gebhart/patrepeval huggingface dataset:
TDP-43 Proteinopathy in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis (2007)

Herein, we review advances in understanding a group of disorders collectively known as TAR-DNA binding protein 43 (TDP-43) proteinopathies since the report that TDP-43 is the major disease protein that mechanistically links frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) with and without motor neuron disease to amyotrophic lateral sclerosis. Because TDP-43 proteinopathy underlies sporadic and familial forms of FTLD-U and amyotrophic lateral sclerosis, they may share similar mechanisms linked to the abnormal hyperphosphorylation, ubiquitination, and cleavage of pathologic TDP-43 to generate C-terminal fragments in brain and spinal cord affected with FTLD-U and amyotrophic lateral sclerosis. TDP-43 proteinopathies are distinct from most other neurodegenerative disorders in which protein misfolding leads to brain amyloidosis, as pathologic TDP-43 forms neuronal and glial inclusions lacking the features of brain amyloid deposits. We discuss the implications of these distinct aspects of TDP-43 proteinopathies for developing better diagnostics and therapeutics for FTLD-U and amyotrophic lateral sclerosis.
Accelerating SIFT on parallel architectures (2009)

SIFT is a widely-used algorithm that extracts features from images; using it to extract information from hundreds of terabytes of aerial and satellite photographs requires parallelization in order to be feasible. We explore accelerating an existing serial SIFT implementation with OpenMP parallelization and GPU execution.
Matrix metalloproteinases in scarless wound healing (2011)

Objectives: Wound healing in skin often results in scar formation, whereas wound healing in oral palatal mucosa is fast and rarely results in scarring. Understanding the mechanisms that promote oral scarless wound healing may provide novel approaches to prevent scar formation in skin. The goal of the study was to compare the abundance of the major collagenases MMP-1 and MMP-13 and gelatinases MMP-2 and MMP-9 in normal unwounded oral mucosa and skin and in experimental excisional wounds in skin (healing results to scar formation) and oral mucosa (wounds heal with minimal scar formation) at various time points post-wounding at the protein level. We hypothesized that the abundance of MMPs will be higher in scarless oral mucosal wound healing, compared to skin wound healing. Methods: Experimental wounds were created in oral palatal mucosa and dorsal skin of red Duroc pigs. Wound biopsies were collected before wounding and at various time points after wounding. The abundance of MMPs at the protein level was assessed by Western blotting and zymography. Results: All studied MMPs showed a significantly increased accumulation in the wound tissue already at day three post-wounding. Their abundance remained high until day 28 when MMP-9 and MMP-13 returned to the level of unwounded tissue, while MMP-1 and MMP-2 remained significantly elevated. Oral mucosal wounds showed in general a robust early up-regulation of MMP-1, MMP-2 and MMP-9 as compared to skin wounds already at day 3 after wounding. In contrast, the peak abundance of these MMPs occurred at day 14 in skin wounds. Unwounded oral mucosa showed significantly higher abundance of total MMP-2 and active MMP-9 as compared to unwounded skin. Thus, MMPs needed for early wound healing response are already present in higher abundance in oral mucosa as compared to skin before tissue injury possibly allowing a fast wound healing response. Conclusions: Results suggest that oral mucosal wound healing is associated with fast and robust regulation of MMPs. Rapid controlled processing of wound extracellular matrix may play a key role in scarless palatal wound healing. In addition, MMPs may regulate inflammatory reaction that plays a central role in scar formation.
Contextual Anomaly Detection in Big Sensor Data (2014)

Performing predictive modelling, such as anomaly detection, in Big Data is a difficult task. This problem is compounded as more and more sources of Big Data are generated from environmental sensors, logging applications, and the Internet of Things. Further, most current techniques for anomaly detection only consider the content of the data source, i.e. the data itself, without concern for the context of the data. As data becomes more complex it is increasingly important to bias anomaly detection techniques for the context, whether it is spatial, temporal, or semantic. The work proposed in this paper outlines a contextual anomaly detection technique for use in streaming sensor networks. The technique uses a well-defined content anomaly detection algorithm for real-time point anomaly detection. Additionally, we present a post-processing context-aware anomaly detection algorithm based on sensor profiles, which are groups of contextually similar sensors generated by a multivariate clustering algorithm. Our proposed research has been implemented and evaluated with real-world data provided by Powersmiths, located in Brampton, Ontario, Canada.
Food Hypersensitivity and Dietary Management in Atopic Dermatitis (1992)

