gebhart/patrepeval huggingface dataset:
Concomitant analysis of Helios and Neuropilin-1 as a marker to detect thymic derived regulatory T cells in naïve mice (2015)

Regulatory T (Treg) cells are characterized by the expression of CD4, CD25 and the intracellular Foxp3. However, these markers do not indicate whether Treg cells are thymic derived Treg (tTreg) cells or peripherally induced Treg (pTreg) cells. Recently, Helios and Neuropilin-1 (Nrp1) has been reported as potential markers for tTreg cells. Herein, we used flow cytometry to examine the proportion of CD4(+)CD8(-)CD25(+) Treg cells expressing Helios, Nrp1 and Foxp3 in thymus, pancreatic draining lymph nodes (PDLNs) and spleen of CD-1 mice, and thymus of NOD and C57BL/6 mice. The frequency of Helios(+) cells was higher than that of Nrp1(+) cells in CD4(+)CD8(-)CD25(+) and CD4(+)CD8(-)CD25(+)Foxp3(+) Treg cells in thymus. Interestingly, the proportion of IL-10(+), Ebi3(+)and CTLA-4(+) cells was higher in Helios(+) than Nrp1(+) tTreg cells. The anti-apoptotic activity of Helios(+) tTreg cells was higher in thymus compared to Nrp1(+) tTreg cells. Nrp1 seems to be expressed at a later developmental stage compared to Helios and Foxp3. Furthermore, the expression of Nrp1 in CD4(+)CD25(+) T cells of younger mice did not increase after stimulating them in vitro with anti-CD3 and -CD28. Thus, under these conditions, Helios could be considered a more reliable marker for distinguishing tTreg cells from pTreg cells than Nrp1.
Change in hepatocyte growth factor concentration promote mesenchymal stem cell‐mediated osteogenic regeneration (2011)

Mesenchymal stem cells (MSCs) play a crucial role in tissue repair by secretion of tissue nutrient factors such as hepatocyte growth factor (HGF). However, studies examining the effects of HGF on the proliferation and differentiation of MSCs used different concentrations of HGF and reported conflicting conclusions. This study aimed to determine the mechanisms by which different concentrations of HGF regulate MSC proliferation and osteogenic differentiation, and validate the mechanism in an animal model of early stage avascular necrosis of femoral head (ANFH). Our results demonstrate that a low concentration of HGF (20 ng/ml) preferentially promotes MSC osteogenic differentiation through increased c-Met expression and phosphorylation, Akt pathway activation, and increased expression of p27, Runx2 and Osterix. In contrast, a high concentration of HGF (100 ng/ml) strongly induced proliferation by inducing strong activation of the ERK1/2 signalling pathway. As validated by animal experiments, high localized expression of HGF achieved by transplantation of HGF transgenic MSCs into ANFH rabbits increased the number of MSCs. Subsequently, 2 weeks after transplantation, HGF levels decreased and MSCs differentiated into osteoblasts and resulted in efficient tissue repair. Our results demonstrate that sequential concentration changes in HGF control the proliferation and osteogenic differentiation of MSCs in vivo. This phenomenon can be exploited therapeutically to induce bone regeneration and, in turn, improve the efficacy of pharmacological intervention for ANFH treatment.
Distributed multiparty desktop conferencing system: MERMAID (1990)

This describes a distributed multiparty desktop conferencing system (MERMAID) and presents its preliminary brief evaluation, obtained as a result of daily use. MERMAID, which is designed based on group collaboration system architecture, provides an environment for widely distributed participants, seated at their desks, to hold real-time conferences by interchanging information through video, voice, and multimedia documents. This system is implemented by using narrow-band ISDN, high-speed data network, and UNIX-based EWSs with electronic writing pads, image scanners, video cameras, microphone-installed loudspeakers, etc. The system provides participants with the means for sharing information in such multimedia forms as video images, voice, text, graphics, still images, and hand drawn figures.
The relationship between melatonin and cortisol rhythms: clinical implications of melatonin therapy (2005)

