gebhart/patrepeval huggingface dataset:
Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine (2010)

Locus ceruleus (LC)-supplied norepinephrine (NE) suppresses neuroinflammation in the brain. To elucidate the effect of LC degeneration and subsequent NE deficiency on Alzheimer's disease pathology, we evaluated NE effects on microglial key functions. NE stimulation of mouse microglia suppressed Abeta-induced cytokine and chemokine production and increased microglial migration and phagocytosis of Abeta. Induced degeneration of the locus ceruleus increased expression of inflammatory mediators in APP-transgenic mice and resulted in elevated Abeta deposition. In vivo laser microscopy confirmed a reduced recruitment of microglia to Abeta plaque sites and impaired microglial Abeta phagocytosis in NE-depleted APP-transgenic mice. Supplying the mice the norepinephrine precursor L-threo-DOPS restored microglial functions in NE-depleted mice. This indicates that decrease of NE in locus ceruleus projection areas facilitates the inflammatory reaction of microglial cells in AD and impairs microglial migration and phagocytosis, thereby contributing to reduced Abeta clearance. Consequently, therapies targeting microglial phagocytosis should be tested under NE depletion.
Multi-beam and single-chip LIDAR with discrete beam steering by digital micromirror device (2018)

A novel Digital Micromirror Device (DMD) based beam steering enables a single chip Light Detection and Ranging (LIDAR) system for discrete scanning points. We present increasing number of scanning point by using multiple laser diodes for Multi-beam and Single-chip DMD-based LIDAR.
Protein Kinase C Activation Regulates Human Serotonin Transporters in HEK-293 Cells via Altered Cell Surface Expression (1997)

Antidepressant- and cocaine-sensitive serotonin (5-hydroxytryptamine, 5-HT) transporters (SERTs) dictate clearance of extracellular 5-HT after release. To explore protein kinase C-mediated SERT regulation, we generated a stable human SERT (hSERT)-expressing cell line (293-hSERT) and evaluated modulation of 5-HT activity via studies of 5-HT flux, hSERT-mediated currents under voltage clamp, and surface distribution of SERT protein. 293-hSERT cells exhibit saturable, high-affinity, and antidepressant-sensitive 5-HT uptake as well as hSERT-dependent whole-cell currents. In these cells, the protein kinase C activator beta-PMA caused a time-dependent reduction in 5-HT uptake capacity (Vmax) after acute application and a reduction in SERT-mediated currents. Effects of beta-PMA were mimicked by the phorbol ester beta-PDBu, were not observed with the inactive alpha-isomers, and could be blocked by treatment of cells with the protein kinase C inhibitor staurosporine. Biotinylation/immunoblot analyses showed that activity reductions are paralleled by a staurosporine-sensitive loss of surface SERT protein. These data indicate that altered surface abundance, rather than reduced catalytic transport efficiency, mediates acute PKC-dependent modulation of 5-HT uptake.
The sequence of the nucleotides at the alpha-sarcin cleavage site in rat 28 S ribosomal ribonucleic acid. (1983)

The sequence of the 521 nucleotides at the 3' end of a rat 28 S rRNA gene was determined. The region encompasses the site of cleavage of 28 S rRNA by the cytotoxin alpha-sarcin. The toxin hydrolyzes a phosphodiester bond on the 3' side of a guanine residue 393 nucleotides from the 3' end. The alpha-sarcin domain is composed of a purine-rich sequence of 14 highly conserved nucleotides.
Helicobacter pylori and gastric diseases (1998)

The isolation of Helicobacter pylori from clinical specimens by Marshall and Warren 15 years ago1 launched revolutions in gastroenterology and microbiology. 2 3 Like other revolutions in history, the original directions of the H pylori story have changed in response to conflicting ideologies, observation, and practices. Currently, enthusiasts, drug companies, and the lay press are putting pressure on physicians to eliminate H pylori from all patients, symptomatic or not, in whom it is detected. There is little evidence that this is appropriate, and management will continue to change as new knowledge emerges and socioeconomic environments change in ways that are relevant to H pylori and clinical medicine. This article looks at past and current trends to anticipate the future of these common bacteria and the disorders associated with them.

