gebhart/patrepeval huggingface dataset:
Extra-territorial pain in rats with a peripheral mononeuropathy: mechano-hyperalgesia and mechano-allodynia in the territory of an uninjured nerve (1994)

The abnormal pain sensations that accompany peripheral neuropathies are sometimes found in a distribution that does not coincide with the territories of nerves or posterior roots. This 'extra-territorial' pain is one of the lines of evidence that has been advanced to support the proposal that these patients suffer from a psychogenic disorder. In the present experiments, rats were prepared with a unilateral chronic constriction injury (CCI) to the sciatic nerve. Beginning on the first postoperative day and continuing for at least 18 days, exaggerated withdrawal reflexes to pinprick stimulation, indicative of mechano-hyperalgesia, were seen on the side of nerve injury in the hindpaw territories of both the injured sciatic nerve and the uninjured saphenous nerve. Beginning on postoperative day 4 and continuing for at least the next 3 weeks, the withdrawal responses to von Frey hair stimulation on the nerve-injured side occurred at a significantly lower threshold, indicating the presence of mechano-allodynia. The severity and time course of the mechano-allodynia were similar in both nerve territories. When tested 18 days after the CCI, mechano-allodynia in the saphenous territory was abolished by an acute saphenous transection, but unaffected by sciatic transection. Conversely, mechano-allodynia evoked from the mid-plantar sciatic territory was abolished by acute sciatic transection, but unaffected by saphenous transection. These results show that rats with an experimental painful peripheral mononeuropathy have extra-territorial pain like that seen in man. Extra-territorial pain may be partly or entirely due to a peripheral nerve injury-evoked dysfunction of pain processing neurons in the central nervous system.
Water, proton, and ion transport: from nanotubes to proteins (2007)

Remarkably, protein channels transporting polar substances such as water, protons, and ions are often lined by predominantly non-polar residues. The unique structural, dynamic, and thermodynamic properties of water and ions in molecular confinement help explain this puzzling observation. Computer simulations of solvated nanotubes and proteins show that weakly polar cavities can be filled by water at equilibrium, but such filling is highly sensitive to small variations in the polarity of the cavity. In the filled state, water forms wires and clusters held together by tight hydrogen bonds. Simulations on quantum energy surfaces also show that 1D water wires in hydrophobic environments facilitate rapid proton motion. The unique properties of water in weakly polar channels help explain the rapid flow of water through molecular pores, the controlled proton flow in enzymes, the gating of ion transport through membrane channels, and the function of mitochondrial proton pumps.
Novel Mesoporous Materials with a Uniform Distribution of Organic Groups and Inorganic Oxide in Their Frameworks (1999)

Novel organic−inorganic hybrid mesoporous materials have been synthesized, in which organic and inorganic oxide moieties are distributed homogeneously at the molecular level in the framework, forming a covalently bonded network. They are highly ordered at the mesoscale, with two- and three-dimensional hexagonal symmetries and well-defined external morphologies. Nitrogen adsorption measurements show a uniform pore-size distribution with pore diameters of 31 and 27 Å, and high surface areas of 750 and 1170 m2/g. The synthetic procedure to polymerize the organosilane monomer containing two trialkoxysilyl groups in the presence of surfactant can be applied to the synthesis of a variety of highly ordered organic−inorganic hybrid mesoporous materials.
The tracrRNA and Cas9 families of type II CRISPR-Cas immunity systems (2013)

