gebhart/patrepeval huggingface dataset:
Deep sequencing of the T-cell receptor repertoire in CD8+ T-large granular lymphocyte leukemia identifies signature landscapes (2013)

New massively parallel sequencing technology enables, through deep sequencing of rearranged T-cell receptor (TCR) Vβ complementarity-determining region 3 (CDR3) regions, a previously inaccessible level of TCR repertoire analysis. The CDR3 repertoire diversity reflects clonal composition, the potential antigenic recognition spectrum, and the quantity of available T-cell responses. In this context, T-large granular lymphocyte (T-LGL) leukemia is a chronic clonal lymphoproliferation of cytotoxic T cells often associated with autoimmune diseases and various cytopenias. Using CD8(+) T-LGL leukemia as a model disease, we set out to evaluate and compare the TCR deep-sequencing spectra of both patients and healthy controls to better understand how TCR deep sequencing could be used in the diagnosis and monitoring of not only T-LGL leukemia but also reactive processes such as autoimmune disease and infection. Our data demonstrate, with high resolution, significantly decreased diversity of the T-cell repertoire in CD8(+) T-LGL leukemia and suggest that many T-LGL clonotypes may be private to the disease and may not be present in the general public, even at the basal level.
T Cell Engineering (2015)

T cells are a new and promising antigen-specific therapeutic option for the treatment of malignant diseases. To achieve antigen specificity against tumor antigens, T cells can be manipulated by gene transfer to express chimeric antigen receptors (CARs). CAR-expressing T cells are called redirected T cells. CARs are composed of an extracellular antibody-derived antigen recognition domain, a transmembrane domain and a cytoplasmatic signal domain. Therefore, redirected T cells combine the exchangeable specificity of an antibody with the cytotoxic machinery of a T cell. Early clinical trials with redirected T cells targeting cluster of differentiation (CD) 19 have shown impressive results in CD19-positive hematological cancers. However, for solid cancers only limited clinical experience exists and new and innovative concepts have to be developed to overcome tumor-mediated immune suppression. Herein, we describe the general design of a CAR, the function of the different domains and the different strategies to produce redirected T cells. Furthermore, we summarize and discuss the preclinical and clinical data indicating the tremendous potential of redirected T cells to become a mainstay of cancer immunotherapy.
Effect of L-arginine supplementation on insulin resistance and serum adiponectin concentration in rats with fat diet. (2015)

Our study shows that L-arginine supplementation in rats fed a HF diet is associated with an increase in insulin sensitivity. Our findings suggest that the underlying mechanism could be at least partially related to an increase in adiponectin concentration.
Live Visualization of HIV-1 Proviral DNA Using a Dual-Color-Labeled CRISPR System (2017)

HIV latency is one of the major problems in HIV/AIDS cure. Imaging single-copy integrated proviral HIV DNA in host cell has both virology and clinical significance but remains technical challenge. Here, we developed a dual-color labeled CRISPR system to image the HIV-1 integrated proviral DNA in latently infected cells. The pair of CRISPRs was fluorescently labeled with two different color QDs using two alternative bioorthogonal ligation reactions. Integrated HIV-sequences are successfully mapped based on the colocalized signals of QDs in living cells. Compared to the existing zinc finger proteins and TALENs, the CRISPR system is much easier to operate and more efficient in imaging of internal genomic loci. Therefore, the proposed method could be not only a powerful tool for imaging proviral HIV-1, but also a versatile platform to image single genomic loci in living cells.
Structure-Function Relationships of ω-Conotoxin GVIA (1997)

The structure-function relationships of the N-type calcium channel blocker, omega-conotoxin GVIA (GVIA), have been elucidated by structural, binding and in vitro and in vivo functional studies of alanine-substituted analogues of the native molecule. Alanine was substituted at all non-bridging positions in the sequence. In most cases the structure of the analogues in aqueous solution was shown to be native-like by 1H NMR spectroscopy. Minor conformational changes observed in some cases were characterized by two-dimensional NMR. Replacement of Lys2 and Tyr13 with Ala caused reductions in potency of more than 2 orders of magnitude in three functional assays (sympathetic nerve stimulation of rat isolated vas deferens, right atrium and mesenteric artery) and a rat brain membrane binding assay. Replacement of several other residues with Ala (particularly Arg17, Tyr22 and Lys24) resulted in significant reductions in potency (<100-fold) in the functional assays, but not the binding assay. The potencies of the analogues were strongly correlated between the different functional assays but not between the functional assays and the binding assay. Thus, the physiologically relevant assays employed in this study have shown that the high affinity of GVIA for the N-type calcium channel is the result of interactions between the channel binding site and the toxin at more sites than the previously identified Lys2 and Tyr13.
mKikGR, a Monomeric Photoswitchable Fluorescent Protein (2008)