Although immune dysfunction is known to play an integral role in the development of atopic dermatitis, no clear delineation of the underlying pathogenic mechanism(s) responsible for this disorder has been proposed. Several factors are known to trigger flares of atopic dermatitis. In the extrinsic form of this disorder, food and airborne allergens may provoke flares of eczema. Research implicating food hypersensitivity in the pathogenesis of atopic dermatitis includes studies of food allergen avoidance in newborn infants at high risk for atopic disease, investigations of children with blinded food challenges, and therapeutic trials of allergen-elimination diets. Taken together, these studies demonstrate a significant pathogenic role for food hypersensitivity in about one-third of children with atopic dermatitis.
Effect of a diazaborine derivative (Sa 84.474) on the virulence of Escherichia coli (1987)

The scope of selective inhibition of lipopolysaccharide (LPS) biosynthesis in virulent organisms with a diazaborine derivative (Sa 84.474) as a means to render them avirulent was explored. A serum resistant Escherichia coli 0111:B4 became serum sensitive following its cultivation in vitro in media containing 1.5 mg/l of Sa 84.474, a concentration shown previously to inhibit over 95% of normal LPS biosynthesis in its mutant J5 strain. An encapsulated E. coli 01:K1 was also converted to serum sensitivity. In addition, Sa 84.474-pretreatment increased the efficiency with which the previously resistant organisms were opsonized in normal human serum and subsequently phagocytosed by granulocytes. In vivo, intravenously inoculated, Sa 84.474-pretreated bacteria were rapidly removed from the blood circulation and were significantly (P less than 0.05) less virulent in inducing lethal peritoneal infections in mice (LD50 4.9 +/- 1 X 10(6) cfu) when compared to untreated control bacteria (LD50 2.2 +/- 0.97 X 10(6) cfu). The results suggest that the LPS plays an important role in the virulence of the two bacterial strains and imply that agents acting in a similar manner but with acceptable selective toxicity might be novel drugs for therapy of Gram-negative bacterial infections.
Purification and Properties of Aldehyde Dehydrogenase from Saccharomyces cerevisiae (1977)

A procedure for the purification of aldehyde dehydrogenase from bakers' yeast (Saccharomyces cerevisiae) is reported. Treatment with acid, heat and organic solvents was avoided and chromatographic and filtration techniques in the presence of phenylmethylsulfonylfluoride were mainly used. An affinity chromatography step using the reactive dye Cibacron blue F3G-A, which was covalently bound to Sepharose 4B, was found to be essential. The enzyme was bound to and then released from the dye. The purified enzyme was shown to be homogeneous by gel filtration, disc electrophoresis and SDS electrophoresis. The molecular weight of the purified enzyme determined by gel filtration was 170,000, which agreed with that of the enzyme in the crude extract. The enzyme was composed of subunits of a molecular weight of 57,000. The specific activity of the enzyme was 20 units per mg of protein under the standard assay conditions. The substrate specificity, the relative maximal velocity, the michaelis constants, the pH optimum, the stability and the activation energy of the enzyme are reported.
Assessment of Ki67 in Breast Cancer: Recommendations from the International Ki67 in Breast Cancer Working Group (2011)

Ki67 immunohistochemistry (IHC), commonly used as a proliferation marker in breast cancer, has limited value for treatment decisions due to questionable analytical validity. The International Ki67 in Breast Cancer Working Group (IKWG) consensus meeting, held in October 2019, assessed the current evidence for Ki67 IHC analytical validity and clinical utility in breast cancer, including the series of scoring studies the IKWG conducted on centrally stained tissues. Consensus observations and recommendations are: 1) as for estrogen receptor and HER2 testing, preanalytical handling considerations are critical; 2) a standardized visual scoring method has been established and is recommended for adoption; 3) participation in and evaluation of quality assurance and quality control programs is recommended to maintain analytical validity; and 4) the IKWG accepted that Ki67 IHC as a prognostic marker in breast cancer has clinical validity but concluded that clinical utility is evident only for prognosis estimation in anatomically favorable estrogen receptor-positive and HER2-negative patients to identify those who do not need adjuvant chemotherapy. In this T1-2, N0-1 patient group, the IKWG consensus is that Ki67 5% or less, or 30% or more, can be used to estimate prognosis. In conclusion, analytical validity of Ki67 IHC can be reached with careful attention to preanalytical issues and calibrated standardized visual scoring. Currently, clinical utility of Ki67 IHC in breast cancer care remains limited to prognosis assessment in stage I or II breast cancer. Further development of automated scoring might help to overcome some current limitations.
Crosslinkable Hydrogels Derived from Cartilage, Meniscus, and Tendon Tissue (2015)