Abstract Disturbances in circadian rhythm have been linked to chronic diseases such as insomnia, hypertension, diabetes, and depression. Here we review recent studies on the age‐related changes in cortisol and melatonin rhythms and then present descriptive statistics on our preliminary findings on the rectification of the cortisol rhythms by melatonin therapy in elderly patients with insomnia. In adults, the melatonin onset typically occurs during low cortisol secretion. Administration of exogenous melatonin around dusk will shift the phase of the human circadian clock to earlier hours (advance phase shift) leading to phase advances in circadian rhythms (e.g., sleep, endogenous melatonin, cortisol). With aging, the production of melatonin declines and is shifted to later hours while the production of cortisol increases and its peak occurs earlier in the night. In a randomized placebo‐controlled crossover study with 8 patients with insomnia aged 55 years and older, a group characterized by low and delayed melatonin production, administration of prolonged‐release melatonin in the evening was able to rectify the early onset cortisol production. This delay in nocturnal cortisol onset may explain in part the improvement in sleep quality in elderly patients with insomnia, in schizophrenics, and in depressed patients. Support of circadian pacemaker function by melatonin may provide a new strategy in the treatment of disorders related to impairments in the internal temporal order. The clinical benefit from a decrease in cortisol during the early part of the night may lie beyond the improvement of sleep into a better control of blood pressure, metabolism, and mood. Drug Dev. Res. 65:119–125, 2005. © 2005 Wiley‐Liss, Inc.
Replicated directory service for weakly consistent distributed caches (2003)

Relais is a replicated directory service that improves Web caching within an organization. Relais connects a distributed set of caches and mirrors, providing the abstraction of a single consistent, shared cache. Relais is based on a replication protocol that exploits the semantics of user requests to guarantee cache coherence. The protocol also exploits the semantics of origin servers to optimize bandwidth requirements. At the entry point for a client, Relais maintains a directory of the contents of each Relais data provider; this minimizes look-up latency, by making it a local operation. The cost of maintaining the directories consistent is minimized thanks to a weak consistency protocol. Relais has been prototyped on top of Squid; it has been in daily use for over a year.
Incidence, risk factors, and outcomes of Fusobacterium species bacteremia (2013)

Fusobacterium spp. bacteremia in our community is uncommon and occurs in approximately 5.5 cases per million population per annum. F. necrophorum occurred in an otherwise young healthy population and was not associated with any mortality. F. nucleatum was found primarily in older patients with chronic medical conditions and was associated with a mortality of approximately 10%. Bacteremias from other Fusobacterium spp. were rare.
Computerized Monitoring of Gas Production to Measure Forage Digestion In Vitro (1993)

The techniques reported in this paper were developed to facilitate the study of the kinetics of forage digestion in vitro by measuring gas production. Fiber disappearance as a measure of the reaction rate has been replaced by the use of computerized pressure sensors to monitor the gaseous products (CO2, CH4) of microbial metabolism. The recording system described requires a computer, pressure sensors, an interface card, and appropriate software to monitor gas production continuously. Several variables, including sample size, inoculum size, vessel size, and type of pressure sensor, have been investigated to determine ranges within which gas production can be measured accurately, and the reproducibility of the results has been established. Because this technique uses small (100-mg) samples, a modified NDF method has been introduced that allows determination of extent of digestion at the end of an incubation in which gas production has been monitored. A strong linear relationship existed between NDF disappearance and gas production.
Binding of adenovirus and its external proteins to Triton X-114. Dependence on pH. (1985)

35S-Labeled adenovirus type 2 (Ad2) (10 ng/ml) was incubated with 1% Triton X-114 at various pH values varying from 3.0 to 8.0. The detergent phase was separated from the aqueous phase by centrifugation, and the amounts of Ad2 were determined in the two phases. At pH 7.0-8.0, less than 5% of Ad2 was associated with the detergent phase; at pH 5.0 or below, about 60% of Ad2 was associated with the detergent phase. When a mixture of 35S-labeled capsid proteins was used at pH 7.0, 60-70% of the total proteins were associated with the detergent at pH 5.0, but less than 5% of the proteins interacted with detergent at pH 7.0. Among the three major external proteins (hexon, penton base, and fiber), penton base had the highest association with Triton X-114 at pH 5.0. Both intact virus and the capsid proteins that were associated with Triton X-114 at pH 5.0 were released into the aqueous phase on subsequent incubation at pH 7.0. On the basis of these results, it is suggested that mildly acidic pH induces amphiphilic properties in adenovirus capsid proteins and may help Ad2 escape from acidic endocytic vesicles.
Lethal oxidative damage and mutagenesis are generated by iron in delta fur mutants of Escherichia coli: protective role of superoxide dismutase (1995)

