gebhart/patrepeval huggingface dataset:
Quantitative Proteomics of Human Fibroblasts with I1061T Mutation in Niemann–Pick C1 (NPC1) Protein Provides Insights into the Disease Pathogenesis* (2015)

Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder characterized by the accumulation of unesterified cholesterol in the late endosomal/lysosomal compartments. Mutations in the NPC1 protein are implicated in 95% of patients with NPC disease. The most prevalent mutation is the missense mutation I1061T that occurs in ∼15–20% of the disease alleles. In our study, an isobaric labeling-based quantitative analysis of proteome of NPC1(I1061T) primary fibroblasts when compared with wild-type cells identified 281 differentially expressed proteins based on stringent data analysis criteria. Gene ontology enrichment analysis revealed that these proteins play important roles in diverse cellular processes such as protein maturation, energy metabolism, metabolism of reactive oxygen species, antioxidant activity, steroid metabolism, lipid localization, and apoptosis. The relative expression level of a subset of differentially expressed proteins (TOR4A, DHCR24, CLGN, SOD2, CHORDC1, HSPB7, and GAA) was independently and successfully substantiated by Western blotting. We observed that treating NPC1(I1061T) cells with four classes of seven different compounds that are potential NPC drugs increased the expression level of SOD2 and DHCR24. We have also shown an abnormal accumulation of glycogen in NPC1(I1061T) fibroblasts possibly triggered by defective processing of lysosomal alpha-glucosidase. Our study provides a starting point for future more focused investigations to better understand the mechanisms by which the reported dysregulated proteins triggers the pathological cascade in NPC, and furthermore, their effect upon therapeutic interventions.
Tolerating denial-of-service attacks: a system approach (2005)

In recent years, Denial of Service (DoS) attacks have been one of the major security threats to large-scale Internet applications. Since 1998, there have been several large scale DoS attacks in the Internet. Some gigantic sites such as Yahoo!, Amazon and Buy.com were shut down during those attacks [1, 2]. In 2001, the “Code Red ” worm was
Variations of Bacterial Populations in Human Feces Measured by Fluorescent In Situ Hybridization with Group-Specific 16S rRNA-Targeted Oligonucleotide Probes (1998)

Six 16S rRNA-targeted oligonucleotide probes were designed, validated, and used to quantify predominant groups of anaerobic bacteria in human fecal samples. A set of two probes was specific for species of the Bacteroides fragilis group and the species Bacteroides distasonis. Two others were designed to detect species of the Clostridium histolyticum and the Clostridium lituseburense groups. Another probe was designed for the genera Streptococcus and Lactococcus, and the final probe was designed for the species of the Clostridium coccoides-Eubacterium rectale group. The temperature of dissociation of each of the probes was determined. The specificities of the probes for a collection of target and reference organisms were tested by dot blot hybridization and fluorescent in situ hybridization (FISH). The new probes were used in initial FISH experiments to enumerate human fecal bacteria. The combination of the two Bacteroides-specific probes detected a mean of 5.4 x 10(10) cells per g (dry weight) of feces; the Clostridium coccoides-Eubacterium rectale group-specific probe detected a mean of 7.2 x 10(10) cells per g (dry weight) of feces. The Clostridium histolyticum, Clostridium lituseburense, and Streptococcus-Lactococcus group-specific probes detected only numbers of cells ranging from 1 x 10(7) to 7 x 10(8) per g (dry weight) of feces. Three of the newly designed probes and three additional probes were used in further FISH experiments to study the fecal flora composition of nine volunteers over a period of 8 months. The combination of probes was able to detect at least two-thirds of the fecal flora. The normal biological variations within the fecal populations of the volunteers were determined and indicated that these variations should be considered when evaluating the effects of agents modulating the flora.
Diketopiperazine derivatives, a new series of platelet-activating factor inhibitors. (1987)

Some diketopiperazine derivatives (3a-f, 4a-f, and 5a-c) related to natural products (1 and 2) have been prepared and evaluated for their inhibition of platelet aggregation induced by platelet-activating factor (PAF).
Peptide−Sugar Ligation Catalyzed by Transpeptidase Sortase:  A Facile Approach to Neoglycoconjugate Synthesis (2008)

