gebhart/patrepeval huggingface dataset:
A λ1 transgene under the control of a heavy chain promoter and enhancer does not undergo somatic hypermutation (1994)

To identify cis-acting elements responsible for targeting somatic hypermutation to immunoglobulin variable regions, we generated transgenic mice which carry a rearranged lambda 1 gene regulated by the heavy chain intron enhancer, E mu, and the heavy chain promoter PH186.2 from the VH186.2 variable region. C57BL/6 x SJL founders were bred with C57BL/6 mice to establish a line carrying a single copy of the transgene. Somatic hypermutation was studied by generating hybridoma cell lines from mice immunized with the hapten (4-hydroxy-3-nitrophenyl)acetyl (NP) coupled to chicken gamma globulin. The immune response in this transgenic line was dominated by the endogenous VH186.2 heavy chain variable region and the transgenic lambda 1 light chain, and the transgene was actively expressed in all hybridomas analyzed. In this work we show that the transgenic V lambda 1 regions do not undergo hypermutation, despite high levels of expression, while the expressed heavy chain V regions accumulate mutations at a rate typical of the NP response in C57BL/6 mice. Thus, within the same B cell, the PH186.2 promoter in connection with E mu drives efficient expression of both a VH and a V lambda region, but only the VH is a target for somatic hypermutation. Our observations show that cis-acting sequences that activate immunoglobulin gene transcription are not sufficient to target somatic hypermutation.
Transport functions and physiological significance of 76 kDa Ral-binding GTPase activating protein (RLIP76). (2002)

We have recently demonstrated that a previously known Ral-binding GTPase activating protein, RLIP76, can also catalyze ATP-dependent transport of various structurally unrelated xeno- and endobiotics irrespective of their net charge (Awasthi et al., 2000, Biochemistry, 39: 9327). RLIP76 is a non-ATP binding cassette (ABC) protein but it has two ATP-binding sites and shows basal ATPase activity which is stimulated in the presence of its transport substrates (allocrites) such as doxorubicin (DOX) and S-(2,4-dinitrophenyl) glutathione (DNP-SG). Proteoliposomes reconstituted with purified RLIP76 catalyze ATP-dependent, saturable transport of DOX, as well as of glutathione-conjugates including leukotrienes (LTC4) and the GSH-conjugate of 4-hydroxynonenal (GS-HNE). In erythrocytes the majority of transport activity for DOX, GS-HNE, and LTC4 is accounted for by RLIP76. Cells exposed to mild oxidative stress show a rapid and transient induction of RLIP76 resulting in an increased efflux of GS-HNE and acquire resistance to oxidative stress mediated toxicity and apoptosis. Cells transfected with RLIP76 acquire resistance to DOX through increased efflux of the drug suggesting its possible role in the mechanisms of drug-resistance. In this article, we discuss the significance of transport functions of RLIP76 highlighting its role in the defense mechanisms against oxidative injury, and modulation of signaling mechanisms.
Reviews, reviews, reviews (2016)

Deputy Editor‐in‐Chief, Dr Patrick Chien, discusses his top articles from this issue in an audio podcast available at: https://soundcloud.com/bjog/january-editors-choice-2017
A Naturally Occurring Basically Charged Human Follicle-Stimulating Hormone (FSH) Variant Inhibits FSH-Induced Androgen Aromatization and Tissue-Type Plasminogen Activator Enzyme Activity in vitro (1998)