The Escherichia coli Fur protein, with its iron(II) cofactor, represses iron assimilation and manganese superoxide dismutase (MnSOD) genes, thus coupling iron metabolism to protection against oxygen toxicity. Iron assimilation is triggered by iron starvation in wild-type cells and is constitutive in fur mutants. We show that iron metabolism deregulation in fur mutants produces an iron overload, leading to oxidative stress and DNA damage including lethal and mutagenic lesions. fur recA mutants were not viable under aerobic conditions and died after a shift from anaerobiosis to aerobiosis. Reduction of the intracellular iron concentration by an iron chelator (ferrozine), by inhibition of ferric iron transport (tonB mutants), or by overexpression of the iron storage ferritin H-like (FTN) protein eliminated oxygen sensitivity. Hydroxyl radical scavengers dimethyl sulfoxide and thiourea also provided protection. Functional recombinational repair was necessary for protection, but SOS induction was not involved. Oxygen-dependent spontaneous mutagenesis was significantly increased in fur mutants. Similarly, SOD deficiency rendered sodA sodB recA mutants nonviable under aerobic conditions. Lethality was suppressed by tonB mutations but not by iron chelation or overexpression of FTN. Thus, superoxide-mediated iron reduction was responsible for oxygen sensitivity. Furthermore, overexpression of SOD partially protected fur recA mutants. We propose that a transient iron overload, which could potentially generate oxidative stress, occurs in wild-type cells on return to normal growth conditions following iron starvation, with the coupling between iron and MnSOD regulation helping the cells cope.
Matriptase‐2 gene (TMPRSS6) variants associate with breast cancer survival, and reduced expression is related to triple‐negative breast cancer (2013)

Matriptase-2 (TMPRSS6) has been identified as a breast cancer risk factor. Here, we examined relationships between TMPRSS6 genetic variations and breast cancer risk and survival, and determined the gene and protein expressions in breast tumors and assessed their clinical importance. Thirteen TMPRSS6 polymorphisms were genotyped in 462 invasive breast cancer cases and 458 controls. Gene expression was analyzed from 83 tumors and protein expression from 370 tumors. We then assessed the statistical significance of associations among genotypes, clinicopathological characteristics and survival. The TMPRSS6 variant rs2543519 was associated with breast cancer risk (p = 0.032). Multivariate analysis showed that four variants had effects on survival-rs2543519 (p = 0.017), rs2235324 (p = 0.038), rs14213212 (p = 0.044) and rs733655 (p = 0.021)-which were used to create a group variable that was associated with poorer prognosis correlating with more alleles related to reduced survival (p = 0.006; risk ratio, 2.375; 95% confidence interval, 1.287-4.382). Low gene expression was related to triple-negative breast cancer (p = 0.0001), and lower protein expression was detected in undifferentiated (p = 0.019), large (p = 0.014) and ductal or lobular tumors (p = 0.036). These results confirm the association of TMRRSS6 variants with breast cancer risk and survival. Matriptase-2 levels decrease with tumor progression, and lower gene expression is seen in poor-prognosis-related triple-negative breast cancers. Our study is the first to show that matriptase-2 gene variants are related to breast cancer prognosis, supporting matriptase-2 involvement in tumor development.
Asthma and poly(ADP-ribose) polymerase inhibition: a new therapeutic approach (2018)

Asthma is a chronic lung disease affecting people of all ages worldwide, and it frequently begins in childhood. Because of its chronic nature, it is characterized by pathological manifestations, including airway inflammation, remodeling, and goblet cell hyperplasia. Current therapies for asthma, including corticosteroids and beta-2 adrenergic agonists, are directed toward relieving the symptoms of the asthmatic response, with poor effectiveness against the underlying causes of the disease. Asthma initiation and progression depends on the T helper (Th) 2 type immune response carried out by a complex interplay of cytokines, such as interleukin (IL) 4, IL5, and IL13, and the signal transducer and activator of transcription 6. Much of the data resulting from different laboratories support the role of poly(ADP-ribose) polymerase (PARP) 1 and PARP14 activation in asthma. Indeed, PARP enzymes play key roles in the regulation and progression of the inflammatory asthma process because they affect the expression of genes and chemokines involved in the immune response. Consistently, PARP inhibition achievable either upon genetic ablation or by using pharmacological agents has shown a range of therapeutic effects against the disease. Indeed, in the last two decades, several preclinical studies highlighted the protective effects of PARP inhibition in various animal models of asthma. PARP inhibitors showed the ability to reduce the overall lung inflammation acting with a specific effect on immune cell recruitment and through the modulation of asthma-associated cytokines production. PARP inhibition has been shown to affect the Th1-Th2 balance and, at least in some aspects, the airway remodeling. In this review, we summarize and discuss the steps that led PARP inhibition to become a possible future therapeutic strategy against allergic asthma.
Treatment of hepatocellular carcinoma (1997)

