gebhart/patrepeval huggingface dataset:
Scc-1, a novel colon cancer susceptibility gene in the mouse: linkage to CD44 (Ly-24, Pgp-1) on chromosome 2. (1992)

Mutations of proto-oncogenes and tumor-suppressor genes lead to neoplastic development. Some germline mutations of these genes increase the tumor susceptibility of their carriers, but the relationship between genes controlling tumor susceptibility and the known oncogenes and tumor-suppressor genes remains unelucidated. Moreover, as tumor susceptibility in mouse is controlled by multiple genes, their identification has been virtually impossible. We therefore developed a new system, the recombinant congenic strains (RCS), which separates individual susceptibility genes into different RC strains, thus facilitating their analysis. To map genes controlling the development of colon cancer, we used the Balb/c-c-STS (CcS/Dem) RC strains. Owing to several unidentified genes, Balb/cHeA mice are relatively resistant and STS/A mice highly susceptible to 1,2-dimethylhydrazine-(DMH)-induced colon adenocarcinomas. Each CcS/Dem strain carries a different subset of about 12.5% of genes of the STS strain on the Balb/c background, and individual STS susceptibility genes became segregated into different RC strains. Using CcS-19, one of the highly susceptible RC strains, we mapped a novel colon tumor susceptibility gene, Scc-1, different from the oncogenes and tumor-suppressor genes known to be involved in colon tumorigenesis, in the vicinity of CD44 (Ly-24, Pgp-1) on chromosome 2. The mapping of the Scc-1 gene indicates that the RCS system can be used to map and study the presently unknown genes which control cancer development.
Synthesis of cobalt ferrite nanoparticles in continuous-flow microreactors (2012)

High quality CoFe2O4 nanoparticles were synthesized only in 16 min, continuously in two coupled microreactors. The first microreactor induced the fast homogenization of the reagents mixture at ambient temperature so Fe3+ and Co2+ hydroxides precipitate, while a second microreactor heated at 98 °C allowed the fast aging and the evolution of amorphous hydroxides into faceted and crystalline CoFe2O4.
Rethinking the Coagulation Cascade (2005)

The concept of coagulation as a "cascade" of proteolytic reactions was a conceptual breakthrough in understanding how the coagulation process acts as a biologic amplifier. The model that it evolved into, with "extrinsic" and "intrinsic" pathways meeting in a common pathway, delineates the interactions between the coagulation proteins and provides a framework for interpreting the common screening coagulation tests. The coagulation "cascade" has significant limitations as a model of how hemostasis occurs in vivo, however. This article describes how the modern view of hemostasis has evolved to emphasize the role of cells in controlling and directing the coagulation reactions. It also highlights how host factors that are not part of the coagulation process per se can influence the effectiveness of coagulation.
Mediator proteins orchestrate enzyme-ssDNA assembly during T4 recombination-dependent DNA replication and repair (2001)

Studies of recombination-dependent replication (RDR) in the T4 system have revealed the critical roles played by mediator proteins in the timely and productive loading of specific enzymes onto single-stranded DNA (ssDNA) during phage RDR processes. The T4 recombination mediator protein, uvsY, is necessary for the proper assembly of the T4 presynaptic filament (uvsX recombinase cooperatively bound to ssDNA), leading to the recombination-primed initiation of leading strand DNA synthesis. In the lagging strand synthesis component of RDR, replication mediator protein gp59 is required for the assembly of gp41, the DNA helicase component of the T4 primosome, onto lagging strand ssDNA. Together, uvsY and gp59 mediate the productive coupling of homologous recombination events to the initiation of T4 RDR. UvsY promotes presynaptic filament formation on 3' ssDNA-tailed chromosomes, the physiological primers for T4 RDR, and recent results suggest that uvsY also may serve as a coupling factor between presynapsis and the nucleolytic resection of double-stranded DNA ends. Other results indicate that uvsY stabilizes uvsX bound to the invading strand, effectively preventing primosome assembly there. Instead, gp59 directs primosome assembly to the displaced strand of the D loop/replication fork. This partitioning mechanism enforced by the T4 recombination/replication mediator proteins guards against antirecombination activity of the helicase component and ensures that recombination intermediates formed by uvsX/uvsY will efficiently be converted into semiconservative DNA replication forks. Although the major mode of T4 RDR is semiconservative, we present biochemical evidence that a conservative "bubble migration" mode of RDR could play a role in lesion bypass by the T4 replication machinery.
Cell-Cycle Reprogramming for PI3K Inhibition Overrides a Relapse-Specific C481S BTK Mutation Revealed by Longitudinal Functional Genomics in Mantle Cell Lymphoma (2014)