It is well known that deglycosylation of gonadotropins by enzymatic or chemical procedures or by deletion of sites for N-linked glycosylation produces antagonistic analogs which are able to interact strongly with the receptor and to inhibit binding of the wild-type hormone. In the present study, we analyzed the antagonistic properties of a naturally occurring basic follicle-stimulating hormone (FSH) charge isoform obtained after high-resolution chromatofocusing of human anterior pituitary glycoprotein extracts. Coincubation of increasing amounts of this isoform with a highly purified human pituitary FSH preparation or with recombinant human FSH at doses equivalent to their corresponding ED50 for estradiol and tissue-type plasminogen activator (tPA) production, inhibited FSH-induced estrogen production and tPA enzyme activity by cultured rat granulosa cells in a dose-dependent manner. These inhibitory effects were apparently exerted at steps following 3',5'-cyclic adenosine monophosphate (cAMP) formation and did not involve activation of the protein kinase C pathway since: (a) at low doses, this basic FSH isoform moderately increased FSH-induced cAMP production by cultured rat granulosa cells; (b) coincubation of the antagonist isoform with dibutyryl cAMP completely inhibited the effects of this cAMP analog on estrogen and tPA production; (c) the isoform was able to stimulate production of cAMP in a human fetal cell line expressing the recombinant human FSH receptor, and (d) the inhibitory effects of the isoform were not affected by staurosporine, a protein kinase C inhibitor. The effects of this isoform upon dibutyryl cAMP-induced estrogen and tPA production were blocked by the addition of a highly specific antibody directed against human FSH, further demonstrating that the antagonistic effects observed were due to FSH-like molecules. In contrast to the inhibitory effects exhibited by this basic FSH isoform, a more acidic FSH charge variant consistently acted as an agonist of pituitary and recombinant FSH on both estrogen production and induction of tPA enzyme activity. These results indicate that the anterior pituitary gland normally produces FSH isoforms which act as either agonists or antagonists of FSH at the target cell level.
17α‐Hydroxylase deficiency in a genetic male and female sibling pair (1981)

The diagnosis of congenital adrenal hyperplasia due to a deficiency of the enzyme 17 alpha-hydroxylase was made in a genetic male and female sibling pair born of parents who were first cousins. The genetic male was a phenotypic female who presented with primary amenorrhea and mild hypertension. The genetic female exhibited absence of secondary sexual characteristics and severe hypertension. The plasma steroid data confirmed the diagnosis of 17 alpha-hydroxylase deficiency in both subjects: low 17 alpha-hydroxyprogesterone, elevated desoxycorticosterone, elevated corticosterone and elevated progesterone. These are the first case reports of 17 alpha-hydroxylase deficiency in a male-female sibling pair, and they add support to the hypothesis that this is an autosomal recessive disorder.
Broadband Power Measurement of High-Voltage, Nanosecond Electric Pulses for Biomedical Applications (2008)

Experimental studies have shown that nanoelectropulses of sufficiently short rise time and duration can trigger cell apoptosis (programmed cell death). Specifically, pulses that last less than 20 ns have been shown to kill a wide variety of human cancer cells in vitro as well as induce tumor regression in vivo. To better understand the mechanisms by which nanopulses affect cancer cells, the electrical characteristics of the cells should be characterized so that it is clear how electrical energy is delivered. To achieve this end, a power measurement device that integrates into a nanopulse transmission line used for in vivo experiments has been designed, built, and calibrated. The device provides voltage and current measurements without disturbing the transmission of the pulse to the biological sample. The in vivo sample can be characterized either by a direct voltage/current measurement or by measuring the incident and reflected voltage pulse and using time domain reflectometry to calculate the impedance. The 3 dB bandwidth of both the microstrip line and the voltage attenuator has been measured to be 900 MHz and 1.25 GHz respectively.
Antioxidant Vitamins, Cancer, and Cardiovascular Disease (1996)

In 1850, an article on the origin of epidemic yellow fever and malaria appeared in the Boston Medical and Surgical Journal. 1 The anonymous author referred to earlier reports that “those who slept under musquito [sic] netting escaped the disease” and that “a gauze screen in a window adds much to the security of . . . the occupant of a chamber, in even the most unsound places.” These observations, which now seem prescient, were used to support the theory that epidemics result from infective spores carried by the wind from decaying organic matter; the netting and screens were believed to . . .
Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses (2008)

The tyrosine kinase inhibitors sorafenib and sunitinib are approved for the treatment of patients with malignant diseases. To analyze the possible use of these compounds in combination with immunotherapeutic approaches, we analyzed the effects of both inhibitors on the immunostimulatory capacity of human dendritic cells (DCs) and the induction of primary immune responses in vivo. Sorafenib, but not sunitinib, inhibits function of DCs, characterized by reduced secretion of cytokines and expression of CD1a, major histocompatibility complex, and costimulatory molecules in response to TLR ligands as well as by their impaired ability to migrate and stimulate T-cell responses. These inhibitory effects are mediated by inhibition of PI3 and MAP kinases and NFkappaB signaling. In contrast, sorafenib had no influence on the phenotype and proliferation of T cells. To analyze the effects of both TKIs on cytotoxic T-cell induction in vivo, C57BL/6 mice were pretreated with sorafenib or sunitinib and immunized with OVA(257-264) peptide. Sorafenib, but not sunitinib, application significantly reduced the induction of antigen-specific T cells. Numbers of regulatory T cells were reduced in peripheral blood mononuclear cells from mice treated with sunitinib. These results indicate that sunitinib, but not sorafenib, is suitable for combination with immunotherapeutic approaches for treatment of cancer patients.
Tyrphostin induces non‐apoptotic programmed cell death in colon tumor cells (1995)

