gebhart/patrepeval huggingface dataset:
Retrovirus-mediated gene therapy for Farber disease. (2008)

Farber disease is a rare lysosomal storage disease (LSD) caused by a deficiency of acid ceramidase (AC). Patients show a classic triad of symptoms including subcutaneous granulomas, laryngeal involvement and painful swollen joints. The most common and severe form has neurological manifestations and patients typically die by the age of two. Current treatment consists of symptomatic supportive care and allogeneic bone marrow transplantation (BMT). However, BMT has shown limited success. Gene therapy has previously been shown to be a promising treatment strategy for monogenetic diseases and has the potential to treat the underlying cause of the disease. Presented here is the first report of in vivo testing of retrovirus-mediated gene therapy strategies for the treatment of Farber disease. Retroviral vectors were engineered to overexpress AC and a cell surface marker, human CD25. Transduction with these viral vectors corrected the enzymatic defect in Farber patient cells and in vivo administration of the lentiviral vector led to long-term expression of the marking transgene as well as increased AC expression in the liver. To determine the effect of over-expression of AC, human CD34+ cells were transduced and transplanted into NOD/SCID animals. It was found that transgene-expressing cells could reconstitute the host. To address the neurological manifestations of Farber disease, vascular endothelial growth factor (VEGF) was investigated as an agent to transiently open the blood brain barrier for entry of lentivirus. It was found that in addition to increasing the amount of therapeutic virus in the brain, VEGF treatment also increased transduction in other organs. Further, to address the concerns of insertional mutagenesis associated with using integrating vectors, an immunotoxin-based strategy was developed as a safety system to clear transduced cells. It was found that a CD25-targeted immunotoxin could eliminate both transduced hematopoietic cells as well as tumor cells over-expressing CD25. This strategy can be employed following gene therapy should an unwanted proliferative event occur. Together, these studies represent considerable advances towards the development of a cure for Farber disease, demonstrating both therapeutic potential and also containing a built-in safety system.
Proceedings: Second international conference on intelligent systems for molecular biology (1994)

This volume provided full papers for presentations at the Second International Conference on Intelligent Systems for Molecular Biology held August 14-17, 1994 at Stanford University, Stanford, California. Each individual paper has been separately abstracted and indexed for the database.
Carboplatin in Combination Therapy for Metastatic Breast Cancer (2004)

Incorporation of carboplatin as a standard agent in first-line treatment of metastatic breast cancer has support from several recent studies. Preliminary results of combination carboplatin/taxane therapy with trastuzumab in metastatic disease are encouraging, and other carboplatin combinations are also being investigated in other phase II and III trials in patients selected based on the HER2 status of their cancer. Results are eagerly awaited.
A RANDOMIZED CLINICAL TRIAL COMPARING OKT3 AND STEROIDS FOR TREATMENT OF HEPATIC ALLOGRAFT REJECTION (1987)

A multiinstitutional randomized trial was undertaken comparing OKT3 with steroids for treatment of hepatic allograft rejection. All patients received baseline immunosuppression with Cyclosporine (CsA) and steroids. At the time of biopsy-confirmed rejection, up to 2 intravenous boluses (250-1000 mg) of methylprednisolone were initially administered. Twenty-eight patients who failed to respond were then randomly assigned to OKT3 or continued steroid therapy. Rescue therapy with the opposite treatment arm was added after 6 days if the primarily allocated protocol failed. Three of 13 patients assigned to the steroid group responded promptly, and continue with good function 7-12 months later. OKT3 rescue was required in 10 patients who failed to improve despite receiving up to 6 g of methylprednisolone (mean: 3.3 g/patient). One patient died of sepsis and hepatic failure. Rejection was reversed in 9 OKT3-rescue patients, 7 of whom are well 1-17 months later. In the OKT3 group, improved allograft function was observed within 72 hr in 11 of 15 patients. Two patients with inadequate response were successfully rescued with steroids; 1 patient underwent retransplantation; and 1 patient developed a biliary fistula that eventually resulted in sepsis and death. In summary, 23 of 28 hepatic recipients (82%) are alive with the original allograft 1-17 (mean 7.8) months after treatment for acute rejection. Another patient is alive 14 months following retransplantation. Eighteen (78%) of the survivors required OKT3 as initial (11) or rescue (7) therapy, whereas only 5 were successfully managed with steroids. OKT3 is superior to steroids for reversing liver allograft rejection and has greatly reduced the need for retransplantation even in recipients selected on the basis of having failed initial steroid therapy.
The Jalview Java alignment editor (2004)