We have discovered the first relapse-specific BTK mutation in patients with MCL with acquired resistance, but not primary resistance, to ibrutinib, and demonstrated a rationale for targeting the proliferative resistant MCL cells by inhibiting CDK4 and the cell cycle in combination with ibrutinib in the presence of BTK(WT) or a PI3K inhibitor independent of BTK mutation. As drug resistance remains a major challenge and CDK4 and PI3K are dysregulated at a high frequency in human cancers, targeting CDK4 in genome-based combination therapy represents a novel approach to lymphoma and cancer therapy. Cancer Discov; 4(9); 1022-35. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 973.
Hybrid Antibodies in Cancer Diagnosis and Therapy (1989)

Monoclonal Antibodies (Mabs) represent a promising tool for cancer diagnosis and therapy. Administration of MAbs alone or conjugated to cytotoxic agents has been attempted but has significant limitations. Another potentially effective approach is the use of bispecific or bifunctional antibodies where the capacity to recognize the tumor cell and the toxic agent or lymphocyte activation molecule are united in one MAb. The hybrid molecule can be produced by chemical linkage between the two parental antibodies, or alternatively by a biological approach that consists in the fusion of the two selected hybridomas. In the resulting quadroma cell the hybridoma immunoglobulin chains recombine randomly to form the bifunctional MAb. In different in vitro and in vivo models, bifunctional MAbs against tumor and CD3 at nanomolar concentration has been shown to promote tumor cell killing by cytotoxic T cells. Specific localization of chemotherapeutic drugs in xenografted tumors has been demonstrated in mice pretreated with hybrid MAbs. The advantages of the hybrid MAb approach are that it should reduce the MAb biodistribution problem and that it involves no chemical manipulation between the functional agent and the MAb molecules.
Crystal structure of trioxacarcin A covalently bound to DNA (2008)

We report a crystal structure that shows an antibiotic that extracts a nucleobase from a DNA molecule 'caught in the act' after forming a covalent bond but before departing with the base. The structure of trioxacarcin A covalently bound to double-stranded d(AACCGGTT) was determined to 1.78 A resolution by MAD phasing employing brominated oligonucleotides. The DNA-drug complex has a unique structure that combines alkylation (at the N7 position of a guanine), intercalation (on the 3'-side of the alkylated guanine), and base flip-out. An antibiotic-induced flipping-out of a single, nonterminal nucleobase from a DNA duplex was observed for the first time in a crystal structure.
Thirty years beyond discovery—Clinical trials in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism (2012)

This review summarizes a presentation made at the retirement Symposium of Prof. Dr. Cornelis Jakobs in November of 2011, highlighting the progress toward clinical trials in succinic semialdehyde dehydrogenase (SSADH) deficiency, a disorder first recognized in 1981. Active and potential clinical interventions, including vigabatrin, L-cycloserine, the GHB receptor antagonist NCS-382, and the ketogenic diet, are discussed. Several biomarkers to gauge clinical efficacy have been identified, including cerebrospinal fluid metabolites, neuropsychiatric testing, MRI, EEG, and measures of GABAergic function including (11 C)flumazenil positron emission tomography (PET) and transcranial magnetic stimulation (TMS). Thirty years after its discovery, encompassing extensive studies in both patients and the corresponding murine model, we are now running an open-label trial of taurine intervention, and are poised to undertake a phase II trial of the GABAB receptor antagonist SGS742.
A new MOSFET structure with self-aligned polysilicon source and drain electrodes (1984)

A new MOSFET structure whose source and drain electrodes are self-aligned to the gate electrode is proposed. The new structure utilizes a second layer of polysilicon which is defined by a preferrential etching to form the source and drain regions. Due to the self-alignment property of the source and drain regions, the total device size is decreased by about 50 percent over the conventional MOS transistors when the same design rule is used. Experimental results of the new structure are presented.
Comparing Effects of Ketamine and Thiopental Administration During Electroconvulsive Therapy in Patients With Major Depressive Disorder (2013)

Ketamine administration during ECT is well tolerated and patients may experience earlier improvement in depressive symptoms, longer seizure duration, and better cognitive performance when compared with thiopental.
Alternating Copolymerization of Cyclohexene Oxide with Carbon Dioxide Catalyzed by (salalen)CrCl Complexes (2009)

