is useful in studying pathogenesis and morphogenesis of norovirus and candidates for antiviral or vaccine development.
Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy (2013)

Rational combinatorial therapeutic strategies have proven beneficial for the management of cancer. Recent success of checkpoint blockade in highly immunogenic tumors has renewed interest in immunotherapy. Regulatory T (T reg) cells densely populate solid tumors, which may promote progression through suppressing anti-tumor immune responses. We investigated the role of T reg cells in murine mammary carcinogenesis using an orthotopic, polyoma middle-T antigen-driven model in Foxp3(DTR) knockin mice. T reg cell ablation resulted in significant determent of primary and metastatic tumor progression. Importantly, short-term ablation of T reg cells in advanced spontaneous tumors led to extensive apoptotic tumor cell death. This anti-tumor activity was dependent on IFN-γ and CD4(+) T cells but not on NK or CD8(+) T cells. Combination of T reg cell ablation with CTLA-4 or PD-1/PD-L1 blockade did not affect tumor growth or improve the therapeutic effect attained by T reg cell ablation alone. However, T reg cell targeting jointly with tumor irradiation significantly reduced tumor burden and improved overall survival. Together, our results demonstrate a major tumor-promoting role of T reg cells in an autochthonous model of tumorigenesis, and they reveal the potential therapeutic value of combining transient T reg cell ablation with radiotherapy for the management of poorly immunogenic, aggressive malignancies.
Distinct Regulation of Internal Ribosome Entry Site-mediated Translation following Cellular Stress Is Mediated by Apoptotic Fragments of eIF4G Translation Initiation Factor Family Members eIF4GI and p97/DAP5/NAT1 (2003)

Many cellular stresses lead to the inhibition of protein synthesis. Despite this, some cellular mRNAs are selectively translated under these conditions. It was suggested that the presence of internal ribosome entry site (IRES) sequences in the 5'-untranslated regions allow these mRNAs to be actively translated despite the overall cessation of protein synthesis. Here we tested the hypothesis that the IRES elements of genes that are involved in the control of cell survival are distinctly regulated by cellular stresses. We show that the transient conditions of cellular stress favor the translation of pro-survival IRES, while the severe apoptotic conditions support translation of pro-death IRES elements. Furthermore, activation of pro-death IRES during the etoposide-induced apoptosis is caspase-dependent and correlates with the expression of apoptotic fragments of two members of the eIF4G translation initiation factor family, p97/DAP5/NAT1 and eIF4GI. Our results suggest that the regulation of IRES translation during stress contributes to the fine-tuning of cell fate.
The Inositol Polyphosphate 5-Phosphatase Ship Is a Crucial Negative Regulator of B Cell Antigen Receptor Signaling (1998)

Ship is an Src homology 2 domain containing inositol polyphosphate 5-phosphatase which has been implicated as an important signaling molecule in hematopoietic cells. In B cells, Ship becomes associated with Fcgamma receptor IIB (FcgammaRIIB), a low affinity receptor for the Fc portion of immunoglobulin (Ig)G, and is rapidly tyrosine phosphorylated upon B cell antigen receptor (BCR)-FcgammaRIIB coligation. The function of Ship in lymphocytes was investigated in Ship-/- recombination-activating gene (Rag)-/- chimeric mice generated from gene-targeted Ship-/- embryonic stem cells. Ship-/-Rag-/- chimeras showed reduced numbers of B cells and an overall increase in basal serum Ig. Ship-/- splenic B cells displayed prolonged Ca2+ influx, increased proliferation in vitro, and enhanced mitogen-activated protein kinase (MAPK) activation in response to BCR-FcgammaRIIB coligation. These results demonstrate that Ship plays an essential role in FcgammaRIIB-mediated inhibition of BCR signaling, and that Ship is a crucial negative regulator of Ca2+ flux and MAPK activation.
An optimal state estimation model of sensory integration in human postural balance (2005)

We propose a model for human postural balance, combining state feedback control with optimal state estimation. State estimation uses an internal model of body and sensor dynamics to process sensor information and determine body orientation. Three sensory modalities are modeled: joint proprioception, vestibular organs in the inner ear, and vision. These are mated with a two degree-of-freedom model of body dynamics in the sagittal plane. Linear quadratic optimal control is used to design state feedback and estimation gains. Nine free parameters define the control objective and the signal-to-noise ratios of the sensors. The model predicts statistical properties of human sway in terms of covariance of ankle and hip motion. These predictions are compared with normal human responses to alterations in sensory conditions. With a single parameter set, the model successfully reproduces the general nature of postural motion as a function of sensory environment. Parameter variations reveal that the model is highly robust under normal sensory conditions, but not when two or more sensors are inaccurate. This behavior is similar to that of normal human subjects. We propose that age-related sensory changes may be modeled with decreased signal-to-noise ratios, and compare the model's behavior with degraded sensors against experimental measurements from older adults. We also examine removal of the model's vestibular sense, which leads to instability similar to that observed in bilateral vestibular loss subjects. The model may be useful for predicting which sensors are most critical for balance, and how much they can deteriorate before posture becomes unstable.
Fabrication of porous silicon by metal-assisted etching using highly ordered gold nanoparticle arrays (2012)

