gebhart/patrepeval huggingface dataset:
Traffic management: a holistic approach to memory placement on numa systems (2013)

NUMA systems are characterized by Non-Uniform Memory Access times, where accessing data in a remote node takes longer than a local access. NUMA hardware has been built since the late 80’s, and the operating systems designed for it were optimized for access locality. They co-located memory pages with the threads that accessed them, so as to avoid the cost of remote accesses. Contrary to older systems, modern NUMA hardware has much smaller remote wire delays, and so remote access costs per se are not the main concern for performance, as we discovered in this work. Instead, congestion on memory controllers and interconnects, caused by memory traffic from data-intensive applications, hurts performance a lot more. Because of that, memory placement algorithms must be redesigned to target traffic congestion. This requires an arsenal of techniques that go beyond optimizing locality. In this paper we describe Carrefour, an algorithm that addresses this goal. We implemented Carrefour in Linux and obtained performance improvements of up to 3.6 × relative to the default kernel, as well as significant improvements compared to NUMA-aware patchsets available for Linux. Carrefour never hurts performance by more than 4 % when memory placement cannot be improved. We present the design of Carrefour, the challenges of implementing it on modern hardware, and draw insights about hardware support that would
On the etiology of Crohn disease. (1996)

Crohn disease (CD) is a chronic, panenteric intestinal inflammatory disease. Its etiology is unknown. Analogous to the tuberculoid and lepromatous forms of leprosy, CD may have two clinical manifestations. One is aggressive and fistulizing (perforating), and the other is contained, indolent, and obstructive (nonperforating) [Gi]-berts, E. C. A. M., Greenstein, A. J., Katsel, P., Harpaz, N. & Greenstein, R. J. (1994) Proc. Natl. Acad. Sci. USA 91, 12721-127241. The etiology, if infections, may be due to Mycobacterium paratuberculosis. We employed reverse transcription PCR using M. paratuberculosis subspecies-specific primers (IS 900) on total RNA from 12 ileal mucosal specimens (CD, n = 8; controls, n = 4, 2 with ulcerative colitis and 2 with colonic cancer). As a negative control, we used Myobacterium avium DNA, originally cultured from the drinking water of a major city in the United States. cDNA sequence analysis shows that all eight cases of Crohn's disease and both samples from the patients with ulcerative colitis contained M. paratuberculosis RNA. Additionally, the M. avium control has the DNA sequence of M. paratuberculosis. We demonstrate the DNA sequence of M. paratuberculosis from mucosal specimens from humans with CD. The potable water supply may be a reservoir of infection. Although M. paratuberculosis signal in CD has been previously reported, a cause and effect relationship has not been established. In part, this is due to conflicting data from studies with empirical antimycobacterial therapy. We conclude that clinical trials with anti-M. paratuberculosis therapy are indicated in patients with CD who have been stratified into the aggressive (perforating) and contained (nonperforating) forms.
Complexes of tetraspanins with integrins: more than meets the eye (2001)

The transmembrane proteins of the tetraspanin superfamily are implicated in a diverse range of biological phenomena, including cell motility, metastasis, cell proliferation and differentiation. The tetraspanins are associated with adhesion receptors of the integrin family and regulate integrin-dependent cell migration. In cells attached to the extracellular matrix, the integrin-tetraspanin adhesion complexes are clustered into a distinct type of adhesion structure at the cell periphery. Various tetraspanins are associated with phosphatidylinositol 4-kinase and protein kinase C isoforms, and they may facilitate assembly of signalling complexes by tethering these enzymes to integrin heterodimers. At the plasma membrane, integrin-tetraspanin signalling complexes are partitioned into specific microdomains proximal to cholesterol-rich lipid rafts. A substantial fraction of tetraspanins colocalise with integrins in various intracellular vesicular compartments. It is proposed that tetraspanins can influence cell migration by one of the following mechanisms: (1) modulation of integrin signalling; (2) compartmentalisation of integrins on the cell surface; or (3) direction of intracellular trafficking and recycling of integrins.
Nightly duration of pineal melatonin secretion determines the reproductive response to inhibitory day length in the ewe (1984)