Multiple sequence alignment remains a crucial method for understanding the function of groups of related nucleic acid and protein sequences. However, it is known that automatic multiple sequence alignments can often be improved by manual editing. Therefore, tools are needed to view and edit multiple sequence alignments. Due to growth in the sequence databases, multiple sequence alignments can often be large and difficult to view efficiently. The Jalview Java alignment editor is presented here, which enables fast viewing and editing of large multiple sequence alignments.
Large bowel fermentation in rats given diets containing raw peas (Pisum sativum) (1990)

The digestion of non-starch polysaccharides (NSP) was studied in rats given semi-purified diets containing 0-500 g raw peas (Pisum sativum)/kg. NSP were equally well digested at all inclusion levels with digestibilities for individual constituents ranging from 0.58 for xylans to 0.99 for arabinose-containing polymers with a total NSP digestibility of 0.79. Increasing the dietary pea inclusion rate increased the amount of substrate flowing to the large bowel (LB) and this was associated with marked increases in caecal tissue and contents masses, a reduction in caecal transit time from 0.88 to 0.43 d and a threefold increase in faecal bacterial output. Caecal pH fell as did the molar proportions of acetate, isobutyrate, isovalerate and valerate whilst butyrate increased when peas were included in the diet. Possible mechanisms for these fermentation end-product changes are discussed. Pea inclusion in the diet was associated with increased volatile fatty acid and 3-hydroxy butyrate concentrations in portal and heart blood. It was concluded that peas are a rich source of fermentable polysaccharides which produce a LB fermentation pattern of potential health benefit.
A Peptide c-Jun N-Terminal Kinase (JNK) Inhibitor Blocks Mechanical Allodynia after Spinal Nerve Ligation: Respective Roles of JNK Activation in Primary Sensory Neurons and Spinal Astrocytes for Neuropathic Pain Development and Maintenance (2006)

Optimal management of neuropathic pain is a major clinical challenge. We investigated the involvement of c-Jun N-terminal kinase (JNK) in neuropathic pain produced by spinal nerve ligation (SNL) (L5). SNL induced a slow (>3 d) and persistent (>21 d) activation of JNK, in particular JNK1, in GFAP-expressing astrocytes in the spinal cord. In contrast, p38 mitogen-activated protein kinase activation was found in spinal microglia after SNL, which had fallen to near basal level by 21 d. Intrathecal infusion of a JNK peptide inhibitor, D-JNKI-1, did not affect normal pain responses but potently prevented and reversed SNL-induced mechanical allodynia, a major symptom of neuropathic pain. Intrathecal D-JNKI-1 also suppressed SNL-induced phosphorylation of the JNK substrate, c-Jun, in spinal astrocytes. However, SNL-induced upregulation of GFAP was not attenuated by spinal D-JNKI-1 infusion. Furthermore, SNL induced a rapid (<12 h) but transient activation of JNK in the L5 (injured) but not L4 (intact) DRG. JNK activation in the DRG was mainly found in small-sized C-fiber neurons. Infusion of D-JNKI-1 into the L5 DRG prevented but did not reverse SNL-induced mechanical allodynia. Finally, intrathecal administration of an astroglial toxin, l-alpha-aminoadipate, reversed mechanical allodynia. Our data suggest that JNK activation in the DRG and spinal cord play distinct roles in regulating the development and maintenance of neuropathic pain, respectively, and that spinal astrocytes contribute importantly to the persistence of mechanical allodynia. Targeting the JNK pathway in spinal astroglia may present a new and efficient way to treat neuropathic pain symptoms.
LightGBM: A Highly Efficient Gradient Boosting Decision Tree (2017)