The programmed cell death inducing effect of the EGF receptor tyrosine kinase inhibitor alpha-cyano-3,4-dihydroxycinnamthioamide (AG213) was investigated in vitro on HT-29 human colon tumor. AG213 at concentrations between 45 to 450 microM blocks the proliferation of HT-29 cells. Morphological findings suggest that the selective tyrosine kinase inhibitor AG213 induces Clarke III type (non-lysosomal vesiculate cytoplasmic) programmed cell death; unlike ATP analog non-selective tyrosine kinase inhibitors like Genistein which were found to induce apoptosis. Cycloheximide and Actinomycin-D reduced the effect of AG213 pointing to the fact that protein and RNA synthesis are also needed for this form of cell death. Acid phosphatase activity was found in the Golgi and in the newly formed intracytoplasmic vacuoles 3 hours after AG213 treatment which disappeared by 6 hours. The induction of Clarke III cell death by tyrosine kinase inhibitors may open a new modality to selective killing of tumor cells.
Differential regulation by protein kinase C isoforms of nitric oxide synthase induction in RAW 264.7 macrophages and rat aortic smooth muscle cells (1997)

1. In RAW 264.7 murine macrophages and rat aortic smooth muscle (RASM) cells lipopolysaccharide (LPS) alone or in combination with interferon gamma (IFN gamma) or forskolin, respectively, stimulated the expression of the 130 kDa inducible isoform of nitric oxide synthase (iNOS) in both a time- and concentration-dependent manner. 2. Incubation with the direct activator of protein kinase C (PKC), phorbol 12-myristate 13-acetate (PMA) alone, did not result in detectable iNOS expression in either cell type. 3. Chronic PMA pretreatment resulted in significant down-regulation of alpha, beta and epsilon isforms of PKC in RAW 264.7 macrophages and corresponded to a 20-30% reduction in LPS-induced iNOS expression. In contrast, IFN gamma alone or in combination with LPS stimulated an approximate 20% and 50% potentiation, respectively. 4. Pre-incubation with PKC inhibitors (calphostin C and H-7) showed similar effects upon stimulated induction of iNOS. 5. In RASM cells chronic PMA pretreatment resulted in down-regulation of alpha and epsilon PKC isoforms and corresponded to potentiation of iNOS expression in response to LPS alone or in combination with forskolin. 6. Co-incubation of RASM cells in the presence of PMA, angiotensin II (AII) or foetal calf serum (FCS) resulted in the inhibition of iNOS expression in response to LPS alone or in combination with forskolin. 7. Differential sensitivity to PKC inhibitors (calphostin C and H-7) was observed in RASM cells and exhibited both negative and positive modulation of stimulated induction. 8. In addition the PKC inhibitor compound Ro-31-8220 abolished stimulated induction in both cell types in response to all treatments. 9. These results suggest that PKC activation is required for induction of the 130 kDa isoform of NOS in both RAW 264.7 macrophages and RASM cells. However, individual PKC isoforms regulate iNOS expression in both a positive and negative manner.
Phenylbutyrate induces apoptosis in human prostate cancer and is more potent than phenylacetate. (1996)