Decellularized tissues have proven to be versatile matrices for the engineering of tissues and organs. These matrices usually consist of collagens, matrix-specific proteins, and a set of largely undefined growth factors and signaling molecules. Although several decellularized tissues have found their way to clinical applications, their use in the engineering of cartilage tissue has only been explored to a limited extent. We set out to generate hydrogels from several tissue-derived matrices, as hydrogels are the current preferred cell carriers for cartilage repair. Equine cartilage, meniscus, and tendon tissue was harvested, decellularized, enzymatically digested, and functionalized with methacrylamide groups. After photo-cross-linking, these tissue digests were mechanically characterized. Next, gelatin methacrylamide (GelMA) hydrogel was functionalized with these methacrylated tissue digests. Equine chondrocytes and mesenchymal stromal cells (MSCs) (both from three donors) were encapsulated and cultured in vitro up to 6 weeks. Gene expression (COL1A1, COL2A1, ACAN, MMP-3, MMP-13, and MMP-14), cartilage-specific matrix formation, and hydrogel stiffness were analyzed after culture. The cartilage, meniscus, and tendon digests were successfully photo-cross-linked into hydrogels. The addition of the tissue-derived matrices to GelMA affected chondrogenic differentiation of MSCs, although no consequent improvement was demonstrated. For chondrocytes, the tissue-derived matrix gels performed worse compared to GelMA alone. This work demonstrates for the first time that native tissues can be processed into crosslinkable hydrogels for the engineering of tissues. Moreover, the differentiation of encapsulated cells can be influenced in these stable, decellularized matrix hydrogels.
Marked prevention of tumor growth and metastasis by a novel immunosuppressive agent, FTY720, in mouse breast cancer models. (2002)

FTY720 is a unique immunosuppressive agent that exerts its activity by inducing apoptosis in lymphocytes. We conducted the present study to investigate the effects of FTY720 on cancer growth and metastasis, as well as its mechanism of action. In vitro treatment with FTY720 induced dramatic cancer cell apoptosis in a mouse breast cancer cell line, JygMC(A). Electron microscopy revealed distinct changes on the cell surface with decreased filopodias and microvilli in cancer cells treated with FTY720 at 2 microM and clear evidence of apoptosis at 10 microM. Interestingly, the effect of FTY720 was significantly less in the normal fibroblasts than in the cancer cells, indicating greater susceptibility of cancer cells to the agent. We then tested the in vivo effect of FTY720 in a mouse breast cancer model created by inoculating JygMC(A) cells (s.c.) in the flank region of BALB/c-nu/nu mice at three different dosages (2, 5, and 10 mg/kg/day; n = 30/group). Tumor growth was markedly suppressed at a dosage of 5 mg/kg or more without notable side effects. In addition, tumor metastasis, which was dramatically evident in control mice, was significantly prevented even at a low dose (2 mg/kg/day), resulting in a significant prolongation of animal survival. These data led us to additionally investigate the mechanism of action, especially the prevention of metastasis at a low dose. FTY720 treatment at 2 microM caused a remarkable cytoskeletal change with deformed and decreased filopodias in cancer cells. In addition, it significantly decreased the ability of cancer cells to adhere and migrate to extracellular matrix components, and markedly reduced the expression of integrins on the cancer cell surface. These results indicate that FTY720 is a potent anticancer agent that induces cancer cell apoptosis and is markedly effective for prevention of metastasis. The changes of cellular structure with reduction of integrin expression may be one of its underlying mechanisms of action.
The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages (2005)