Gradient Boosting Decision Tree (GBDT) is a popular machine learning algorithm, and has quite a few effective implementations such as XGBoost and pGBRT. Although many engineering optimizations have been adopted in these implementations, the efficiency and scalability are still unsatisfactory when the feature dimension is high and data size is large. A major reason is that for each feature, they need to scan all the data instances to estimate the information gain of all possible split points, which is very time consuming. To tackle this problem, we propose two novel techniques: Gradient-based One-Side Sampling (GOSS) and Exclusive Feature Bundling (EFB). With GOSS, we exclude a significant proportion of data instances with small gradients, and only use the rest to estimate the information gain. We prove that, since the data instances with larger gradients play a more important role in the computation of information gain, GOSS can obtain quite accurate estimation of the information gain with a much smaller data size. With EFB, we bundle mutually exclusive features (i.e., they rarely take nonzero values simultaneously), to reduce the number of features. We prove that finding the optimal bundling of exclusive features is NP-hard, but a greedy algorithm can achieve quite good approximation ratio (and thus can effectively reduce the number of features without hurting the accuracy of split point determination by much). We call our new GBDT implementation with GOSS and EFB LightGBM. Our experiments on multiple public datasets show that, LightGBM speeds up the training process of conventional GBDT by up to over 20 times while achieving almost the same accuracy.
Vibration immunity and Ampere's circuital law for a near perfect triangular Faraday current sensor (1996)

We report a common-mode rejection scheme for a bulk-optic triangular Faraday current sensor that can eliminate optical noise induced by fibre-link vibration. The sensor's exploitation of Ampere's circuital law is also demonstrated.
Targeted therapy of athymic mice bearing GW-39 human colonic cancer micrometastases with 131I-labeled monoclonal antibodies. (1992)

The therapeutic potential of radiolabeled antibodies is usually evaluated in experimental animal models bearing s.c. xenografts. We have established a micrometastatic model of the GW-39 human colonic carcinoma in the nude mouse lung (J. Natl. Cancer Inst., 83: 627-632, 1991) and presented preliminary findings on the efficacy of a 131I-anticarcinoembryonic antigen (CEA) antibody in this model. We now extend our observations on the use of radioiodinated labeled monoclonal antibodies (MAbs) to treat multiple small tumor nodules. Biodistribution and dosimetry analysis was performed for intact and F(ab')2 of NP-4 anti-CEA IgG, Mu-9 anti-colon-specific antigen IgG, isotype-matched irrelevant anti-AFP IgG, and intact MAb 34A anti-lung endothelial IgG antibody. Comparisons were made for rad dose delivered to small s.c. tumors, normal lung, lung with tumor nodules, and isolated tumor nodules. Survival curves were generated for tumor-bearing animals treated 1, 7, or 14 days after tumor cell implantation with these antibodies using the maximal tolerated dose for intact antibodies (275 microCi) and for F(ab')2 fragments (1.2 mCi). The studies established the following observations: (a) in contrast to previous results in a bulky tumor model in hamsters, intact antibodies are more therapeutic than MAb fragments for both NP-4 and Mu-9; (b) tumor nodule size, even on the microscopic level, affects therapeutic outcome; antibodies were more effective when administered 7 days postimplantation (mean nodule diameter, 150 microns) compared with treatment 14 days postimplantation (mean nodule diameter, 750 microns); (c) administration of radioiodinated Mu-9 was exquisitely effective on single avascular tumor cells that had seeded in lung; irrelevant antibody was minimally radiotoxic; (d) as in the bulky disease model, the anti-colon-specific antigen p antibody delivers a higher rad dose than the anti-CEA antibody and is significantly more therapeutic in the micrometastasis model; (e) a higher affinity anti-CEA antibody (MN-14) recognizing the same epitope on CEA as NP-4 was equally therapeutic; (f) the use of MAb directed against the lung endothelium was not as therapeutic as a tumor-associated antibody; and (g) all tumor-associated antibodies were more efficacious than administration of the maximal tolerated dose of 5-fluorouracil and leucovorin in this human tumor-xenograft model. These results provide further support for the use of radioimmunotherapy in the handling of minimal disease, probably as part of an adjuvant treatment regimen.
Mismatch ligation during non-homologous end joining pathway: kinetic characterization of human DNA ligase IV/XRCC4 complex (2007)

Ligase IVLigase IV/
European headache federation consensus on the definition of resistant and refractory migraine (2020)