H pylori is one of a large family of related bacteria that are well adapted to persist in the stomachs of vertebrates for the life span of their hosts. It is likely that H pylori has colonised our stomachs since well before we became humans.4 Studies of primates and human populations in developing countries suggest that, until the last century, nearly all humans carried H pylori or closely related bacteria in their stomachs. H pylori can thus be regarded as indigenous or “normal” flora, which most humans acquire within the first few years of childhood and then carry for life.

With socioeconomic development, fewer children are acquiring H pylori .5 This is a worldwide phenomenon that seems to have preceded the introduction of antibiotics, although it may have been accelerated by their widespread use. The reasons for the decline in the prevalence of H pylori colonisation are unknown. Improved nutrition and clean water have been proposed. An alternative hypothesis is that most transmission is from child to child …
Emergence of Fatal Avian Influenza in New England Harbor Seals (2012)

The emergence of new strains of influenza virus is always of great public concern, especially when the infection of a new mammalian host has the potential to result in a widespread outbreak of disease. Here we report the emergence of an avian influenza virus (H3N8) in New England harbor seals which caused an outbreak of pneumonia and contributed to a U.S. federally recognized unusual mortality event (UME). This outbreak is particularly significant, not only because of the disease it caused in seals but also because the virus has naturally acquired mutations that are known to increase transmissibility and virulence in mammals. Monitoring the spillover and adaptation of avian viruses in mammalian species is critically important if we are to understand the factors that lead to both epizootic and zoonotic emergence.
Hydrogen Sulfide Mediates Cardioprotection Through Nrf2 Signaling (2009)

These results reveal that the cardioprotective effects of H(2)S are mediated in large part by a combination of antioxidant and antiapoptotic signaling.
Transport of nutrients and hormones through the blood-brain barrier. (1984)

The transport of circulating nutrients (glucose, amino acids, ketone bodies, choline, and purines) through the brain endothelial wall, i.e., the blood-brain barrier (BBB), is an important regulatory step in several substrate-limited pathways of brain metabolism. The in vivo kinetics of nutrient transport has been well characterized in the rat, and the kinetic constants of saturable (Km, Vmax) and nonsaturable (KD) transport through the BBB are now known for more than 30 circulating nutrients. The kinetic constants can be used to gain insight into the important rate-limiting role played by BBB nutrient transport in the regulation of brain metabolism and function. Unlike most nutrients, steroid and thyroid hormones circulate tightly bound to plasma proteins. However, owing to favorable kinetic relationships among brain capillary transit times and rates of hormone dissociation from plasma proteins and hormone diffusion through the brain endothelia, the BBB is able to strip hormones off circulating plasma proteins. With regard to peptide hormone, no specific BBB transport systems for peptides have been identified thus far. However, peptides are able to rapidly distribute into brain interstitial space at the circumventricular organs. In addition, specific receptors for insulin are located on the BBB. The presence of BBB peptide receptors provides a mechanism by which circulating peptides may rapidly influence brain function without the peptide crossing the BBB.
The Preclinical Pharmacology of BIBN4096BS, a CGRP Antagonist (2005)

CGRP is an important neuropeptide found throughout the cardiovascular system. However, until recently it has been difficult to define its pharmacology or physiological role because of the lack of suitable antagonists. BIBN4096BS is a high-affinity, nonpeptide antagonist that shows much greater selectivity for human CGRP1 receptors compared to any other drug. Its pharmacology has been defined with studies on transfected cells or cell lines endogenously expressing receptors of known composition. These have allowed confirmation that in many human blood vessels, CGRP is working via CGRP1 receptors. However, it also interacts with other CGRP-activated receptors, of unknown composition. In vivo, clinical studies have shown that BIBN4096BS is likely to be useful in the treatment of migraine. It has also been used to define the role of CGRP in phenomena such as plasma extravasation and cardioprotection following ischemia.
Targeting BET Bromodomains for Cancer Treatment (2015)

The bromodomain and extraterminal (BET) subfamily of bromodomain-containing proteins has emerged in the last few years as an exciting, novel target group. BRD4, the best studied BET protein, is implicated in a number of hematological and solid tumors. This is linked to its role in modulating transcription elongation of essential genes involved in cell cycle and apoptosis such as c-Myc and BCL2. Potent BET inhibitors with promising antitumor efficacy in a number of preclinical cancer models have been identified in recent years. This led to clinical studies focusing mostly on the treatment of leukemia and lymphoma, and first encouraging signs of efficacy have already been reported. Here we discuss the biology of BRD4, its known interaction partners and implication in different tumor types. Further, we summarize the current knowledge on BET bromodomain inhibitors.
Illegitimate recombination induced by DNA double-strand breaks in a mammalian chromosome. (1994)