Glycoconjugate synthesis involving sugar and polypeptide remains a formidable challenge. Here we report a novel enzymatic method involving an unprecedented sortase-catalyzed transamidation reaction for site-specific engineering of sugars into native proteins. We show that sugars appended with a 6-aminohexose moiety can be efficiently ligated to peptides and proteins encoded with a LPXTG sortase recognition sequence. This robust reaction provides an elegant and simple approach for generating neoglycoproteins with an amide-linked sugar moiety at the carboxy terminus.
Cellular pharmacology of the combination of the DNA topoisomerase I inhibitor SN-38 and the diaminocyclohexane platinum derivative oxaliplatin. (1999)

CPT-11, a DNA topoisomerase I inhibitor, and oxaliplatin, a diaminocyclohexane platinum derivative, are cytotoxic agents that have demonstrated clinical antitumor activity in colorectal cancer. Given the therapeutic potential of their combination, we studied the cellular pharmacology of SN-38, the active metabolite of CPT-11, and oxaliplatin in the human colon cancer HT29 cell line. Growth inhibition was studied after a 1- or 24-h exposure to SN-38 or oxaliplatin, given alone or in combination. The cytotoxicity analysis by the isobolograms method elicited synergy. SN-38 delayed the reversion of oxaliplatin-induced DNA interstrand cross-links (ISCs), measured in cells by alkaline elution. The amount of detectable ISCs 15 h after a 1-h exposure to 10 microm oxaliplatin was 27% of the ISC peak levels and increased to 68% in the presence of 0.1 microM SN-38. The presence of oxaliplatin DNA adducts led to a 3.3-fold increase in the SN-38-induced DNA elongation inhibition, as measured by pulse-labeling alkaline elution. Inhibition of DNA and RNA synthesis was longer after exposure to the combination of oxaliplatin and SN-38 than after exposure to each agent alone. Consistently, flow cytometry analyses revealed that preexposure to oxaliplatin enhanced SN-38-induced S-phase arrest. Filter binding assays indicated that the cells arrested in S-phase at 48 h were undergoing apoptosis. Hence, supra-additive cytotoxicity appears related to major modifications in the cellular response to DNA damage rather than to changes in DNA damage formation. The combination of CPT-11 and oxaliplatin induced a 2-fold higher tumor growth reduction in vivo than did oxaliplatin alone at feasible nonlethal doses. This study provides a rationale for the optimal use of CPT-11 and oxaliplatin in combination.
Peptide‐antibody conjugates for tumour therapy: A MHC‐class‐II‐restricted tetanus toxin peptide coupled to an anti‐IG light chain antibody can induce cytotoxic lysis of a human B‐cell lymphoma by specific CD4 T cells (1994)

Anti-idiotype antibody therapy of B-cell lymphomas, despite numerous promising experimental and clinical studies, has so far met with limited success. Tailor-made monoclonal anti-idiotype antibodies have been injected into a large series of lymphoma patients, with a few impressive complete tumour remissions but a large majority of negative responses. The results presented here suggest that, by coupling to antilymphoma idiotype antibodies a few molecules of the tetanus toxin universal epitope peptide P2 (830-843), one could markedly increase the efficiency of this therapy. We show that after 2-hr incubation with conjugates consisting of the tetanus toxin peptide P2 coupled by an S-S bridge to monoclonal antibodies directed to the lambda light chain of human immunoglobulin, human B-lymphoma cells can be specifically lysed by a CD4 T-lymphocyte clone specific for the P2 peptide. Antibody without peptide did not induce B-cell killing by the CD4 T-lymphocyte clone. The free cysteine-peptide was also able to induce lysis of the B-lymphoma target by the T-lymphocyte clone, but at a molar concentration 500 to 1000 times higher than that of the coupled peptide. Proliferation assays confirmed that the antibody-peptide conjugate was antigenically active at a much lower concentration than the free peptide. They also showed that antibody-peptide conjugates required an intact processing function of the B cell for peptide presentation, which could be selectively inhibited by leupeptin and chloroquine.(ABSTRACT TRUNCATED AT 250 WORDS)
Salmonella bacteraemia in a tertiary children's hospital (2004)