Copolymerization of cyclohexene oxide with carbon dioxide was investigated by using chromium complexes with salalen ligands which are reduced analogues of salen ones (salen-H2 = N,N′-disalicylidene-1,2-ethylenediamine). Although the use of (salalen)CrCl complexes alone without additives was not effective for the copolymerization, a mixture of (salalen)CrCl complexes and onium salts catalyzed the copolymerization with relatively high catalytic activity. Particularly, the present catalyst system showed the highest catalytic activity under atmospheric pressure of CO2 among those ever reported. In general, the obtained copolymers consisted of almost perfectly alternating structure. Structural analysis of the copolymers by MALDI-TOF mass spectrometry revealed that chloride initiated the copolymerization. In addition, concomitant water was found to work as a chain transfer reagent and a bifunctional initiator.
High Contrast Ramsey Fringes with Coherent-Population-Trapping Pulses in a Double Lambda Atomic System (2005)

We report the observation of Raman-Ramsey fringes using a double lambda scheme creating coherent population trapping in an atomic ensemble combined with pulsed optical radiations. The observation was made in a Cs vapor mixed with ${\mathrm{N}}_{2}$ buffer gas in a closed cell. The double lambda scheme is created with $\mathrm{lin}\ensuremath{\perp}\mathrm{lin}$ polarized laser beams leading to higher contrast than the usual simple lambda scheme. The pulsed trapping technique leads to narrow fringe widths scaling as $1/(2T)$ with high contrasts which are no longer limited by the saturation effect. This technique operates in a different way from the classical Ramsey sequence: the signal is done by applying a long trapping pulse to prepare the atomic state superposition, and fringe detection is accomplished by optical transmission during a short second trapping pulse without any perturbation of the dark state.
Can reliable values of Young's modulus be deduced from Fisher's (1971) spinning lens measurements? (2006)

The current textbook view of the causes of presbyopia rests very largely on a series of experiments reported by R.F. Fisher some three decades ago, and in particular on the values of lens Young's modulus inferred from the deformation caused by spinning excised lenses about their optical axis (Fisher 1971) We studied the extent to which inferred values of Young's modulus are influenced by assumptions inherent in the mathematical procedures used by Fisher to interpret the test and we investigated several alternative interpretation methods. The results suggest that modelling assumptions inherent in Fisher's original method may have led to systematic errors in the determination of the Young's modulus of the cortex and nucleus. Fisher's conclusion that the cortex is stiffer than the nucleus, particularly in middle age, may be an artefact associated with these systematic errors. Moreover, none of the models we explored are able to account for Fisher's claim that the removal of the capsule has only a modest effect on the deformations induced in the spinning lens.
Marked grid labeling (2003)

The grid labeling problem is an instance of the correspondence problem that occurs when structured light is used to gather range data. Here, spatial labeling is examined as an approach to resolving labeling ambiguities. Spatial labeling is attractive since there are no additional costs of acquisition time or subsequent processing time. A grid labeling algorithm is presented which combines the spatial marking technique of J. LeMigne and A.M. Waxman (1984) with the constraint propagation approach of G. Stockman and G. Hu (1986). It is found accurate grid labeling using the marked grid can be accomplished using a subset of Stockman and Hu's constraints. The structured light pattern used and the grid labeling algorithm that makes use of the special markers are described. The results of experiments using this pattern are presented.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Bacteria-cytokine interactions in health and disease (1998)

Bacteria and infectious diseases bacterial virulence factors cytokines, homeostasis, networks and disease lipopolysaccharide - structure and function lipopolysaccharide and cytokines - a tangled web bacteria and cytokines - beyond lipopolysaccharide pharmacological modulation of cytokines bacteria-cytokine interactions in health and disease - a new synthesis.
Inhibition of virulence factor expression in Staphylococcus aureus by the Staphylococcus epidermidis agr pheromone and derivatives (1999)

The agr quorum-sensing system in Staphylococci controls the production of surface proteins and exoproteins. In the pathogenic species Staphylococcus aureus, these proteins include many virulence factors. The extracellular signal of the quorum-sensing system is a thiolactone-containing peptide pheromone, whose sequence varies among the different staphylococcal strains. We demonstrate that a synthetic Staphylococcus epidermidis pheromone is a competent inhibitor of the Staphylococcus aureus agr system. Derivatives of the pheromone, in which the N-terminus or the cyclic bond structure was changed, were synthesized and their biological activity was determined. The presence of a correct N-terminus and a thiolactone were absolute prerequisites for an agr-activating effect in S. epidermidis, whereas inhibition of the S. aureus agr system was less dependent on the original structure. Our results show that effective quorum-sensing blockers that suppress the expression of virulence factors in S. aureus can be designed based on the S. epidermidis pheromone.
SRPK2: A Differentially Expressed SR Protein-specific Kinase Involved in Mediating the Interaction and Localization of Pre-mRNA Splicing Factors in Mammalian Cells (1998)