A simple method for the fabrication of porous silicon (Si) by metal-assisted etching was developed using gold nanoparticles as catalytic sites. The etching masks were prepared by spin-coating of colloidal gold nanoparticles onto Si. An appropriate functionalization of the gold nanoparticle surface prior to the deposition step enabled the formation of quasi-hexagonally ordered arrays by self-assembly which were translated into an array of pores by subsequent etching in HF solution containing H2O2. The quality of the pattern transfer depended on the chosen preparation conditions for the gold nanoparticle etching mask. The influence of the Si surface properties was investigated by using either hydrophilic or hydrophobic Si substrates resulting from piranha solution or HF treatment, respectively. The polymer-coated gold nanoparticles had to be thermally treated in order to provide a direct contact at the metal/Si interface which is required for the following metal-assisted etching. Plasma treatment as well as flame annealing was successfully applied. The best results were obtained for Si substrates which were flame annealed in order to remove the polymer matrix - independent of the substrate surface properties prior to spin-coating (hydrophilic or hydrophobic). The presented method opens up new resources for the fabrication of porous silicon by metal-assisted etching. Here, a vast variety of metal nanoparticles accessible by well-established wet-chemical synthesis can be employed for the fabrication of the etching masks.
Breast carcinoma in young women previously treated for Hodgkin disease. (1990)

The increased risk of a second malignant neoplasm developing after treatment for Hodgkin disease is well documented. Subsequent development of breast cancer in women who have been treated for Hodgkin disease is a relatively rare association. To date, no reports of the mammographic detection of breast cancer in this group of women have been published. We report six patients who developed seven breast cancers after treatment for Hodgkin disease. The average age of the women at the time of diagnosis of breast cancer was 33.5 years; diagnosis was made 10-23 years after treatment. There appears to be an increased prevalence of breast carcinoma in women who have been treated for Hodgkin disease. This association should receive further study to evaluate appropriate modifications in routine breast cancer screening for these women.
ARE CONSUMERS READY FOR FEE-BASED ONLINE SERVICES? (2003)

Many online service businesses are beginning to charge fees for services that they used to provide for free.It is unclear whether consumers are ready to embrace this practice.This study explores the critical issue of consumer attitudes toward fee-based online services.The results of the study indicate that consumers' willingness to pay for online services is likely to be influenced by their perceived value of convenience these services provide, as well as by the extent to which they utilize these services.While the study finds that consumers are more willing to pay for services that are qualitatively better than free services, there is also indication that the belief remains strong among many that online services that were free in the past should remain free.The findings of this study will contribute to the formulation and implementation of sustainable business models for e-businesses in the service sector.
Confronting an Upsurge in Opiate Deaths with Limited Resources (2017)

The dramatic increase in drug-related deaths in the last decade has presented fiduciary and logistical difficulties to medicolegal jurisdictions of all types and sizes. New Hampshire, with a centralized state medical examiner system of death investigation, has been confronted with the task of investigating these drug-related deaths against the backdrop of statutory hurdles inhibiting a nimble response to the situation. This has led to a collaborative approach with law enforcement and the state Department of Justice in terms of triaging drug deaths to full autopsy versus external examination with toxicology testing. Preliminary data suggest that between 11 and 13% of suspected drug deaths have an alternative cause of death revealed by autopsy. Positive toxicological findings were documented in 97.5% of cases in which only an external examination was performed; however, some of these cases may have had undetected, significant internal findings that could have accounted for an alternative cause of death if an autopsy had been performed. While the case triage system described has temporarily addressed the acute problem, the issue of the medical examiner's appropriate role in the adequate evaluation of public health and safety remains extant. Furthermore, noncompliance with the National Association of Medical Examiners inspection and accreditation standards puts this agency, and others facing the same issues, at risk of losing full accreditation status until such resource issues are addressed by legislators and other stakeholders in the quality of medicolegal death investigation in the United States.
Autism and Familial Major Mood Disorder: Are They Related? (2004)