We examined DNA double-strand-break-induced mutations in the endogenous adenine phosphoribosyl-transferase (APRT) gene in cultured Chinese hamster ovary cells after exposure to restriction endonucleases. PvuII, EcoRV, and StuI, all of which produce blunt-end DNA double-strand breaks, were electroporated into CHO-AT3-2 cells hemizygous at the APRT locus. Colonies of viable cells containing mutations at APRT were expanded, and the mutations that occurred during break repair were analyzed at the DNA sequence level. Restriction enzyme-induced mutations consisted of small deletions of 1 to 36 bp, insertions, and combinations of insertions and deletions at the cleavage sites. Most of the small deletions involved overlaps of one to four complementary bases at the recombination junctions. Southern blot analysis revealed more complex mutations, suggesting translocation, inversion, or insertion of larger chromosomal fragments. These results indicate that blunt-end DNA double-strand breaks can induce illegitimate (nonhomologous) recombination in mammalian chromosomes and that they play an important role in mutagenesis.
Novel c-di-GMP recognition modes of the mouse innate immune adaptor protein STING (2013)

The mammalian ER protein STING (stimulator of interferon genes; also known as MITA, ERIS, MPYS or TMEM173) is an adaptor protein that links the detection of cytosolic dsDNA to the activation of TANK-binding kinase 1 (TBK1) and its downstream transcription factor interferon regulatory factor 3 (IFN3). Recently, STING itself has been found to be the direct receptor of bacterial c-di-GMP, and crystal structures of several human STING C-terminal domain (STING-CTD) dimers in the apo form or in complex with c-di-GMP have been published. Here, a novel set of structures of mouse STING-CTD (mSTING(137-344)) in apo and complex forms determined from crystals obtained under different crystallization conditions are reported. These novel closed-form structures exhibited considerable differences from previously reported open-form human STING-CTD structures. The novel mSTING structures feature extensive interactions between the two monomers, a unique asymmetric c-di-GMP molecule with one guanine base in an unusual syn conformation that is well accommodated in the dimeric interface with many direct specific interactions and two unexpected equivalent secondary peripheral c-di-GMP binding sites. Replacement of the amino acids crucial for specific c-di-GMP binding in mSTING significantly changes the ITC titration profiles and reduces the IFN-β reporter luciferase activity. Taken together, these results reveal a more stable c-di-GMP binding mode of STING proteins that could serve as a template for rational drug design to stimulate interferon production by mammalian cells.
Blocking Antibodies Targeting the CD39/CD73 Immunosuppressive Pathway Unleash Immune Responses in Combination Cancer Therapies (2019)

Immune checkpoint inhibitors have revolutionized cancer treatment. However, many cancers are resistant to ICIs, and the targeting of additional inhibitory signals is crucial for limiting tumor evasion. The production of adenosine via the sequential activity of CD39 and CD73 ectoenzymes participates to the generation of an immunosuppressive tumor microenvironment. In order to disrupt the adenosine pathway, we generated two antibodies, IPH5201 and IPH5301, targeting human membrane-associated and soluble forms of CD39 and CD73, respectively, and efficiently blocking the hydrolysis of immunogenic ATP into immunosuppressive adenosine. These antibodies promoted antitumor immunity by stimulating dendritic cells and macrophages and by restoring the activation of T cells isolated from cancer patients. In a human CD39 knockin mouse preclinical model, IPH5201 increased the anti-tumor activity of the ATP-inducing chemotherapeutic drug oxaliplatin. These results support the use of anti-CD39 and anti-CD73 monoclonal antibodies and their combination with immune checkpoint inhibitors and chemotherapies in cancer.
Immune Response, Accommodation, and Tolerance to Transplantation Carbohydrate Antigens (2004)