The recent demonstration and utilization of fluorescent proteins whose fluorescence can be switched on and off has greatly expanded the toolkit of molecular and cell biology. These photoswitchable proteins have facilitated the characterization of specifically tagged molecular species in the cell and have enabled fluorescence imaging of intracellular structures with a resolution far below the classical diffraction limit of light. Applications are limited, however, by the fast photobleaching, slow photoswitching, and oligomerization typical for photoswitchable proteins currently available. Here, we report the molecular cloning and spectroscopic characterization of mKikGR, a monomeric version of the previously reported KikGR that displays high photostability and switching rates. Furthermore, we present single-molecule imaging experiments that demonstrate that individual mKikGR proteins can be localized with a precision of better than 10 nanometers, suggesting their suitability for super-resolution imaging.
An evaluation of the TRIPS computer system (2009)

The TRIPS system employs a new instruction set architecture (ISA) called Explicit Data Graph Execution (EDGE) that renegotiates the boundary between hardware and software to expose and exploit concurrency. EDGE ISAs use a block-atomic execution model in which blocks are composed of dataflow instructions. The goal of the TRIPS design is to mine concurrency for high performance while tolerating emerging technology scaling challenges, such as increasing wire delays and power consumption. This paper evaluates how well TRIPS meets this goal through a detailed ISA and performance analysis. We compare performance, using cycles counts, to commercial processors. On SPEC CPU2000, the Intel Core 2 outperforms compiled TRIPS code in most cases, although TRIPS matches a Pentium 4. On simple benchmarks, compiled TRIPS code outperforms the Core 2 by 10% and hand-optimized TRIPS code outperforms it by factor of 3. Compared to conventional ISAs, the block-atomic model provides a larger instruction window, increases concurrency at a cost of more instructions executed, and replaces register and memory accesses with more efficient direct instruction-to-instruction communication. Our analysis suggests ISA, microarchitecture, and compiler enhancements for addressing weaknesses in TRIPS and indicates that EDGE architectures have the potential to exploit greater concurrency in future technologies.
Low Affinity Interaction of Human or Rat T Cell Adhesion Molecule CD2 with Its Ligand Aligns Adhering Membranes to Achieve High Physiological Affinity (1997)

The mechanism by which low affinity adhesion molecules function to produce stable cell-cell adhesion is unknown. In solution, the interaction of human CD2 with its ligand CD58 is of low affinity (500 mM-1) and the interaction of rat CD2 with its ligand CD48 is of still lower affinity (40 mM-1). At the molecular level, however, the two systems are likely to be topologically identical. Fluorescently labeled glycosylphosphatidylinositol-anchored CD48 and CD58 were prepared and incorporated into supported phospholipid bilayers, in which the ligands were capable of free lateral diffusion. Quantitative fluorescence imaging was used to study the binding of cell surface human and rat CD2 molecules to the fluorescent ligands in contact areas between Jurkat cells and the bilayers. These studies provide two major conclusions. First, CD2/ligand interactions cooperate to align membranes with nanometer precision leading to a physiologically effective two-dimensional affinity. This process does not require the intact cytoplasmic tail of CD2. Second, the degree of membrane alignment that can be achieved by topologically similar receptors deteriorates with decreasing affinity. This suggests an affinity limit for the ability of this mode of cooperativity to achieve stable cell-cell adhesion at approximately 10 mM-1.
Glycerol conversion to acrylonitrile by consecutive dehydration over WO3/TiO2 and ammoxidation over Sb-(Fe,V)-O (2012)