Family history studies of autism consistently reveal a large subgroup with a high incidence of major mood disorder in family members, suggesting the two entities are related clinically and genetically. This review examines this concept, comparing current clinlical and biological knowledge of autism and major mood disorder, and advances the hypothesis that this subgroup of autism represents an early-life phenotype of major mood disorder. If confirmed, this hypothesis would suggest that the basic biological defects determining major mood disorders may have prominent neurodevelopmental and cognitive dimensions. Testing of the hypothesis will depend on genetic studies.
Enzyme Mechanism from Isotope Effects (1991)

THEORETICAL BASIS FOR ISOTOPE EFFECTS. Theoretical Basis for Primary and Secondary Hydrogen Isotope Effects. Origins and Interpretations of Heavy-Atom Isotope Effects. Theoretical Basis and Mechanistic Utility of Solvent Isotope Effects. Hydrogen Tunneling and Coupled Motion in Enzyme Reactions. ISOTOPE EFFECTS IN ENZYME-CATALYZED REACTIONS. Isotope Effects on the Transient Kinetics of Enzyme Reactions. Instrinsic Isotope Effects in Enzyme-Catalyzed Reactions. Kinetic and Regulatory Mechanisms of Enzymes from Isotope Effects. pH Dependence of Isotope Effects in Enzyme-Catalyzed Reactions. Multiple Isotope Effects in Enzyme-Catalyzed Reactions. METHODS FOR THE DETERMINATION OF ISOTOPE EFFECTS (LIMITED APPLICATIONS). Methods for the Determination of Competitive and Noncompetitive Kinetic Isotope Effects. Heavy Atom Isotope Effects Using the Isotope Ratio Mass Spectrometer. Use of the Stable Isotope Remote Label Technique to Determine Isotope Effects in Enzyme-Catalyzed Reactions. Measuring the Gram-Atom Percent of Deuterium in Heavy Water by Absorption Spectroscopy. ISOTOPE EFFECTS IN SPECIFIC ENZYMIC REACTIONS. Isotope Effects on Enzyme-Catalyzed Redox Reactions. Kinetic Isotope Effects for Hydrolase Reactions. Isotope Effects on Enzyme Catalyzed b-Eliminations. Isotope Effects in Enzyme-Catalyzed Group Transfer Reactions. Triosephosphate Isomerase and Proline Racemase: Revelation of Reaction Energetics. Isotope Effects in Reactions Catalyzed by Thymidylate Synthase.
SIGNIFICANT PROGRESS IN PORCINE ISLET MASS ISOLATION UTILIZING LIBERASE HI FOR ENZYMATIC LOW-TEMPERATURE PANCREAS DIGESTION1 (1999)

Background. Frequent success in human islet isolation is prevented by the large variability of scarce organ donors; this favors the future utilization of pigs as donors for clinical islet xenotransplantation. Porcine-specific difficulties of islet isolation are attributed to the intrinsic fragility of islets during pancreas digestion. Methods. To preserve islet integrity during efficient pancreas dissociation, porcine pancreata (n=48) were distended after cold storage with cold University of Wisconsin solution containing Liberase HI and digested at 24-28°C using digestion-filtration. Pancreata distended with University of Wisconsin solution containing well-proven crude collagenase and digested at 32-34°C served as controls (n=46). Monolayer Ficolldiatrizoate gradient purification was performed in a Cobe 2991. Results. Purified yield of islet equivalents per pancreas (mean ± SEM) was almost doubled by Liberase HI compared with crude collagenase (526,480±46,560 vs. 270,270±19,420; P<0.0001) and also significantly increased comparing islet equivalents per gram of pancreas (4,210±320 vs. 2,640±245; P=0.0004). Islet integrity was better preserved during Liberase HI digestion compared with crude collagenase digestion as indicated by isolation index (2.1±0.1 vs. 1.4±0.1; P<0.0001). Purity, viability, and in vitro function of islets did not differ between experimental groups. Preserved in vivo function of islets isolated by Liberase HI was demonstrated after subcapsular transplantation into 16 diabetic nude rats. Conclusions. If the problems related to xenograft rejection and xenosis could be solved, low-temperature digestion of porcine pancreata using Liberase HI could serve as an essential prerequisite for successful 1:1 xenotransplantation of pig islets into type 1 diabetic human recipients.
Tight Integration of Spatial and Spectral Features for BSS with Deep Clustering Embeddings (2017)