We hope, that the updated EHF definition will be able to solve the conflicts that have limited the use of definitions which have been put forward in the past. Only with a widely accepted definition, progresses in difficult-to-treat migraine can be achieved. This new definition has also the aim to increase the understanding of the impact of the migraine as a disease with all of its social, legal and healthcare implications. It is the hope of the EHF Expert Consensus Group that the proposed criteria will stimulate further clinical, scientific and social attention to patients who suffer from migraine which is difficult-to-treat.
Meteorites as Catalysts for Prebiotic Chemistry (2013)

From outer space: Twelve meteorite specimens, representative of their major classes, catalyse the synthesis of nucleobases, carboxylic acids, aminoacids and low-molecular-weight compounds from formamide (see figure). Different chemical pathways are identified, the yields are high for a prebiotic process and the products come in rich and composite panels. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
On the theory of plasma streamer development (2009)

The temporal dynamics of initial stage of breakdown development in high-pressure gases, i.e., ionization avalanche initiation and development, its transition to plasma avalanche and then to plasma streamer, is discussed. Simple formulas for times of transitions between various breakdown stages and ionization front propagation velocities at individual stages are derived.
AMINO ACID REQUIREMENTS OF HERPES SIMPLEX VIRUS IN HUMAN CELLS (1964)

Tankersley, Robert W., Jr. (Medical College of Virginia, Richmond). Amino acid requirements of herpes simplex virus in human cells. J. Bacteriol. 87:609-613. 1964.-Progressive infection of human cells minimally infected with herpes simplex virus requires 11 of the amino acids of Eagle's medium, and glutamine. Lysine is not required, but rather exerts a partially inhibitory effect upon virus multiplication. Infected cells deprived of arginine support neither cytopathogenic effects nor virus replication; when arginine is replaced, a prompt and extensive infection follows. The effect of nutritional deficiencies on virus infection is discussed.
Inhaled mannitol for the treatment of mucociliary dysfunction in patients with bronchiectasis: Effect on lung function, health status and sputum (2005)

Mannitol significantly improved the health status over 12 days and this improvement was maintained for 6-10 days after cessation of treatment. In addition, mannitol reduced the tenacity, increased the hydration of mucus acutely and improved cough clearability in patients with bronchiectasis.
Modern Heuristic Search Methods (1996)

Partial table of contents: Modern Heuristic Techniques. TECHNIQUES. Localized Simulated Annealing in Constraint Satisfaction and Optimization. Observing Logical Interdependencies in Tabu Search: Methods and Results. Reactive Search: Toward Self-Tuning Heuristics. Integrating Local Search into Genetic Algorithms. CASE STUDIES. Local Search for Steiner Trees in Graphs. Local Search Strategies for the Vehicle Fleet Mix Problem. A Tabu Search Algorithm for Some Discrete-Continuous Scheduling Problems. The Analysis of Waste Flow Data from Multi-Unit Industrial Complexes Using Genetic Algorithms. The Evolution of Solid Object Designs Using Genetic Algorithms. The Convoy Movement Problem with Initial Delays. A Brief Comparison of Some Evolutionary Optimization Methods. Index.
Differential anticoagulant activity of heparin fragments prepared using microbial heparinase. (1982)

Heparin of an average molecular weight of 13,000 with known polydispersity was degraded using microbial heparinase. The kinetics of this degradation were followed by four assays which measured the anticoagulant activity of the heparin digestion products. Both clotting and amidolytic chromogenic assays were used to measure heparin-potentiated inhibition of both thrombin and Factor Xa. These assays showed different profiles throughout the digestion and were related to the average molecular weight of the digestion products.l The final products of this enzymatic digestion were fractionated on the basis of size and their anticoagulant activities were measured. Fragments causing Factor Xa inhibition but not thrombin inhibition were isolated. Anticoagulant activity was found in a fragment as small as a tetrasaccharide.
In vivo cytotoxic T lymphocyte induction with soluble proteins administered in liposomes (1992)

The in vivo induction of a CTL response usually requires that Ag be endogenously synthesized so that appropriate processing can occur. In most of the few examples where successful CTL induction was reported with proteins and peptides, unacceptable adjuvants or means of Ag formulation were used. In the present report, liposomes were used to incorporate the soluble proteins OVA and beta-galactosidase. This simple and convenient to use approach, which requires minimal amounts of Ag, results in priming for a CD8+ CTL response and the establishment of immunologic memory. The liposome approach may not only prove a convenient means of inducing CTL responses in vivo but may also be useful to study the mechanisms of Ag processing.
Recent advances in feeding suppressing agents: potential therapeutic strategy for the treatment of obesity (2001)