Treatment of patients with hepatocellular carcinoma (HCC) is largely influenced by local resources and the clinical stage of the disease. Hepatic resection is the treatment of choice for patients with HCC and normal liver. Tumour size and number, and liver status are common guidelines for choosing treatment in patients with cirrhosis. Hepatic resection and liver transplantation offered the best chances of cure in patients with a single small tumour. The 3-year survival of these patients was definitively better than that of historical controls. In the setting of patients with well-preserved liver function, a controlled study comparing the cost-efficacy of resection and transplantation is deemed necessary by many, but it is hardly feasible for both ethical and practical considerations. One major drawback of surgery in patients with a small tumour is early tumour spread to regional lymph-nodes, which favours early tumour recurrence after operation. Patients with more advanced tumour disease were rarely eligible for surgery and had dismal prognoses. For those with small tumours who were not eligible for surgery, percutaneous ethanol injection appeared to be a cost-saving and effective treatment modality. Arterial embolization is the only recommendable palliative treatment of patients with large tumours and poor hepatic function.
Development of the domain name system (1988)

The Domain Name System (DNS) provides name service for the DARPA Internet. It is one of the largest name services in operation today, serves a highly diverse community of hosts, users, and networks, and uses a unique combination of hierarchies, caching, and datagram access. This paper examines the ideas behind the initial design of the DNS in 1983, discusses the evolution of these ideas into the current implementations and usages, notes conspicuous surprises, successes and shortcomings, and attempts to predict its future evolution.
The Amino Terminus of Varicella-Zoster Virus (VZV) Glycoprotein E Is Required for Binding to Insulin-Degrading Enzyme, a VZV Receptor (2007)

Varicella-zoster virus (VZV) glycoprotein E (gE) is required for VZV infection. Although gE is well conserved among alphaherpesviruses, the amino terminus of VZV gE is unique. Previously, we showed that gE interacts with insulin-degrading enzyme (IDE) and facilitates VZV infection and cell-to-cell spread of the virus. Here we define the region of VZV gE required to bind IDE. Deletion of amino acids 32 to 71 of gE, located immediately after the predicted signal peptide, resulted in loss of the ability of gE to bind IDE. A synthetic peptide corresponding to amino acids 24 to 50 of gE blocked its interaction with IDE in a concentration-dependent manner. However, a chimeric gE in which amino acids 1 to 71 of VZV gE were fused to amino acids 30 to 545 of herpes simplex virus type 2 gE did not show an increased level of binding to IDE compared with that of full-length HSV gE. Thus, amino acids 24 to 71 of gE are required for IDE binding, and the secondary structure of gE is critical for the interaction. VZV gE also forms a heterodimer with glycoprotein gI. Deletion of amino acids 163 to 208 of gE severely reduced its ability to form a complex with gI. The amino portion of IDE, as well an IDE mutant in the catalytic domain of the protein, bound to gE. Therefore, distinct motifs of VZV gE are important for binding to IDE or to gI.
CpG Methylation of Human Papillomavirus Type 16 DNA in Cervical Cancer Cell Lines and in Clinical Specimens: Genomic Hypomethylation Correlates with Carcinogenic Progression (2003)