A retrospective study was conducted between July 1990 and July 2002 to investigate the epidemiology, clinical characteristics, and the outcome of Salmonella bacteraemia in children. A total of 148 episodes of bacteraemia were identified in 144 children. The annual incidence ranged from 1.6 to 8.3 cases per 100,000 children < or = 14 y of age, and higher numbers of cases occurred in summer than in winter months. In 22 children the bacteraemia was caused by S. typhi and in 122 by S. non-typhi. S. enteritidis was the most common serotype isolated. Resistance to ampicillin was exhibited by 28.5% of Salmonella isolates, whereas all S. typhi isolates were susceptible to commonly used antibiotics. The mean age was 40.3 months (range 50 d to 14 y). Children with S. typhi bacteraemia were significantly older than children with S. non-typhi bacteraemia (7.8 vs 2.4 y, p < 0.01). 11 children were immunosuppressed. The immunosuppressed children had longer duration of fever, longer hospitalization stay, and higher relapse rates compared to normal children (p < 0.05). Four children developed complications and 1 died. Although the incidence of S. typhi bacteraemia is decreasing, the non-typhi species continue to cause significant morbidity in our geographical region.
A phase I/II study of MM-111, a novel bispecific antibody that targets the ErB2/ErB3 heterodimer, in combination with trastuzumab in advanced refractory HER2-positive breast cancer. (2011)

TPS119 Background: The ErbB2/ErbB3 oncogenic heterodimer is the most potent ErbB receptor pairing with respect to strength of interaction, receptor tyrosine phosphorylation, and downstream signaling through mitogen activated protein kinase and phosphoinositide-3 kinase pathways. MM-111 is a novel bispecific antibody fusion protein that specifically targets the ErbB2/ErbB3 heterodimer and abrogates binding of ErbB3's ligand heregulin. In preclinical models of HER-2+ solid tumors, MM-111 inhibits ligand-induced ErbB3 phosphorylation, cell cycle progression, and tumor growth. ErbB2 (HER2) is a well established target of anticancer agents such as trastuzumab and lapatinib for HER2+ cancers, specifically breast and gastric. ErbB3 signaling has emerged as an important mechanism of resistance to ErbB2 (HER-2) targeted agents in clinical use, and preclinical data demonstrates that MM-111 potentiates the antitumor activity of trastuzumab. This first-in-human phase I/II study evaluates the safety and tolerability of MM-111 in combination with trastuzumab and preliminarily explores efficacy in HER-2+ advanced breast cancer (ABC). Methods: This is a phase I/II, open label, multicenter, dose-escalation study that will evaluate the safety, pharmacokinetics (PK), and efficacy of MM-111 + trastuzumab. There is a dose escalation phase followed by an expansion cohort. The dose escalation phase utilizes a standard "3 + 3" design where doses of MM-111 will be escalated until the phase II dose is identified in combination with trastuzumab given at the approved dose and regimen. Once the MTD or phase II dose is identified, an expansion cohort will be enrolled to further evaluate the safety and efficacy of doublet. Key exploratory analyses will include an evaluation of safety and efficacy and levels of expression and/or amplification of HER2 and heregulin. As of January 1 2011, cohorts 1 thru 2 have been completed without DLT. A total of 7 patients have been treated. Enrollment to cohort 3 is ongoing.
G-Protein Signaling Through Tubby Proteins (2001)

Dysfunction of the tubby protein results in maturity-onset obesity in mice. Tubby has been implicated as a transcription regulator, but details of the molecular mechanism underlying its function remain unclear. Here we show that tubby functions in signal transduction from heterotrimeric GTP-binding protein (G protein)-coupled receptors. Tubby localizes to the plasma membrane by binding phosphatidylinositol 4,5-bisphosphate through its carboxyl terminal "tubby domain." X-ray crystallography reveals the atomic-level basis of this interaction and implicates tubby domains as phosphorylated-phosphatidyl- inositol binding factors. Receptor-mediated activation of G protein alphaq (Galphaq) releases tubby from the plasma membrane through the action of phospholipase C-beta, triggering translocation of tubby to the cell nucleus. The localization of tubby-like protein 3 (TULP3) is similarly regulated. These data suggest that tubby proteins function as membrane-bound transcription regulators that translocate to the nucleus in response to phosphoinositide hydrolysis, providing a direct link between G-protein signaling and the regulation of gene expression.
The Cost Effectiveness of Vaccinating against Lyme Disease (1999)