The pineal controls the reproductive response of ewes to both stimulatory (short) and inhibitory (long) day lengths. Melatonin, a pineal hormone whose nocturnal secretion is entrained by photoperiod, mediates the effect of stimulatory photoperiod. We now report that melatonin also mediates the effect of inhibitory day length, monitored as response to estradiol negative feedback on luteinizing hormone (LH) secretion. Ovariectomized, estradiol-implanted ewes were pinealectomized and intravenously infused with melatonin to restore the nightly melatonin rise. Following transfer from short to long days, and a concurrent switch from short- to long-day melatonin patterns, LH dropped precipitously in pinealectomized ewes, matching the photoinhibitory response of pineal intact controls. LH dropped similarly in pinealectomized ewes when long-day melatonin was infused under short days. Pinealectomized ewes transferred from long to short days displayed a marked LH rise, provided melatonin was also switched to the short-day pattern. LH remained suppressed if long-day melatonin was infused following transfer to short days. These data indicate the nighttime melatonin rise mediates reproductive responses to inhibitory, as well as stimulatory photoperiods; they further suggest the duration of this rise controls suppression of LH under long days. Rather than being strictly pro- or antigonadal, the pineal participates in measuring day length.
Development and Optimization of a Novel Assay To Measure Neutralizing Antibodies against Clostridium difficile Toxins (2013)

Clostridium difficile produces two major virulence toxins, toxin A (TcdA) and toxin B (TcdB). Antitoxin antibodies, especially neutralizing antibodies, have been shown to be associated with a lower incidence of C. difficile infection (CDI) recurrence, and antibody levels are predictive of asymptomatic colonization. The development of an assay to detect the presence of neutralizing antibodies in animal and human sera for the evaluation of vaccine efficacy is highly desired. We have developed such an assay, which allows for the quantification of the effect of toxins on eukaryotic cells in an automated manner. We describe here the optimization of this assay to measure toxin potency as well as neutralizing antibody (NAb) activity against C. difficile toxins using a design-of-experiment (DOE) methodology. Toxin concentration and source, cell seeding density, and serum-toxin preincubation time were optimized in the assay using Vero cells. The assay was shown to be robust and to produce linear results across a range of antibody concentrations. It can be used to quantify neutralizing antibodies in sera of monkeys and hamsters immunized with C. difficile toxoid vaccines. This assay was shown to correlate strongly with traditional assays which rely on labor-intensive methods of determining neutralizing antibody titers by visual microscopic inspection of intoxicated-cell monolayers. This assay has utility for the selection and optimization of C. difficile vaccine candidates.
Constructions for perfect maps and pseudorandom arrays (1988)

A construction of perfect maps, i.e. periodic r*v binary arrays in which each n*m binary matrix appears exactly once, is given. A similar construction leads to arrays in which only the zero n*m matrix does not appear and to a construction in which only a few n*m binary matrices do not appear. A generalization to the nonbinary case is given. The constructions involve an interesting problem in shift-register theory. The solution is given for almost all the case of this problem.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Constant interaction-time scatter/gather browsing of very large document collections (1993)

The Scatter/Gather document browsing method uses fast document clustering to produce table-of-contents-like outlines of large document collections. Previous work [1] developed linear-time document clustering algorithms to establish the feasibility of this method over moderately large collections. However, even linear-time algorithms are too slow to support interactive browsing of very large collections such as Tipster, the DARPA standard text retrieval evaluation collection. We present a scheme that supports constant interaction-time Scatter/Gather of arbitrarily large collections after near-linear time preprocessing. This involves the construction of a cluster hierarchy. A modification of Scatter/Gather employing this scheme, and an example of its use over the Tipster collection are presented.
Flexible carbon nanotube sensors for nerve agent simulants (2006)