The indirect ammoxidation of glycerol to acrylonitrile via intermediate formation of acrolein was studied using a tandem reactor coupling a dehydration step with an ammoxidation step. For the first step of dehydration of glycerol to acrolein, we used a previously optimized WO3/TiO2 catalyst, while Sb-V-O or Sb-Fe-O catalysts were developed and used for the subsequent ammoxidation step. Especially, the Sb-Fe-O catalysts were found highly selective and thus were more-deeply investigated. The corresponding catalysts were characterized by nitrogen physisorption, X-ray powder diffraction, thermogravimetric analysis, X-ray photoelectron spectroscopy, and temperature-programmed reduction in the presence of H2. We found that the presence of a FeSbO4 mixed phase on the synthesized samples was correlated to a high selectivity to acrylonitrile. Further, we observed an increase in selectivity to acrylonitrile with the reaction time, which was explained by the progressive formation of additional amounts of FeSbO4 on the catalysts during the reaction. Finally, the reaction parameters (temperature, catalyst amount, molar NH3/AC ratio and molar O2/AC ratio) for the catalyst with an Sb/Fe molar ratio of 0.6 were optimized, whereby a maximum yield in acrylonitrile of 40% (based on glycerol) could be achieved.
Halofuginone-an Inhibitor of Collagen Type I Synthesis-Prevents Postoperative Formation of Abdominal Adhesions (1998)

Upregulation of collagen synthesis appears to have a critical role in the pathophysiology of postoperative adhesions. Halofuginone, an inhibitor of collagen type I synthesis, could be used as an important tool in understanding the role of collagen in adhesion formation, and it may become a novel and promising antifibrotic agent for preventing postoperative adhesion formation.
ALS3 and ALS8 represent a single locus that encodes a Candida albicans adhesin; functional comparisons between Als3p and Als1p (2004)

The ALS (agglutinin-like sequence) gene family of Candida albicans encodes eight cell-surface glycoproteins, some of which are involved in adherence to host surfaces. A mutational analysis of each ALS gene is currently being performed to deduce the functions of the encoded proteins and to better understand the role of these proteins in C. albicans biology and pathogenesis. This paper describes construction of an als3/als3 mutant and comparison of its phenotype to an als1/als1 strain. Efforts to disrupt ALS3 indicated that the gene could be deleted in two transformation steps, suggesting that the gene is encoded by a single locus and that the ALS3-like locus, ALS8, does not exist. Strains lacking ALS3 or ALS1 did not exhibit a defect in germ tube formation when grown in RPMI 1640 medium, but the als1/als1 mutant formed significantly fewer germ tubes in Lee medium. Analysis of ALS3 and ALS1 promoter activity using green fluorescent protein (GFP) reporter strains and flow cytometry showed that when cells are placed into medium that promotes germ tube formation, ALS1 is transcribed prior to ALS3. Comparison of the mutant strains in adhesion assays showed that the als3/als3 strain was defective in adhesion to both human umbilical vein endothelial cells (HUVEC) and buccal epithelial cells (BEC), but not to fibronectin-coated plastic plates. In contrast, the als1/als1 strain showed decreased adherence to HUVEC, but adherence to BEC and fibronectin were the same as wild-type controls. Inoculation of the buccal reconstituted human epithelium (RHE) model of oral candidiasis with the mutant strains showed nearly a total lack of adhesion and epithelial destruction by the als3/als3 mutant while the als1/als1 strain showed only a slightly reduced degree of epithelial destruction compared to the wild-type control. Adhesion data presented here suggest that, in the assays performed, loss of Als3p affects C. albicans adhesion more than loss of Als1p. Collectively, these results demonstrate functional similarities and differences between Als1p and Als3p, and suggest the potential for more complex interrelationships between the ALS genes and their encoded proteins.
Botulinum Toxin in the Treatment of Focal Hyperhidrosis and Dyshidrotic Hand Dermatitis (2002)