Reversible phosphorylation plays an important role in pre-mRNA splicing in mammalian cells. Two kinases, SR protein-specific kinase (SRPK1) and Clk/Sty, have been shown to phosphorylate the SR family of splicing factors. We report here the cloning and characterization of SRPK2, which is highly related to SRPK1 in sequence, kinase activity, and substrate specificity. Random peptide selection for preferred phosphorylation sites revealed a stringent preference of SRPK2 for SR dipeptides, and the consensus derived may be used to predict potential phosphorylation sites in candidate arginine and serine-rich (RS) domain-containing proteins. Phosphorylation of an SR protein (ASF/SF2) by either SRPK1 or 2 enhanced its interaction with another RS domain-containing protein (U1 70K), and overexpression of either kinase induced specific redistribution of splicing factors in the nucleus. These observations likely reflect the function of the SRPK family of kinases in spliceosome assembly and in mediating the trafficking of splicing factors in mammalian cells. The biochemical and functional similarities between SRPK1 and 2, however, are in contrast to their differences in expression. SRPK1 is highly expressed in pancreas, whereas SRPK2 is highly expressed in brain, although both are coexpressed in other human tissues and in many experimental cell lines. Interestingly, SRPK2 also contains a proline-rich sequence at its NH2 terminus, and a recent study showed that this NH2-terminal sequence has the capacity to interact with a WW domain protein in vitro. Together, our studies suggest that different SRPK family members may be uniquely regulated and targeted, thereby contributing to splicing regulation in different tissues, during development, or in response to signaling.
Development of Burkholderia mallei and pseudomallei vaccines (2013)

Burkholderia mallei and Burkholderia pseudomallei are Gram-negative bacteria that cause glanders and melioidosis, respectively. Inhalational infection with either organism can result in severe and rapidly fatal pneumonia. Inoculation by the oral and cutaneous routes can also produce infection. Chronic infection may develop after recovery from acute infection with both agents, and control of infection with antibiotics requires prolonged treatment. Symptoms for both meliodosis and glanders are non-specific, making diagnosis difficult. B. pseudomallei can be located in the environment, but in the host, B. mallei and B. psedomallei are intracellular organisms, and infection results in similar immune responses to both agents. Effective early innate immune responses are critical to controlling the early phase of the infection. Innate immune signaling molecules such as TLR, NOD, MyD88, and pro-inflammatory cytokines such as IFN-γ and TNF-α play key roles in regulating control of infection. Neutrophils and monocytes are critical cells in the early infection for both microorganisms. Both monocytes and macrophages are necessary for limiting dissemination of B. pseudomallei. In contrast, the role of adaptive immune responses in controlling Burkholderia infection is less well understood. However, T cell responses are critical for vaccine protection from Burkholderia infection. At present, effective vaccines for prevention of glanders or meliodosis have not been developed, although recently development of Burkholderia vaccines has received renewed attention. This review will summarize current and past approaches to develop B. mallei and B. pseudomalllei vaccines, with emphasis on immune mechanisms of protection and the challenges facing the field. At present, immunization with live attenuated bacteria provides the most effective and durable immunity, and it is important therefore to understand the immune correlates of protection induced by live attenuated vaccines. Subunit vaccines have typically provided less robust immunity, but are safer to administer to a wider variety of people, including immune compromised individuals because they do not reactivate or cause disease. The challenges facing B. mallei and B. pseudomalllei vaccine development include identification of broadly protective antigens, design of efficient vaccine delivery and adjuvant systems, and a better understanding of the correlates of protection from both acute and chronic infection.
Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. (1993)