Chemiresistor-based vapour sensors made from network films of single-walled carbon nanotube (SWNT) bundles on flexible plastic substrates (polyethylene terephthalate, PET) can be used to detect chemical warfare agent simulants for the nerve agents Sarin (diisopropyl methylphosphonate, DIMP) and Soman (dimethyl methylphosphonate, DMMP). Large, reproducible resistance changes (75-150%), are observed upon exposure to DIMP or DMMP vapours, and concentrations as low as 25 ppm can be detected. Robust sensor response to simulant vapours is observed even in the presence of large equilibrium concentrations of interferent vapours commonly found in battle-space environments, such as hexane, xylene and water (10 000 ppm each), suggesting that both DIMP and DMMP vapours are capable of selectively displacing other vapours from the walls of the SWNTs. Response to these interferent vapours can be effectively filtered out by using a 2 µm thick barrier film of the chemoselective polymer polyisobutylene (PIB) on the SWNT surface. These network films are composed of a 1-2 µm thick non-woven mesh of SWNT bundles (15-30 nm diameter), whose sensor response is qualitatively and quantitatively different from previous studies on individual SWNTs, or a network of individual SWNTs, suggesting that vapour sorption at interbundle sites could be playing an important role. This study also shows that the line patterning method used in device fabrication to obtain any desired pattern of films of SWNTs on flexible substrates can be used to rapidly screen simulants at high concentrations before developing more complicated sensor systems.
Genome economization and a new approach to the species concept in bacteria (1999)

The direct experimental evidence presented here shows that Escherichia coli cells can lose a part of their DNA during prolonged starvation. Under stringent conditions cells with a reduced DNA content achieve reproductive advantage over those that maintain their original genome size. Thus, the majority or nearly all of the cells of a long-starved bacterial population undergo genome size reduction. The loss of DNA seems to occur at random in different cells of a population and, thus, their DNA content may vary significantly from one another. The heterogeneity at the DNA level seems to be reflected in conspicuous morphological variability as well. We suggest that, in evolutionary terms, the general dynamics of bacterial genome organization involve two contrasting mechanisms: genome economization (size reduction by DNA loss) and genome loading (acquisition of exogenous DNA and its maintenance in the genome). The former, strengthening the so–called r strategy, might have resulted in the limited genome size of prokaryotes ranging up to 9.5 Mb. The latter explains the widespread horizontal, interspecific gene transfer (general genetic mixing) in bacteria. In the light of the above findings we propose a species concept in bacteria which is comparable to the biological species concept based on reproductive incompatibility.
Neonatal Estrogen Exposure Up-Regulates Estrogen Receptor Expression in the Developing and Adult Rat Prostate Lobes* (1997)

Neonatal exposure to estrogens results in permanent imprints of the rat prostate gland. To delineate the direct target of estrogen action within that tissue, the present study examined estrogen receptor (ER) expression by immunocytochemistry and in situ hybridization. ER were confined to mesenchymal cells in the urogenital sinus and proximal regions of the budding prostate lobes of newborn control rat prostates, and this expression declined after morphogenesis. Exposure to estradiol benzoate on days 1, 3, and 5 resulted in induction of ER expression in periductal smooth muscle cells from the proximal regions out to the distal tips of the developing prostate lobes. This ER expression was associated with the appearance of ER messenger RNA in those cells; thus, it was concluded that the up-regulation of ER by estrogens is mediated at the message level. Autoregulation of ER expression was next examined in adult prostates that had been exposed to oil or estrogens neonatally. Day 70 rats were castrated and given testosterone with or without estradiol for 7 days before death. Estrogen exposure in adulthood induced low levels of epithelial cell ER in the lateral lobe. Neonatal estrogenization increased the sensitivity of lateral lobe epithelial cells to this autoregulation, as the incidence and intensity of ER immunostaining were markedly increased. No autoinduction of ER was observed in adult ventral or dorsal prostatic lobes. From the present study we conclude that smooth muscle cells are the targets of estrogen action in the developmentally estrogenized prostate and that estrogen amplifies its own effects through auto-up-regulation of ER. In addition, lateral lobe epithelial cells are sensitive to estrogen up-regulation of ER, which may in part account for the lobe-specific effects observed after neonatal estrogenization of the prostate gland.
Triplex formation by morpholino oligodeoxyribonucleotides in the HER-2/neu promoter requires the pyrimidine motif (2001)