Excessive sweating may cause considerable disability, with psychological, social and occupational consequences. Primary hyperhidrosis may also play a key role in the pathogenesis of dyshidrotic dermatitis and some other skin diseases.The aim of the present work was to evaluate a novel treatment of hyperhidrosis namely chemical sweat gland denervation with botulinum toxin type A (Btx A). The effects of multiple intradermal injections of Btx A (total dose Botox® 0.5 U/cm2 on one occasion) were evaluated in palmar and axillary hyperhidrosis, using patients as their own controls. The abolition of sweating was objectified by comparing measured evaporation and the size of the sweating area assessed in iodine-starch tests between the treated and untreated side before and one week after unilateral injections. Hyperhidrosis disappeared or was highly reduced in 22 of 26 patients with an effect duration of 8-9 months in most patients. Side-effects of palmar Btx A injections were restricted to a transient weakness of the hand muscles. This was studied by measurements of compound muscle action potentials of intrinsic muscles of the hand at supramaximal nerve stimulation and of muscle strength before and 3 weeks after treatment with Btx A and at a late follow-up after 15 – 37 weeks. Post-treatment values of these measures of intrinsic hand muscle function were significantly reduced at 3 weeks and had almost returned to normal at 37 weeks. Sweat gland histology and immunoreactivity were studied in skin biopsy specimens taken before and 2.5 – 6 months post-treatment. The lumen of the secretory tubule was diminished, but no atrophy of sweat gland cells was seen. A tendency to reduced staining with the neuronal marker PGP 9.5 suggested sudomotor nerve degeneration. Immunoreactivity of the neurotransmitters VIP and CGRP was unchanged.Patients with primary focal hyperhidrosis were found to have a marked reduction of life quality (increased Dermatology Life Quality Index score) – a reduction which, however, was almost reversed at measurement 5 months after treatment with Btx A.Ten patients with vesicular hand dermatitis were treated unilateraly with Btx A. Seven out of ten displayed marked improvement in both objective and subjective ranking measures of the dermatitis.In conclusion, focal hyperhidrosis and dyshidrotic hand dermatitis may be effectively treated with intradermal injections of botulinum toxin. Side-effects occur, but are minor and transient. The reduced sweat production is associated with minor changes in sweat gland histology and innervation. The considerably impaired quality of life demonstrated in patients with primary hyperhidrosis can be largely reversed by intradermal Btx A therapy.
Degradable, drug-eluting stents: a new frontier for the treatment of coronary artery disease (2005)

This article reviews the clinical use of stents in the treatment of coronary artery disease and the rationale for the use of degradable, drug-eluting polymer stents. The authors note the challenges of using off-the-shelf polymers for the development of degradable stents, as well as the interplay between polymer properties and a functional stent design. Drug-eluting metal stents are the most significant advancement in the treatment of coronary artery disease, and have significantly reduced the occurrence of in-stent restenosis after placement. Some regard drug-eluting metal stents as the final technologic advancement in the treatment of coronary artery disease, others consider the future development of degradable, drug-eluting stents as the next logical step.
Comparison of Fungizone, Amphotec, AmBisome, and Abelcet for Treatment of Systemic Murine Cryptococcosis (1998)

Three lipid-based formulations of amphotericin B have been approved for use in various countries. The aim of this study was to compare Amphotec (ABCD; Sequus), AmBisome (AmBi; Nexstar), Abelcet (ABLC; The Liposome Co.), and conventional deoxycholate amphotericin B (Fungizone; Bristol Meyers Squibb) for the treatment of experimental systemic cryptococcosis. A model was established in 10-week-old female CD-1 mice by intravenous (i.v.) injection of 6.25 x 10(5) viable Cryptococcus neoformans yeast cells. Therapy began 4 days later, with i.v. administration three times per week for 2 weeks. Mice received either no treatment, 1 mg of Fungizone per kg of body weight, or 1, 5, or 10 mg of ABCD, AmBi, or ABLC per kg. Ninety percent of control mice died between days 15 and 34. All treatment regimens except ABLC at 1 mg/kg prolonged survival compared with no treatment (P < 0.01 to 0.001). All mice receiving 5 or 10 mg of ABCD or AmBi per kg and 90% of mice given 10 mg of ABLC per kg survived, whereas < or =50% of those given other treatment regimens survived. Fungizone was the least effective of the four formulations, with 5 or 10 mg of ABCD, AmBi, or ABLC per kg resulting in a significantly better outcome than Fungizone (P < 0.001). Among the three formulations, ABCD and AmBi were equally effective, both being better than ABLC at equal 5- or 10-mg/kg doses (P < 0.001). Comparison of residual infectious burdens in various organs showed that each drug had some dose-responsive efficacy in three or more organs at escalating doses. In the brain, ABCD or AmBi at 5 or 10 mg/kg or ABLC at 10 mg/kg was more effective than Fungizone at 1 mg/kg or no treatment, while ABCD or AmBi at 1 mg/kg was as effective as ABLC at 10 mg/kg. Similar results were obtained for the kidneys and lungs. In the spleen, ABCD at 10 mg/kg cured all mice of infection and was superior to all other regimens. In the liver, AmBi at 5 mg/kg was superior to an equal dose of ABCD or ABLC. Overall, the efficacies of ABCD and AmBi were equal to that of Fungizone at 1 mg/kg and were about 10-fold better than that of ABLC, particularly in the brain; a comparative rank order of efficacies was ABCD approximately equal to AmBi > ABLC >> Fungizone. This is the first study that compared all four amphotericin B formulations.
Metastatic Pancreatic Cancer 2008: Is the Glass Less Empty? (2008)