Infection with genital human papillomaviruses (HPVs) is the primary cause of cervical cancer. The infection is widespread, and little is known about the secondary factors associated with progression from subclinical infection to invasive carcinoma. Here we report that HPV genomes are efficiently targeted in vivo by CpG methylation, a well-known mechanism of transcriptional repression. Indeed, it has been shown previously that in vitro-methylated HPV type 16 (HPV-16) DNA is transcriptionally repressed after transfection into cell cultures. By using a scan with the restriction enzyme McrBC, we observed a conserved profile of CpG hyper- and hypomethylation throughout the HPV-16 genomes of the tumor-derived cell lines SiHa and CaSki. Methylation is particularly high in genomic segments overlying the late genes, while the long control region (LCR) and the oncogenes are unmethylated in the single HPV-16 copy in SiHa cells. In 81 patients from two different cohorts, the LCR and the E6 gene of HPV-16 DNA were found to be hypermethylated in 52% of asymptomatic smears, 21.7% of precursor lesions, and 6.1% of invasive carcinomas. This suggests that neoplastic transformation may be suppressed by CpG methylation, while demethylation occurs as the cause of or concomitant with neoplastic progression. These prevalences of hyper- and hypomethylation also indicate that CpG methylation plays an important role in the papillomavirus life cycle, which takes place in asymptomatic infections and precursor lesions but not in carcinomas. Bisulfite modification revealed that in most of the HPV-16 genomes of CaSki cells and of asymptomatic patients, all 11 CpG dinucleotides that overlap with the enhancer and the promoter were methylated, while in SiHa cells and cervical lesions, the same 11 or a subset of CpGs remained unmethylated. Our report introduces papillomaviruses as models to study the mechanism of CpG methylation, opens research on the importance of this mechanism during the viral life cycle, and provides a marker relevant for the etiology and diagnosis of cervical cancer.
Singlet-Singlet and Triplet-Triplet Energy Transfer in Bichromophoric Cyclic Peptides (2002)

Intramolecular singlet-singlet (SSET) and triplet-triplet (TTET) energy transfer have been studied in two cyclic octapeptides, 1A and 2A, and their open chain analogs, 1B and 2B. The peptides are constructed by a solid phase synthetic technique from enantiomerically pure amino acids with alternating chirality. Cyclic peptides with this arrangement of amino acids preferentially adopt flat, disk-like conformations where the peptide side chains lie on the outside of the ensemble. In 1A, benzophenone and naphthalene chromophores are incorporated as 4-benzoyl-L-phenylalanine and 2-naphtyl-L-alanine at positions 1 and 5 in the peptide sequence while in 2A, these chromophores occupy positions 1 and 3. Molecular modeling studies indicate that the interchromophore separation is larger in 1A than in 2A. This difference in separation is apparent from the observation of TTET energy transfer in 2A, which is consistent with the short range nature of TTET. Low temperature phosphorescence results indicate that intramolecular TTET is efficient in 2A and 2B and occurs with a rate of kTTET &gt; 9.4x103 s-1. Intramolecular SSET occurs efficiently within these cyclic and open chain peptides. 1A undergoes intramolecular SSET from the naphthalene chromophore to the benzophenone chromophore with kSSET &gt; 3.7x107 s-1, while in 2A with kSSET &gt;3.0x107 s-1. Results obtained by modeling, UV-Visible spectroscopy, fluorescence and phosphorescence spectroscopies and transient absorption experiments are described.
Lethal Escherichia coli and Salmonella typhimurium endotoxemia is mediated through different pathways (2001)

Despite the differences in the molecular structure between lipopolysaccharides (LPS) isolated from Escherichia coli, Klebsiella pneumoniae or Salmonella typhimurium, the potential differences in their biological effects in vivo have not been investigated. In the present study, TNF and LT double knock-out (TNF−/−LT−/−) mice were almost as susceptible as TNF+/+LT+/+ controls to S. typhimurium LPS, but they were significantly more resistant to lethal endotoxemia induced by E. coli or K. pneumoniae LPS. The effect was not due to endotoxin-associated proteins. In the knock-out mice, this difference in lethality was accompanied by decreased interleukin-1 (IL-1) and interferon-γ (IFN-γ) production after challenge with E. coli LPS, whereas after S. typhimurium LPS more IL-1 and IFN-γ were produced. In contrast, more IL-10 was produced after challenge of mice with E. coli LPS than with S. typhymurium LPS. The hypothesis that a combination of pro-inflammatory cytokines is responsible for the mortality after S. typhimurium LPS was suggested by experiments in mice deficient in IL-1β-converting enzyme (ICE−/− mice). ICE-/-mice, lacking mature IL-1β and IL-18, but also defective in IFN-γ and TNF production, were completely protected against both E. coli and S. typhimurium LPS. Experiments in Toll-like receptor (TLR)-4 defective mice suggested that the difference is not due to differential activation of TLR4. In conclusion, TNF and LT play a central role in the lethality due to E. coli LPS, whereas the lethal effects of S. typhimurium LPS are mediated through mechanisms also involving other cytokines such as IFN-γ, IL-1 and IL-18.