Biglycan, a small leucine-rich proteoglycan, is a ubiquitous ECM component; however, its biological role has not been elucidated in detail. Here we show that biglycan acts in macrophages as an endogenous ligand of TLR4 and TLR2, which mediate innate immunity, leading to rapid activation of p38, ERK, and NF-kappaB and thereby stimulating the expression of TNF-alpha and macrophage inflammatory protein-2 (MIP-2). In agreement, the stimulatory effects of biglycan are significantly reduced in TLR4-mutant (TLR4-M), TLR2-/-, and myeloid differentiation factor 88-/- (MyD88-/-) macrophages and completely abolished in TLR2-/-/TLR4-M macrophages. Biglycan-null mice have a considerable survival benefit in LPS- or zymosan-induced sepsis due to lower levels of circulating TNF-alpha and reduced infiltration of mononuclear cells in the lung, which cause less end-organ damage. Importantly, when stimulated by LPS-induced proinflammatory factors, macrophages themselves are able to synthesize biglycan. Thus, biglycan, upon release from the ECM or from macrophages, can boost inflammation by signaling through TLR4 and TLR2, thereby enhancing the synthesis of TNF-alpha and MIP-2. Our results provide evidence for what is, to our knowledge, a novel role of the matrix component biglycan as a signaling molecule and a crucial proinflammatory factor. These findings are potentially relevant for the development of new strategies in the treatment of sepsis.
Rapid Monitoring of Site-Specific Glycosylation Microheterogeneity of Recombinant Human Interferon-γ (1996)

An analytical system is presented for rapid assessment of site-specific microheterogeneity of the two potential N-linked glycosylation sites of recombinant human interferon-gamma (IFN-gamma) derived from Chinese hamster ovary cell culture. The target protein is first purified from culture supernatant by immunoaffinity chromatography, and the acidic eluent is neutralized via an in-line mixing tee. On-line proteolysis is rapidly performed by an immobilized trypsin cartridge, and reversed-phase chromatography isolates the two pools of glycopeptides representing the potential glycosylation sites. Following off-line analysis by matrix-assisted laser-desorption ionization/time-of-flight (MALDI/TOF) mass spectrometry, observed mass shifts of glycopeptides relative to the known masses of their amino acid portions are correlated to site-specific oligosaccharide structures. Desialylation of glycopeptides by sialidase treatment on the MALDI sample plate allows for quantitative estimations of asialoglycan structures by MALDI/TOF. This methodology permits glycoprotein microheterogeneity to be evaluated in a time frame of approximately 2 h, utilizing as little as 0.5 microgram (25 pmol) of product. Results of monitoring a batch culture are presented as well as analysis of a culture containing deoxymannojirimycin, an inhibitor of glycoprotein processing.
Osteoarthritis of the Knee (2006)

A 66-year-old woman who is overweight reports bilateral knee pain of gradual onset during the past several months that increasingly has limited her activities. Last week, when walking down the stairs, she nearly fell when her knee gave way. She does not recall having injured her knee, and she has no morning stiffness and no pain in other joints. She has tried taking up to eight extra-strength (500 mg each) acetaminophen tablets daily without success and has never had ulcers or stomach bleeding. How should the patient be evaluated and treated?
Generation of arbitrary intensity profiles by dynamic jaws or multileaf collimators (1994)

An algorithm, which calculates the motions of the collimator jaws required to generate a given arbitrary intensity profile, is presented. The intensity profile is assumed to be piecewise linear, i.e., to consist of segments of straight lines. The jaws move unidirectionally and continuously with variable speed during radiation delivery. During each segment, at least one of the jaws is set to move at the maximum permissible speed. The algorithm is equally applicable for multileaf collimators (MLC), where the transmission through the collimator leaves is taken into account. Examples are presented for different intensity profiles with varying degrees of complexity. Typically, the calculation takes less than 10 ms on a VAX 8550 computer.
Enantioselective, Palladium-Catalyzed α-Arylation of N-Boc-pyrrolidine (2006)