Recent advances in discriminatively trained mask estimation networks to extract a single source utilizing beamforming techniques demonstrate, that the integration of statistical models and deep neural networks (DNNs) are a promising approach for robust automatic speech recognition (ASR) applications. In this contribution we demonstrate how discriminatively trained embeddings on spectral features can be tightly integrated into statistical model-based source separation to separate and transcribe overlapping speech. Good generalization to unseen spatial configurations is achieved by estimating a statistical model at test time, while still leveraging discriminative training of deep clustering embeddings on a separate training set. We formulate an expectation maximization (EM) algorithm which jointly estimates a model for deep clustering embeddings and complex-valued spatial observations in the short time Fourier transform (STFT) domain at test time. Extensive simulations confirm, that the integrated model outperforms (a) a deep clustering model with a subsequent beamforming step and (b) an EM-based model with a beamforming step alone in terms of signal to distortion ratio (SDR) and perceptually motivated metric (PESQ) gains. ASR results on a reverberated dataset further show, that the aforementioned gains translate to reduced word error rates (WERs) even in reverberant environments.
Anti sense DNA down-regulates proteins kinase C-epsilon and enhances vasopressin-stimulated Na+ absorption in rabbit cortical collecting duct. (1995)

Hormonal activation of protein kinase C (PKC) is a major signaling mechanism regulating salt and water transport in the distal nephron. We used antisense DNA to down-regulate a PKC isoform in the rabbit cortical collecting duct (CCD) and examined its role in mediating arginine vasopressin's (AVP) effect on salt transport in the CCD. Immunoblots demonstrate that PKC-epsilon (diacylglycerol sensitive) and PKC-zeta (diacylglycerol insensitive) are the major PKC isoforms in both freshly isolated and primary cultures of rabbit CCDs. Rabbit CCDs grown on semi-permeable supports, displayed a positive baseline short circuit current (Isc), which was abolished by amiloride, demonstrating active Na+ absorption. Both AVP and 8-chloro-phenylthio-cAMP (8CPTcAMP) transiently increased Isc, however, within 40 min Isc fell below baseline. Down-regulation of PKC-epsilon, as confirmed by immunoblot, was achieved either by treatment with a PKC-epsilon-specific antisense oligonucleotide or 48 h of 1 microM PMA. In PKC-epsilon down-regulated cells, 8CPTcAMP produced a sustained, rather than transient, increase in Isc. We suggest cAMP stimulates Na+ transport, but secondary activation of PKC-epsilon results in the sustained inhibition of Na+ transport seen in response to vasopressin in the CCD.
The olfactory receptor universe--from whole genome analysis to structure and evolution. (2004)

Olfactory receptors (ORs) constitute the largest gene-family in the vertebrate genome. We have attempted to provide a comprehensive view of the OR universe through diverse tools of bioinformatics and computational biology. Among others, we have constructed the Human Olfactory Receptor Data Exploratorium (HORDE, http://bioportal.weizmann.ac.il/HORDE/) as a free online resource, which integrates information on ORs from different species. We studied the genomic organization of 853 human ORs and divided the repertoire into 135 clusters, accessible through our new cluster viewer feature. An analysis of intact and pseudogenized ORs in different clusters, as well as of OR expression patterns, is provided, relevant to OR transcription control. Coding single nucleotide polymorphisms were integrated; these are to be used for genotype-phenotype correlation studies. HORDE allows a unique opportunity for discerning protein structural and functional information of the individual OR proteins. By applying novel data analysis strategies to the >3000 OR genes of mouse, dog and human within HORDE, we have generated a set of refined rhodopsin-based homology models for ORs. For model improvement, we employed a novel analysis of specific positions along the seven transmembrane helices at which prolines generate helix-breaking kinks. The model shows family-specific structural features, including idiosyncratic kink patterns, which lead to significant differences in the inferred odorant binding site structure. Such analyses form a basis for a comprehensive sequence-based classification of OR proteins in terms of potential odorant binding specificities.
Efficiency of the Hybrid Capture 2 HPV DNA Test in Cervical Cancer Screening (2003)

The aim of this study was to determine the efficiency of the Hybrid Capture 2 (HC2; Digene, Gaithersburg, MD) human papillomavirus (HPV) assay for the detection of cervical neoplasia.
U-Net: Convolutional Networks for Biomedical Image Segmentation (2015)

There is large consent that successful training of deep networks requires many thousand annotated training samples. In this paper, we present a network and training strategy that relies on the strong use of data augmentation to use the available annotated samples more efficiently. The architecture consists of a contracting path to capture context and a symmetric expanding path that enables precise localization. We show that such a network can be trained end-to-end from very few images and outperforms the prior best method (a sliding-window convolutional network) on the ISBI challenge for segmentation of neuronal structures in electron microscopic stacks. Using the same network trained on transmitted light microscopy images (phase contrast and DIC) we won the ISBI cell tracking challenge 2015 in these categories by a large margin. Moreover, the network is fast. Segmentation of a 512x512 image takes less than a second on a recent GPU. The full implementation (based on Caffe) and the trained networks are available at http://lmb.informatik.uni-freiburg.de/people/ronneber/u-net .