Triplex-forming oligonucleotides (TFOs) are good candidates to be used as site-specific DNA-binding agents. Two obstacles encountered with TFOs are susceptibility to nuclease activity and a requirement for magnesium for triplex formation. Morpholino oligonucleotides were shown in one study to form triplexes in the absence of magnesium. In the current study, we have compared phosphodiester and morpholino oligonucleotides targeting a homopurine-homopyrimidine region in the human HER2/neu promoter. Using gel mobility shift analysis, our data demonstrate that triplex formation by phosphodiester oligonucleotides at the HER-2/neu promoter target is possible with pyrimidine-parallel, purine-antiparallel and mixed sequence (GT)-antiparallel motifs. Only the pyrimidine-parallel motif morpholino TFO was capable of efficient triple helix formation, which required low pH. Triplex formation with the morpholino TFO was efficient in low or no magnesium. The pyrimidine motif TFOs with either a phosphodiester or morpholino backbone were able to form triple helices in the presence of potassium ions, but required low pH. We have rationalized the experimental observations with detailed molecular modeling studies. These data demonstrate the potential for the development of TFOs based on the morpholino backbone modification and demonstrate that the pyrimidine motif is the preferred motif for triple helix formation by morpholino oligonucleotides.
Cerestat and other NMDA antagonists in ischemic stroke (1997)

A wealth of experimental evidence demonstrates that cerebral ischemia causes excessive release of glutamate and that glutamate contributes to ischemic injury. Glutamate antagonism by any of several mechanisms can ameliorate the extent of infarction. These antagonists comprise noncompetitive blockers of the ion channel associated with the N-methyl-D-aspartate (NMDA) receptor [e.g., aptiganel (Cerestat)], competitive antagonists of the glutamate recognition site of the NMDA receptor (e.g., selfotel) or of the glycine recognition site (e.g., ACEA 1021, GV150526), antagonists at the polyamine site (e.g., eliprodil), and drugs that may interfere with glutamate release by sodium channel blockade as well as having other actions (e.g., lubeluzole, 619C89). Clinical experience suggests that although some NMDA antagonists are poorly tolerated at putative neuroprotective doses (e.g., selfotel), potentially neuroprotective plasma concentrations can be achieved in humans with others (e.g., aptiganel), though tolerable adverse effects are frequently observed. These clinical effects include hypertension (which is probably preferable to the hypotension seen with nimodipine and lifarizine), sedation, confusion or hallucinations and, at high doses, catatonia. Glycine antagonists may be associated with fewer adverse effects, but preclinical studies suggest that brain penetration may be low. Although recent studies with selfotel and eliprodil have been discontinued because of insufficient evidence for a satisfactory risk/benefit ratio, encouraging experience with aptiganel, magnesium, and glycine antagonists has prompted continued clinical trials with these agents. To be of sufficient size to detect a clinically useful improvement in outcome, these trials need to be large (600-1,000 patients). Present trials with aptiganel (Cerestat) are comparing the efficacy and tolerability of two doses vs. placebo in patients treated within 6 hours of ischemic stroke. Outcome is assessed by the modified Rankin Scale at 3 months.
Monoclonal antibodies for radioimmunodetection of tumours and for targeting. (1983)

A monoclonal antibody 791T/36 prepared against human osteogenic sarcoma has been used to detect primary and metastatic colorectal carcinomas by external imaging of patients following injection of 131I-labelled antibody. In 10 of 11 patients radiolabelled 791T/36 antibody localized in tumours, the tumour: non tumour ratio of radioactivity ranging from 1.5:1 to 8.1. 791T/36 antibody was also evaluated for its potential for targeting anti-tumour agents including cytotoxic drugs (Vindesine) and immunomodulating agents (interferon0. Vindesine-791T/36 conjugates were preferentially cytotoxic in vitro for target cells expressing the 791T/36 antibody defined antigen. Also interferon conjugated to 791T/36 antibody, like free interferon activated peripheral blood natural killer cell activity. These in vitro tests together with related studies on antibody localization in vivo indicate the potential of monoclonal antibody targeting of anti-tumour agents.
C1s Inhibition by BIVV009 (Sutimlimab) Prevents Complement-Enhanced Activation of Autoimmune Human B Cells In Vitro (2019)