The major protein subunit of the paired helical filaments (PHF) of Alzheimer disease (AD) is the microtubule-associated protein tau. Tau is a family of phosphopolypeptides that are abnormally phosphorylated in PHF. In this study, a non-PHF pool of tau abnormally phosphorylated at Ser-199/202, and tau not phosphorylated at this site (AD P-tau and AD tau, respectively) were isolated from the 27,000 x g to 200,000 x g fraction of AD brain homogenate by extraction in 8 M urea, followed by dialysis against Tris buffer. AD P-tau and AD tau were further purified and separated from each other by acid precipitation, glial fibrillary acidic protein affinity chromatography, and phosphocellulose chromatography. The resulting AD P-tau and AD tau preparations were free of cytoskeletal proteins, ubiquitin, and beta-amyloid peptide. Immunochemical and morphological analysis of AD P-tau preparations revealed that most of the protein was of non-PHF origin. The AD P-tau was about 3-4-fold (approximately 8 mol P04/mol protein, M(r) 41,318) more phosphorylated than cytosolic tau from AD and control brains. Unlike PHF, the AD P-tau lacked ubiquitin. In AD brain the levels of cytosolic tau were about half of those in control aged cases. These findings suggest that the abnormal phosphorylation of tau in AD occurs in the cytosol.
In vivo imaging of amyloid plaques (2008)

生体内分子の非侵襲的画像化をめざした分子イメージング法が様々な分野に応用されているが，アルツハイマー病（AD）研究においては特徴的病理像である老人斑を描出するアミロイドイメージング技術が近年，大いに発展を遂げている．アミロイドイメージングは，人口の高齢化とともに急増するADを早期発見する検査として，さらには脳内Aβの沈着過程をモニタリングする新たな薬効評価系として，診断・治療評価の両面から強く期待されている．アミロイドの検出法としては，PET，SPECT，MRI，近赤外光イメージングなどを用いた手法が提案されているが，PETを用いた方法が現在の主流である．PETを用いたイメージングでは，老人斑への結合選択性に優れたプローブ開発が成功のカギを握る．プローブはアミロイドβタンパクへの高い結合親和性に加えて，高い脳血液関門透過性と正常組織からの速やかなクリアランスが要求される．これまでにプローブの候補化合物が数多く開発され，Thioflavin-T誘導体である［11C］PIBや［18F］FDDNP，［11C］BF-227などのプローブが実用化されている．これらのPETプローブを用いたアミロイドイメージングでは，ADの臨床診断を受けた大多数の患者の大脳皮質で集積異常を示す．またADの病前段階に相当する軽度認知障害（MCI）の過半数の症例も異常集積がみられ，将来のADへの進行を予測する指標となる．また健康成人の中にも異常所見を認める者が一定数存在する．これらは無症候段階でのアミロイド沈着を検出している可能性が高く，発症前診断へ向けたエビデンスの蓄積が求められる．本検査のさらなる普及をめざし，18F標識PETプローブやSPECT用プローブの開発が進められている．
Synthesis of Novel Lipids in Saccharomyces cerevisiae by Heterologous Expression of an Unspecific Bacterial Acyltransferase (2004)

The bifunctional wax ester synthase/acyl-coenzyme A:diacylglycerol acyltransferase (WS/DGAT) is the key enzyme in storage lipid accumulation in the gram-negative bacterium Acinetobacter calcoaceticus ADP1, mediating wax ester, and to a lesser extent, triacylglycerol (TAG) biosynthesis. Saccharomyces cerevisiae accumulates TAGs and steryl esters as storage lipids. Four genes encoding a DGAT (Dga1p), a phospholipid:diacylglycerol acyltransferase (Lro1p) and two acyl-coenzyme A:sterol acyltransferases (ASATs) (Are1p and Are2p) are involved in the final esterification steps in TAG and steryl ester biosynthesis in this yeast. In the quadruple mutant strain S. cerevisiae H1246, the disruption of DGA1, LRO1, ARE1, and ARE2 leads to an inability to synthesize storage lipids. Heterologous expression of WS/DGAT from A. calcoaceticus ADP1 in S. cerevisiae H1246 restored TAG but not steryl ester biosynthesis, although high levels of ASAT activity could be demonstrated for WS/DGAT expressed in Escherichia coli XL1-Blue in radiometric in vitro assays with cholesterol and ergosterol as substrates. In addition to TAG synthesis, heterologous expression of WS/DGAT in S. cerevisiae H1246 resulted also in the accumulation of fatty acid ethyl esters as well as fatty acid isoamyl esters. In vitro studies confirmed that WS/DGAT is capable of utilizing a broad range of alcohols as substrates comprising long-chain fatty alcohols like hexadecanol as well as short-chain alcohols like ethanol or isoamyl alcohol. This study demonstrated the highly unspecific acyltransferase activity of WS/DGAT from A. calcoaceticus ADP1, indicating the broad biocatalytic potential of this enzyme for biotechnological production of a large variety of lipids in vivo in prokaryotic as well as eukaryotic expression hosts.