The carbohydrate antigens, blood groups A and B, and the alpha-gal epitope (Galalpha1-3Gal) are major risk factors in transplantation. Transplantation across ABO barriers may result in rejection by elicited anti-blood group antibodies, accommodation where elicited anti-blood group antibodies do not reject the graft, or tolerance where no anti-blood group antibodies are produced and the graft is not rejected. alpha1,3Galactosyltransferase knockout mice that lack alpha-gal epitopes but produce the anti-Gal antibody serve as a model for studying these immune responses. Knockout mice underwent transplantation heterotopically with wild-type mouse heart expressing alpha-gal epitopes and subsequently received lymphocytes including naive and memory anti-Gal B cells. The type of elicited immune response was found to be associated with the period that anti-Gal B cells were exposed to alpha-gal epitopes of the graft in the absence of T-cell help. Immediate T-cell help induced production of cytolytic anti-Gal antibodies that reject the graft, whereas delayed T-cell help induced production of accommodating anti-Gal antibodies. In the absence of T-cell help for prolonged periods, anti-Gal B cells exposed to alpha-gal epitopes were deleted, resulting in tolerance. Similar variations in the extent of T-cell help may determine the B-cell response to incompatible A or B antigens. The experimental model further suggests that active tolerance induction before transplantation may be achieved by gene therapy with autologous bone marrow cells or autologous lymphocytes manipulated to express the incompatible transplantation carbohydrate antigen by introduction of the corresponding glycosyltransferase gene into these cells.
Transformation of Legacy Software into Client/Server Applications through Pattern-Based Rearchitecturing (2008)

In this article, we address the problem of modularizing legacy applications with monolithic structure, primarily focusing on business software written in an object-oriented programming language. We introduce theTransFormr toolkit that guides the developer through the entire incremental transformation process. It is the goal of the transformation to separate the original software into several independent replaceable components to support the migration of legacy code to new hardware or to integrate legacy components into modern enterprise applications. We show the effectiveness of our approach by demonstrating a pattern-based transformation of classes in a case study.
Natural skin surface pH is on average below 5, which is beneficial for its resident flora (2006)

Variable skin pH values are being reported in literature, all in the acidic range but with a broad range from pH 4.0 to 7.0. In a multicentre study (N = 330), we have assessed the skin surface pH of the volar forearm before and after refraining from showering and cosmetic product application for 24 h. The average pH dropped from 5.12 +/- 0.56 to 4.93 +/- 0.45. On the basis of this pH drop, it is estimated that the 'natural' skin surface pH is on average 4.7, i.e. below 5. This is in line with existing literature, where a relatively large number of reports (c. 50%) actually describes pH values below 5.0; this is in contrast to the general assumption, that skin surface pH is on average between 5.0 and 6.0. Not only prior use of cosmetic products, especially soaps, have profound influence on skin surface pH, but the use of plain tap water, in Europe with a pH value generally around 8.0, will increase skin pH up to 6 h after application before returning to its 'natural' value of on average below 5.0. It is demonstrated that skin with pH values below 5.0 is in a better condition than skin with pH values above 5.0, as shown by measuring the biophysical parameters of barrier function, moisturization and scaling. The effect of pH on adhesion of resident skin microflora was also assessed; an acid skin pH (4-4.5) keeps the resident bacterial flora attached to the skin, whereas an alkaline pH (8-9) promotes the dispersal from the skin.
ELECTROWETTING-BASED MICROACTUATION OF DROPLETS FOR DIGITAL MICROFLUIDICS (2001)

Engineering—Electrical and Computer) ELECTROWETTING-BASED MICROACTUATION OF DROPLETS FOR DIGITAL MICROFLUIDICS by Michael George Pollack Department of Electrical and Computer Engineering Duke University
The Electrophysiological Effects of Lithium in the Rat (1977)

The effects of lithium on the tail nerve conduction velocity of the rat were studied. No effect of lithium on the conduction velocity was found, even at toxic serum lithium levels. No effect of lithium on repetitive stimulation of the distal forelimb flexor muscles was seen. The results suggest that electrophysiological measurements do not provide an effective means of titrating serum lithium levels in the rat. The results may have clinical signficance since they provide evidence against neuropathic or neuromuscular transmission defects as the cause of the transient weakness of some patients taking lithium.
Enhancing microbial metabolite and enzyme production: current strategies and challenges (2014)

OPINION article Front. Microbiol., 18 December 2014Sec. Systems Microbiology Volume 5 - 2014 | https://doi.org/10.3389/fmicb.2014.00718
Dominant phenotypes produced by the HD mutation in STHdhQ111 striatal cells (2000)