Pancreatic cancer is the fourth most common cause of adult cancer death in the U.S. The high mortality rate from pancreatic cancer is a result of the high incidence of metastatic disease at the time of diagnosis, an often fulminant clinical course, and the lack of adequate systemic therapies. Unfortunately, only 5%-25% of patients present with tumors amenable to resection. The median disease-free survival interval following resection for operable pancreatic cancer is 13.4 months for patients treated with adjuvant gemcitabine and 6.9 months for untreated patients. A much higher percentage of patients present with metastatic disease (40%-45%) or locally advanced disease (40%), and have median survival times of 3-6 months or 8-12 months, respectively. The frustrating lack of significant clinical advancements in the treatment of metastatic pancreatic cancer remains one of medical oncology's biggest disappointments. The past decade-long frustration has resulted in regulators, investigators, and practicing oncologists gradually lowering their standards/expectations with regard to interpreting clinical trials. Two of the more important examples of this include the approval of gemcitabine plus erlotinib and the use of a progression-free survival advantage to defend the use of gemcitabine plus oxaliplatin. Given the marginal benefit of systemic antineoplastics, a scholarly review inclusive of other palliative strategies will help oncologists optimize the care of pancreatic cancer patients. This article examines the existing evidence in support of a role for palliative therapy in metastatic pancreatic cancer, describes recent developments with newer chemotherapeutic and molecular-targeted agents, and explores future study designs.
Altered TFEB-mediated lysosomal biogenesis in Gaucher disease iPSC-derived neuronal cells (2015)

Gaucher disease (GD) is caused by mutations in the GBA1 gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase). The severe forms of GD are associated with neurodegeneration with either rapid (Type 2) or slow progression (Type 3). Although the neurodegenerative process in GD has been linked to lysosomal dysfunction, the mechanisms involved are largely unknown. To identify the lysosomal alterations in GD neurons and uncover the mechanisms involved, we used induced pluripotent stem cells (iPSCs) derived from patients with GD. In GD iPSC-derived neuronal cells (iPSC-NCs), GBA1 mutations caused widespread lysosomal depletion, and a block in autophagic flux due to defective lysosomal clearance of autophagosomes. Autophagy induction by rapamycin treatment in GD iPSC-NCs led to cell death. Further analysis showed that in GD iPSC-NCs, expression of the transcription factor EB (TFEB), the master regulator of lysosomal genes, and lysosomal gene expression, were significantly downregulated. There was also reduced stability of the TFEB protein and altered lysosomal protein biosynthesis. Treatment of mutant iPSC-NCs with recombinant GCase (rGCase) reverted the lysosomal depletion and autophagy block. The effect of rGCase on restoring lysosomal numbers in mutant cells was enhanced in the presence of overexpressed TFEB, but TFEB overexpression alone did not reverse the lysosomal depletion phenotype. Our results suggest that GBA1 mutations interfere with TFEB-mediated lysosomal biogenesis, and that the action of GCase in maintaining a functioning pool of lysosomes is exerted in part through TFEB. The lysosomal alterations described here are likely to be a major determinant in GBA1-associated neurodegeneration.