Phenylbutyrate (PB), a novel lead compound for prostate cancer therapy, has molecular activities distinct from its metabolite, phenylacetate (PA). Both PB and PA promote differentiation in human prostate cancer cell lines, yet little data exist comparing the cytotoxic effects of each drug. We found that PB is more potent than PA in vitro; PB is 1.5-2.5 times more active at inhibiting growth and inducing programmed cell death than PA at clinically achievable doses against each human prostate cancer line studied. PB is equipotent to sodium butyrate, which induces apoptosis and differentiation through multiple mechanisms. Exposure of prostate cancer cell lines to PB reduces their DNA synthesis, leads to fragmentation of genomic DNA, and causes 50-60% of cells to undergo apoptosis. These PB-induced effects are 2-10 times greater than those of the control or PA. The stereotypical changes of apoptosis can be seen with sodium butyrate at similar concentrations, but not with PA. Prostate cancer cell lines overexpressing P-glycoprotein or possessing heterogeneous molecular alterations, including p53 mutations, are also sensitive to the effects of PB. In vivo, Copenhagen rats treated with oral PB had delayed growth of the androgen refractory Dunning R-3327 MAT-LyLu prostate cancer subline by 30-45% in a dose-dependent manner. These results demonstrate that PB induces cytotoxicity via apoptosis in human prostate cancer, in addition to its differentiating properties.
cis-acting RNA elements required for replication of bovine viral diarrhea virus–hepatitis C virus 5′ nontranslated region chimeras (1998)

Pestiviruses, such as bovine viral diarrhea virus (BVDV), share many similarities with hepatitis C virus (HCV) yet are more amenable to virologic and genetic analysis. For both BVDV and HCV, translation is initiated via an internal ribosome entry site (IRES). Besides IRES function, the viral 5' nontranslated regions (NTRs) may also contain cis-acting RNA elements important for viral replication. A series of chimeric RNAs were used to examine the function of the BVDV 5' NTR. Our results show that: (1) the HCV and the encephalomyocarditis virus (EMCV) IRES element can functionally replace that of BVDV; (2) two 5' terminal hairpins in BVDV genomic RNA are important for efficient replication; (3) replacement of the entire BVDV 5' NTR with those of HCV or EMCV leads to severely impaired replication; (4) such replacement chimeras are unstable and efficiently replicating pseudorevertants arise; (5) pseudorevertant mutations involve deletion of 5' sequences and/or acquisition of novel 5' sequences such that the 5' terminal 3-4 bases of BVDV genome RNA are restored. Besides providing new insight into functional elements in the BVDV 5' NTR, these chimeras may prove useful as pestivirus vaccines and for screening and evaluation of anti-HCV IRES antivirals.
Genomic Profiling of Advanced-Stage, Metaplastic Breast Carcinoma by Next-Generation Sequencing Reveals Frequent, Targetable Genomic Abnormalities and Potential New Treatment Options (2015)

Our results indicate that genomic profiling using next-generation sequencing can identify clinically meaningful alterations that have the potential to guide targeted treatment decisions in most patients with metastatic MPBC.
Integrated fiber Mach–Zehnder interferometer for electro-optic switching (2002)

Molten alloys under high pressure were used to obtain fibers with long internal electrodes that are solid at room temperature. An integrated Mach-Zehnder interferometer was constructed from a twin-core twin-hole fiber that permitted application of an electric field preferentially to one of the cores. Good stability and a switching voltage of 1.4kV were measured with a 1-m-long fiber device with a quadratic voltage dependence.
Calculating Synergistic and Antagonistic Responses of Herbicide Combinations (1967)

The responses of herbicides applied singly are used in calculating the “expected” response when they are combined. The expected response for a combination is obtained by taking the product of the percent-of-control values for herbicides applied alone and dividing by (100)n-1 where n is the number of herbicides in the combination.
Argument extraction for supporting public policy formulation (2013)

In this paper we describe an application of language technology to policy formulation, where it can support policy makers assess the acceptance of a yet-unpublished policy before the policy enters public consultation. One of the key concepts is that instead of relying on thematic similarity, we extract arguments expressed in support or opposition of positions that are general statements that are, themselves, consistent with the policy or not. The focus of this paper in this overall pipeline, is identifying arguments in text: we present and empirically evaluate the hypothesis that verbal tense and mood are good indicators of arguments that have not been explored in the relevant literature. 1
Mesos: a platform for fine-grained resource sharing in the data center (2011)