To determine the cost effectiveness of vaccinating against Lyme disease, we used a decision tree to examine the impact on society of six key components. The main measure of outcome was the cost per case averted. Assuming a 0.80 probability of diagnosing and treating early Lyme disease, a 0.005 probability of contracting Lyme disease, and a vaccination cost of $50 per year, the mean cost of vaccination per case averted was $4,466. When we increased the probability of contracting Lyme disease to 0.03 and the cost of vaccination to $100 per year, the mean net savings per case averted was $3,377. Since few communities have average annual incidences of Lyme disease >0. 005, economic benefits will be greatest when vaccination is used on the basis of individual risk, specifically, in persons whose probability of contracting Lyme disease is >0.01.
Long range attachments - a method to simulate inextensible clothing in computer games (2012)

Inextensibility is one of the most fundamental properties of cloth. Existing approaches to handle inextensibility often require solving global non-linear systems and remain computationally expensive for computer game uses. Real time performance can be achieved by allowing damping or stretching at reduced solver costs, but these compromise visual realism - the cloth either looks stretchy or fine wrinkles get lost.Our long range attachment (LRA) method exploits that typical game character clothing tends to be attached to some kinematic parts of the character. LRA method applies unilateral distance constraint between free particles of the cloth to distant attachment point on the character, preventing them from stretching away from the kinematically driven attachments (e.g. shoulder for a cape). This simple step provides an efficient shortcut for enforcing global inextensibility that can be readily implemented into existing game physics methods such as PBD.
Dynamic histomorphometry of alveolar bone remodeling in the adult rat (1980)

Alveolar bone normally undergoes remodeling on one side of the socket and modeling on the opposite side as the tooth migrates at a rate of 6.7 micrometer per day. Periodontal ligament width, however, remains constant. Because of this very high turnover rate, this bone is a good model to study bone modeling and remodeling activities. This study was undertaken in order to measure the different cellular events occurring during tooth migration along the alveolar bone of the rat. The histomorphometric measurements performed on this model permitted us to calculate the duration of each phase of the remodeling cycle, i.e., resorption lasts about 1.5 days and reversal about 3.5 days. Since the duration of the forming phase is about 1 day (Guyomard and Baron, '74), the total duration of each remodeling cycle is about 6 days. This time is very short compared to 60--120 days in adult human trabecular bone. Additionally, in this model each osteoclast resorbs 2--4 times its own volume of bone per day. Based on this knowledge, it will be possible to measure accurately the effects of experimental conditions on bone cells and bone remodeling in this rat alveolar bone model.
E.M.C. Measurements on the Electrical Equipment of Cars (1977)

Two measuring methods one of the sus ceptibility to disturbances and the other of the intensity of the disturbances generated by electrical and electronic devices used on cars are here described. The measurements are performed using a network which is equivalent to the electrical network of cars and has been particularly designed for this type of tests. Therefore these e.m.c. measuring methods can give experimental results that are strictly related to the effective working conditions of the devices under test.
Gain-distributed feedback filters (1995)

Equivalent circuits are developed for gain-distributed feedback filters. The filters can be tuned by endloading. Side-coupling of the filters to a signal waveguide results in channel-dropping filters. These active filters suppress undesired resonances more effectively than passive filters.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Oxidation-stable amine-containing adsorbents for carbon dioxide capture (2018)

Amine-containing solids have been investigated as promising adsorbents for CO<sub>2</sub> capture, but the low oxidative stability of amines has been the biggest hurdle for their practical applications. Here, we developed an extra-stable adsorbent by combining two strategies. First, poly(ethyleneimine) (PEI) was functionalized with 1,2-epoxybutane, which generates tethered 2-hydroxybutyl groups. Second, chelators were pre-supported onto a silica support to poison p.p.m.-level metal impurities (Fe and Cu) that catalyse amine oxidation. The combination of these strategies led to remarkable synergy, and the resultant adsorbent showed a minor loss of CO<sub>2</sub> working capacity (8.5%) even after 30 days aging in O<sub>2</sub>-containing flue gas at 110 °C. This corresponds to a ~50 times slower deactivation rate than a conventional PEI/silica, which shows a complete loss of CO<sub>2</sub> uptake capacity after the same treatment. The unprecedentedly high oxidative stability may represent an important breakthrough for the commercial implementation of these adsorbents.
Depletion of NK Cells Improves Cognitive Function in the Alzheimer Disease Mouse Model (2020)