This communication discloses the first instance of the enantioselective Pd-catalyzed alpha-arylation of N-Boc-pyrrolidine. The methodology relies on Beak's sparteine-mediated, enantioselective deprotonation of N-Boc-pyrrolidine to form the 2-pyrrolidinolithium specices in high enantiomeric ratio (er). Transmetalation of this intermediate with zinc chloride generates the stereochemically rigid, 2-pyrrolidinozinc reagent, which was readily coupled to a variety of functionalized aryl halides at room temperature using a catalyst generated from Pd(OAc)2 and PtBu3-HBF4. A diverse array of 2-aryl-N-Boc-pyrrolidines was synthesized using this methodology, providing adducts consistently in a 96:4 er. A survey of the stoichiometry revealed that as little as 0.3 equiv of zinc could be used in the coupling reaction, and the 2-pyrrolidinozinc reagent was found to exhibit stereochemical stability up to 60 degrees C. The method allows for the most convergent and reliable preparation of a broad range of functionalized 2-aryl-N-Boc-pyrrolidines in high enantioselectivity, which is highlighted in this report by the enantioselective synthesis of (R)-nicotine.
Correction of Murine Hemophilia A and Immunological Differences of Factor VIII Variants Delivered by Helper-dependent Adenoviral Vectors (2007)

Bioengineering of the factor VIII (FVIII) molecule has led to the production of variants that overcome poor secretion and/or rapid inactivation. We tested six modified FVIII variants for in vivo efficacy by expressing them from helper-dependent adenoviral (HD-Ad) vectors. We constructed a wild-type (WT) variant, a B-domain-deleted (BDD) variant, a point mutant for improved secretion (F309S), a variant with a partial B-domain deletion for improved secretion (N6), a combination of the point mutant and partial BDD variant (F309N6), and an inactivation-resistant (IR8) FVIII variant. All the constructs expressed functional protein after injection of high-dose HD-Ad. Activity ranged from 20 to 50% with WT, to approximately 100% with the N6 and F309N6 variants. Interestingly, mice treated with N6 showed long-term FVIII activity and phenotypic correction for up to 74 weeks, with low anti-FVIII antibody titer. Importantly, the N6 variant was therapeutically efficacious even after a 50% reduction of viral dose, thereby indicating that transgene modification itself can improve the dose efficacy of HD-Ad. This finding is significant, because dose efficacy is a key factor in clinical application. In summary, bioengineering of the FVIII molecule may be an effective approach to improving the safety, immunogenicity, and efficacy of HD-Ad gene therapy in hemophilia A (HA).
The role of osteopontin in tumorigenesis and metastasis. (1997)

Osteopontin (OPN) is a calcium-binding phosphoprotein which is believed to play a role in several different and apparently distinct cellular processes. Recently, expression of OPN has been linked to tumorigenesis and metastasis in several experimental animal models and human patient studies. Precisely what role OPN plays in these processes is far from clear. OPN is known to importantly contribute to cell adhesion interactions, possibly mediated by the highly conserved GRGDS amino acid sequence, a motif found on a number of proteins which play a role in cell adhesion. In addition, OPN has binding affinity for several different cellular receptors, potentially allowing it to stimulate various signaling pathways and influence distinct cellular events which may ultimately favor tumorigenesis or metastasis.
A design and verification methodology for secure isolated regions (2016)

Hardware support for isolated execution (such as Intel SGX) enables development of applications that keep their code and data confidential even while running in a hostile or compromised host. However, automatically verifying that such applications satisfy confidentiality remains challenging. We present a methodology for designing such applications in a way that enables certifying their confidentiality. Our methodology consists of forcing the application to communicate with the external world through a narrow interface, compiling it with runtime checks that aid verification, and linking it with a small runtime that implements the narrow interface. The runtime includes services such as secure communication channels and memory management. We formalize this restriction on the application as Information Release Confinement (IRC), and we show that it allows us to decompose the task of proving confidentiality into (a) one-time, human-assisted functional verification of the runtime to ensure that it does not leak secrets, (b) automatic verification of the application's machine code to ensure that it satisfies IRC and does not directly read or corrupt the runtime's internal state. We present /CONFIDENTIAL: a verifier for IRC that is modular, automatic, and keeps our compiler out of the trusted computing base. Our evaluation suggests that the methodology scales to real-world applications.