We present Mesos, a platform for sharing commodity clusters between multiple diverse cluster computing frameworks, such as Hadoop and MPI. Sharing improves cluster utilization and avoids per-framework data replication. Mesos shares resources in a fine-grained manner, allowing frameworks to achieve data locality by taking turns reading data stored on each machine. To support the sophisticated schedulers of today's frameworks, Mesos introduces a distributed two-level scheduling mechanism called resource offers. Mesos decides how many resources to offer each framework, while frameworks decide which resources to accept and which computations to run on them. Our results show that Mesos can achieve near-optimal data locality when sharing the cluster among diverse frameworks, can scale to 50,000 (emulated) nodes, and is resilient to failures.
Motion Compensation Assisted Motion Adaptive Interlaced-to-Progressive Conversion (2004)

Block-wise processing of motion compensated interlaced-to-progressive conversion (MC-IPC) can cause spurious errors that degrade converted image quality significantly. This paper presents a novel IPC method based on motion adaptive IPC (MA-IPC) with its adaptation assisted by the motion compensation. The motion adaptation is performed with respect to a motion selected from a limited set based on the accuracy evaluated with a reduced and overlapped block. The use of the reduced and overlapped blocks makes evaluation of the accuracy more precise, and implementation less costly. The motion adaptation structure ensures that any possible error occurs pixel-wise so that the block-wise spurious errors can be eliminated. The estimation of the motion is performed efficiently with data already available for the motion adaptation. The proposed motion compensation assisted MA-IPC method provides image quality similar to the MC-IPC, for those images, the MC-IPC offers significant improvement over the MA-IPC, yet at considerably lower computational and implementation costs.
Functional Analysis of the Genes of Yeast Chromosome V by Genetic Footprinting (1996)

Genetic footprinting was used to assess the phenotypic effects of Ty1 transposon insertions in 268 predicted genes of chromosome V of Saccharomyces cerevisiae. When seven selection protocols were used, Ty1 insertions in more than half the genes tested (157 of 268) were found to result in a detectable reduction in fitness. Results could not be obtained for fewer than 3 percent of the genes tested (7 of 268). Previously known mutant phenotypes were confirmed, and, for about 30 percent of the genes, new mutant phenotypes were identified.
Defining a rob Regulon in Escherichia coli by Using Transposon Mutagenesis (2000)

The Rob protein of Escherichia coli is a member of the AraC-XylS family of prokaryotic transcriptional regulators and is expressed constitutively. Deletion of the rob gene increases susceptibility to organic solvents, while overexpression of Rob increases tolerance to organic solvents and resistance to a variety of antibiotics and to the superoxide-generating compound phenazine methosulfate. To determine whether constitutive levels of Rob regulate basal gene expression, we performed a MudJ transposon screen in a rob deletion mutant containing a plasmid that allows for controlled rob gene expression. We identified eight genes and confirmed that seven are transcriptionally activated by normal expression of Rob from the chromosomal rob gene (inaA, marR, aslB, ybaO, mdlA, yfhD, and ybiS). One gene, galT, was repressed by Rob. We also demonstrated by Northern analysis that basal expression of micF is significantly higher in wild-type E. coli than in a rob deletion mutant. Rob binding to the promoter regions of most of these genes was substantiated in electrophoretic mobility shift assays. However, Mu insertions in individual Rob-regulated genes did not affect solvent sensitivity. This phenotype may depend on changes in the expression of several of these Rob-regulated genes or on other genes that were not identified. Rob clearly affects the basal expression of genes with a broad range of functions, including antibiotic resistance, acid adaptation, carbon metabolism, cell wall synthesis, central intermediary metabolism, and transport. The magnitudes of Rob's effects are modest, however, and the protein may thus play a role as a general transcription cofactor.
How I treat hemophagocytic lymphohistiocytosis (2011)

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation, occurring as either a familial disorder or a sporadic condition, in association with a variety of triggers. This immune dysregulatory disorder is prominently associated with cytopenias and a unique combination of clinical signs and symptoms of extreme inflammation. Prompt initiation of immunochemotherapy is essential for survival, but timely diagnosis may be challenging because of the rarity of HLH, its variable presentation, and the time required to perform diagnostic testing. Therapy is complicated by dynamic clinical course, high risk of treatment-related morbidity, and disease recurrence. Here, we review the clinical manifestations and patterns of HLH and describe our approach to the diagnosis and therapy for this elusive and potentially lethal condition.