Obesity is an increasingly prevalent health problem for which no ideal treatments are available, especially for long-term maintenance of body loss. The only approved drugs are centrally acting appetite suppressants that modulate monoamine neurotransmitters in the brain. Since the discovery of leptin, and the fact it modulates neuropeptide systems in the CNS, attention has shifted from amines to peptides. Many researchers have focused on these neuropeptide systems in the CNS and their involvement in energy balance. With an effort to identify molecules involved in feeding behaviour and energy expenditure in the brain, especially in the hypothalamic nuclei, a series of novel potential targets for the development of anti-obesity agents, as well as potential drug candidates, are being given attention. Many pharmaceutical companies have large programmes directed at the development of new modulators of neuropeptide receptors, antagonists of appetite enhancing peptides and agonists of appetite suppressing peptides, including neuropeptide Y receptors and melanocortin receptors. This review covers recent targets for drug discovery of anti-obesity agents and patents focusing on the receptors.
Expression of α2‐macroglobulin receptor/low density lipoprotein receptor‐related protein is increased in reactive and neoplastic glial cells (1994)

alpha 2-Macroglobulin receptor/low density lipoprotein receptor-related protein (alpha 2M-R/LRP) is a multi-functional cell-surface receptor that has been implicated in diverse physiologic processes. In normal human brain, alpha 2M-R/LRP is expressed principally by pyramidal neurons with localization to cell bodies and proximal processes. By contrast, alpha 2M-R/LRP is not present in either the cell bodies or processes of most normal macroglia (including astrocytes). In this investigation, we studied the expression of alpha 2M-R/LRP in the brain, following tissue injury or neoplastic transformation, by immunohistochemistry. Significantly increased alpha 2M-R/LRP immunoreactivity was identified in reactive astrocytes, indicating the expression of this receptor is regulated in vivo in response to brain injury. alpha 2M-R/LRP immunoreactivity was also detected in glial cell tumors; this finding is novel since malignant transformation is typically thought to turn off expression of this receptor.
Systemic and subcutaneous microvascular Po2 dissociation during 4-h hemorrhagic shock in conscious hamsters (1996)

The relationship between systemic and microvascular Po2 in subcutaneous connective tissue and hemodynamics was investigated during 4-h hemorrhagic shock (40 mmHg) in conscious Syrian hamsters (n = 66) fitted with a dorsal skinfold window. Systemic blood gases, metabolic parameters, arteriolar, venular, and tissue Po2, microvascular red blood cell velocity, and blood flow were evaluated in survivors (S) and nonsurvivors (NS). Surviving animals were resuscitated with shed blood. Microvascular and tissue Po2 were measured by phosphorescence decay of Pd-meso-tetra (4-carboxyphenyl) porphyrin (30 mg/kg body wt iv). Shock caused a significant dissociation between systemic arterial and microvascular arteriolar Po2 levels. Arterial Po2 increased from 59.7 +/- 12.0 to 110.8 +/- 19.7 mmHg (S) and from 64.0 +/- 13.7 to 128.5 +/- 10.1 mmHg (NS), whereas Po2 in large arterioles decreased from 56.9 +/- 5.5 (control) to 29.5 +/- 20.1 (S) and 6.0 +/- 5.7 mmHg (NS). Correspondingly, tissue Po2 fell from 24.1 +/- 6.8 (control) to 0.9 +/- 0.6 (S) and 0.4 +/- 0.3 mmHg (NS). Venous Po2 decreased from 28.8 +/- 3.7 to 20.4 +/- 4.1 (S) and from 28.0 +/- 2.9 to 16.3 +/- 0.5 mmHg (NS). Shock outcome and tissue oxygenation were predicted by arterial blood gases and metabolic and microcirculatory conditions but not by central venous Po2.
Incretin-like effects of small molecule trace amine-associated receptor 1 agonists (2015)

We have identified TAAR1 as a novel integrator of metabolic control, which acts on gastrointestinal and pancreatic islet hormone secretion. Thus TAAR1 qualifies as a novel and promising target for the treatment of type 2 diabetes and obesity.