Despite mounting evidence suggesting the involvement of the immune system in regulating brain function, the specific role of immune and inflammatory cells in neurodegenerative diseases remain poorly understood. In this study, we report that depletion of NK cells, a type of innate lymphocytes, alleviates neuroinflammation, stimulates neurogenesis, and improves cognitive function in a triple-transgenic Alzheimer disease (AD) mouse model. NK cells in the brains of triple-transgenic AD mouse model (3xTg-AD) mice exhibited an enhanced proinflammatory profile. Depletion of NK cells by anti-NK1.1 Abs drastically improved cognitive function of 3xTg-AD mice. NK cell depletion did not affect amyloid β concentrations but enhanced neurogenesis and reduced neuroinflammation. Notably, in 3xTg-AD mice depleted of NK cells, microglia demonstrated a homeostatic-like morphology, decreased proliferative response and reduced expression of neurodestructive proinflammatory cytokines. Together, our results suggest a proinflammatory role for NK cells in 3xTg-AD mice and indicate that targeting NK cells might unlock novel strategies to combat AD.
Mechanism of Triclosan Inhibition of Bacterial Fatty Acid Synthesis (1999)

Triclosan is a broad-spectrum antibacterial agent that inhibits bacterial fatty acid synthesis at the enoyl-acyl carrier protein reductase (FabI) step. Resistance to triclosan in Escherichia coli is acquired through a missense mutation in the fabI gene that leads to the expression of FabI[G93V]. The specific activity and substrate affinities of FabI[G93V] are similar to FabI. Two different binding assays establish that triclosan dramatically increases the affinity of FabI for NAD+. In contrast, triclosan does not increase the binding of NAD+ to FabI[G93V]. The x-ray crystal structure of the FabI-NAD+-triclosan complex confirms that hydrogen bonds and hydrophobic interactions between triclosan and both the protein and the NAD+ cofactor contribute to the formation of a stable ternary complex, with the drug binding at the enoyl substrate site. These data show that the formation of a noncovalent "bi-substrate" complex accounts for the effectiveness of triclosan as a FabI inhibitor and illustrates that mutations in the FabI active site that interfere with the formation of a stable FabI-NAD+-triclosan ternary complex acquire resistance to the drug.
Metallic Nanowires by Full Wafer Stencil Lithography (2008)

Aluminum and gold nanowires were fabricated using 100 mm stencil wafers containing nanoslits fabricated with a focused ion beam. The stencils were aligned and the nanowires deposited on a substrate with predefined electrical pads. The morphology and resistivity of the wires were studied. Nanowires down to 70 nm wide and 5 mum long have been achieved showing a resistivity of 10 microOmegacm for Al and 5 microOmegacm for Au and maximum current density of approximately 10(8) A/cm(2). This proves the capability of stencil lithography for the fabrication of metallic nanowires on a full wafer scale.
Different Approaches for Noninvasive Prenatal Diagnosis of Genetic Diseases Based on PNA‐Mediated Enriched PCR (2006)

The aim of this work was to develop advanced and accessible protocols for noninvasive prenatal diagnosis of genetic diseases. We are evaluating different technologies for mutation detection, based on fluorescent probe hybridization of the amplified product and pyrosequencing, a technique that relies on the incorporation of nucleotides in a primer-directed polymerase extension reaction. In a previous investigation, we have already proven that these approaches are sufficiently sensitive to detect a few copies of a minority-mutated allele in the presence of an excess of wild-type DNA, In this work, in order to further enhance the sensitivity, we have employed a mutant enrichment amplification strategy based on the use of peptide nucleic acids (PNAs). These DNA analogues bind wild-type DNA, thus interfering with its amplification while still allowing the mutant DNA to become detectable. We have synthesized different PNAs, which are highly effective in clamping wild-type DNA in the beta-globin gene region, where four beta-thalassemia mutations are located (IVSI.110, CD39, IVSI.1, IVSI.6) plus HbS. The fluorescence microchip readout allows us to monitor the extent of wild-type allele inhibition, thus facilitating the assessment of the optimal PNA concentration.