Lengthening a glutamine tract in huntingtin confers a dominant attribute that initiates degeneration of striatal neurons in Huntington's disease (HD). To identify pathways that are candidates for the mutant protein's abnormal function, we compared striatal cell lines established from wild-type and Hdh(Q111) knock-in embryos. Alternate versions of full-length huntingtin, distinguished by epitope accessibility, were localized to different sets of nuclear and perinuclear organelles involved in RNA biogenesis and membrane trafficking. However, mutant STHdh(Q111) cells also exhibited additional forms of the full-length mutant protein and displayed dominant phenotypes that did not mirror phenotypes caused by either huntingtin deficiency or excess. These phenotypes indicate a disruption of striatal cell homeostasis by the mutant protein, via a mechanism that is separate from its normal activity. They also support specific stress pathways, including elevated p53, endoplasmic reticulum stress response and hypoxia, as potential players in HD.
Molecular profiling of dilated cardiomyopathy that progresses to heart failure (2016)

Dilated cardiomyopathy (DCM) is defined by progressive functional and structural changes. We performed RNA-seq at different stages of disease to define molecular signaling in the progression from pre-DCM hearts to DCM and overt heart failure (HF) using a genetic model of DCM (phospholamban missense mutation, PLN<sup>R9C/+</sup>). Pre-DCM hearts were phenotypically normal yet displayed proliferation of nonmyocytes (59% relative increase vs. WT, <i>P</i> = 8 × 10<sup>-4</sup>) and activation of proinflammatory signaling with notable cardiomyocyte-specific induction of a subset of profibrotic cytokines including TGFβ2 and TGFβ3. These changes progressed through DCM and HF, resulting in substantial fibrosis (17.6% of left ventricle [LV] vs. WT, <i>P</i> = 6 × 10<sup>-33</sup>). Cardiomyocytes displayed a marked shift in metabolic gene transcription: downregulation of aerobic respiration and subsequent upregulation of glucose utilization, changes coincident with attenuated expression of PPARα and PPARγ coactivators -1α (PGC1α) and -1β, and increased expression of the metabolic regulator T-box transcription factor 15 (<i>Tbx15</i>). Comparing DCM transcriptional profiles with those in hypertrophic cardiomyopathy (HCM) revealed similar and distinct molecular mechanisms. Our data suggest that cardiomyocyte-specific cytokine expression, early fibroblast activation, and the shift in metabolic gene expression are hallmarks of cardiomyopathy progression. Notably, key components of these profibrotic and metabolic networks were disease specific and distinguish DCM from HCM.
Non-transgenic genome modifications in a hemimetabolous insect using zinc-finger and TAL effector nucleases (2012)

Hemimetabolous, or incompletely metamorphosing, insects are phylogenetically relatively basal and comprise many pests. However, the absence of a sophisticated genetic model system, or targeted gene-manipulation system, has limited research on hemimetabolous species. Here we use zinc-finger nuclease and transcription activator-like effector nuclease technologies to produce genetic knockouts in the hemimetabolous insect Gryllus bimaculatus. Following the microinjection of mRNAs encoding zinc-finger nucleases or transcription activator-like effector nucleases into cricket embryos, targeting of a transgene or endogenous gene results in sequence-specific mutations. Up to 48% of founder animals transmit disrupted gene alleles after zinc-finger nucleases microinjection compared with 17% after microinjection of transcription activator-like effector nucleases. Heterozygous offspring is selected using mutation detection assays that use a Surveyor (Cel-I) nuclease, and subsequent sibling crosses create homozygous knockout crickets. This approach is independent from a mutant phenotype or the genetic tractability of the organism of interest and can potentially be applied to manage insect pests using a non-transgenic strategy.
Bivalent Diketopiperazine-Based Tropomysin Receptor Kinase C (TrkC) Antagonists (2010)

Bivalent molecules containing two beta-turn mimics with side chains that correspond to hot-spots on the neurotrophin NT-3 were prepared. Binding assays showed the mimetics to be selective TrkC ligands, and biological assays showed one mimetic to be an antagonist of the TrkC receptor.
Expression Level of Valosin-Containing Protein Is Strongly Associated With Progression and Prognosis of Gastric Carcinoma (2003)

The prognostic significance of VCP expression level in GC was demonstrated.