The classical pathway of complement (CP) can mediate C3 opsonization of Ags responsible for the costimulation and activation of cognate B lymphocytes. In this manner, the complement system acts as a bridge between the innate and adaptive immune systems critical for establishing a humoral response. However, aberrant complement activation is often observed in autoimmune diseases in which C3 deposition on self-antigens may serve to activate self-reactive B cell clones. In this study, we use BIVV009 (Sutimlimab), a clinical stage, humanized mAb that specifically inhibits the CP-specific serine protease C1s to evaluate the impact of upstream CP antagonism on activation and proliferation of normal and autoimmune human B cells. We report that BIVV009 significantly inhibited complement-mediated activation and proliferation of primary human B cells. Strikingly, CP antagonism suppressed human Ig-induced activation of B cells derived from patients with rheumatoid arthritis. These results suggest that clinical use of CP inhibitors in autoimmune patients may not only block complement-mediated tissue damage, but may also prevent the long-term activation of autoimmune B cells and the production of autoantibodies that contribute to the underlying pathologic condition of these diseases.
Modulation of Dendritic Cell Differentiation and Maturation by Decoy Receptor 3 (2002)

Decoy receptor 3 (DcR3), a soluble receptor belonging to the TNFR superfamily, is a receptor for both Fas ligand (FasL) and LIGHT. It has been demonstrated that DcR3 is up-regulated in lung and colon cancers, thus promoting tumor growth by neutralizing the cytotoxic effects of FasL and LIGHT. In this study, we found that DcR3.Fc profoundly modulated dendritic cell differentiation and maturation from CD14(+) monocytes, including the up-regulation of CD86/B7.2, and the down-regulation of CD40, CD54/ICAM-1, CD80/B7.1, CD1a, and HLA-DR. Moreover, DcR3-treated dendritic cells suppressed CD4(+) T cell proliferation in an allogeneic MLR and up-regulated IL-4 secretion of CD4(+)CD45RA(+) T cells. This suggests that DcR3.Fc may act not only as a decoy receptor to FasL and LIGHT, but also as an effector molecule to skew T cell response to the Th2 phenotype.
Teaming up to crack innovation and enterprise integration. (2008)

In the continuing quest for business growth, many CEOs are turning to their CIOs and IT organizations because technology is essential to two compelling sources of growth: innovation and integration. Innovation, of course, is doing new things that customers ultimately appreciate and value--not only developing new generations of products, services, channels, and customer experience but also conceiving new business processes and models. Integration is making the multiple units, functions, and sites of large organizations work together to increase capacity, improve performance, lower cost structure, and discover opportunities for improvement that don't appear until you look across functions.
Regulation of Small GTPases by GEFs, GAPs, and GDIs (2013)

Small GTPases use GDP/GTP alternation to actuate a variety of functional switches that are pivotal for cell dynamics. The GTPase switch is turned on by GEFs, which stimulate dissociation of the tightly bound GDP, and turned off by GAPs, which accelerate the intrinsically sluggish hydrolysis of GTP. For Ras, Rho, and Rab GTPases, this switch incorporates a membrane/cytosol alternation regulated by GDIs and GDI-like proteins. The structures and core mechanisms of representative members of small GTPase regulators from most families have now been elucidated, illuminating their general traits combined with scores of unique features. Recent studies reveal that small GTPase regulators have themselves unexpectedly sophisticated regulatory mechanisms, by which they process cellular signals and build up specific cell responses. These mechanisms include multilayered autoinhibition with stepwise release, feedback loops mediated by the activated GTPase, feed-forward signaling flow between regulators and effectors, and a phosphorylation code for RhoGDIs. The flipside of these highly integrated functions is that they make small GTPase regulators susceptible to biochemical abnormalities that are directly correlated with diseases, notably a striking number of missense mutations in congenital diseases, and susceptible to bacterial mimics of GEFs, GAPs, and GDIs that take command of small GTPases in infections. This review presents an overview of the current knowledge of these many facets of small GTPase regulation.