CRISPR-Cas is a rapidly evolving RNA-mediated adaptive immune system that protects bacteria and archaea against mobile genetic elements. The system relies on the activity of short mature CRISPR RNAs (crRNAs) that guide Cas protein(s) to silence invading nucleic acids. A set of CRISPR-Cas, type II, requires a trans-activating small RNA, tracrRNA, for maturation of precursor crRNA (pre-crRNA) and interference with invading sequences. Following co-processing of tracrRNA and pre-crRNA by RNase III, dual-tracrRNA:crRNA guides the CRISPR-associated endonuclease Cas9 (Csn1) to cleave site-specifically cognate target DNA. Here, we screened available genomes for type II CRISPR-Cas loci by searching for Cas9 orthologs. We analyzed 75 representative loci, and for 56 of them we predicted novel tracrRNA orthologs. Our analysis demonstrates a high diversity in cas operon architecture and position of the tracrRNA gene within CRISPR-Cas loci. We observed a correlation between locus heterogeneity and Cas9 sequence diversity, resulting in the identification of various type II CRISPR-Cas subgroups. We validated the expression and co-processing of predicted tracrRNAs and pre-crRNAs by RNA sequencing in five bacterial species. This study reveals tracrRNA family as an atypical, small RNA family with no obvious conservation of structure, sequence or localization within type II CRISPR-Cas loci. The tracrRNA family is however characterized by the conserved feature to base-pair to cognate pre-crRNA repeats, an essential function for crRNA maturation and DNA silencing by dual-RNA:Cas9. The large panel of tracrRNA and Cas9 ortholog sequences should constitute a useful database to improve the design of RNA-programmable Cas9 as genome editing tool.
Inhibition of experimental autoimmune encephalomyelitis in SJL mice by oral administration of retro-inverso derivative of encephalitogenic epitope P87 – 99 (1999)

Retro-inverso modification of peptides preserves parent peptide overall topology and provides at the same time stability to proteolysis, leading to derivatives with prolonged half-life in vitro and in vivo. In this study the encephalitogenic epitope P87 - 99 of myelin basic protein has been prepared in the retro-inverso form to examine its biological activity in a murine model of multiple sclerosis. Experiments of in vivo T cell tolerance induction in SJL mice revealed that the retro-inverso peptide was able to induce a selective T cell hyporesponsiveness, as measured by a reduction in the proliferative response of lymphnode T cells after antigen challenge. Oral administration of retro-inverso peptide decreased the disease severity significantly and delayed considerably the disease onset in treated mice. Enhancement of resistance to proteolysis by retro-inverso modification of encephalitogenic epitopes may increase the therapeutic value of oral tolerance induction in the treatment of multiple sclerosis and other Th1-associated inflammatory disorders.
Prevention of Autoimmune Diabetes With Nonactivating Anti-CD3 Monoclonal Antibody (1992)

Autoreactive T cells mediate diabetes in animal models of insulin-dependent diabetes mellitus (IDDM) and are believed to cause the disease in humans. Therefore, immunotherapies directed against T cells are of particular interest for the treatment of IDDM. One candidate for such immunotherapy is anti-CD3 monoclonal antibodies (MoAbs), but clinical side effects are common with anti-CD3 treatment due to the ability of these MoAbs to activate T cells in vivo. However, F(ab')2 fragments of anti-CD3 are nonactivating and immunosuppressive. We evaluated the effects of whole anti-CD3 MoAb and F(ab')2 fragments in the setting of experimental autoimmune diabetes. Treatment with whole MoAb or F(ab')2 fragments significantly reduced the hyperglycemia induced with multiple low dosages of streptozocin (MDSDM; 232 +/- 23 mg/dl, P less than 0.01 and 235 +/- 16 mg/dl, P less than 0.01 vs. 325 +/- 25 mg/dl, respectively) in male CD1 mice. Both whole MoAb and F(ab')2 fragments suppressed the development of insulitis (P less than 0.001). Treatment with whole MoAb resulted in marked weight loss (10.4 +/- 1.5% of total body wt), and the mice appeared ill and listless, whereas, mice treated with F(ab')2 fragments gained weight (4.9 +/- 5.5% of total body wt) and appeared healthy. Treatment with whole MoAb caused activation of T cells in vivo as reflected by proliferation of freshly isolated spleen cells to recombinant interleukin-2. Depletion of T cells with whole MoAb was more pronounced than with F(ab')2 fragments, and T-cell receptor (TCR) reexpression on remaining cells occurred with F(ab')2 fragments within 48 h after F(ab')2 treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Identification of the TCL1 gene involved in T-cell malignancies. (1994)

The TCL1 locus on chromosome 14q32.1 is frequently involved in chromosomal translocations and inversions with one of the T-cell receptor loci in human T-cell leukemias and lymphomas. The chromosome 14 region translocated or rearranged involves approximately 350 kb of DNA at chromosome band 14q32.1. Within this region we have identified a gene coding for a 1.3-kb transcript, expressed only in restricted subsets of cells within the lymphoid lineage and expressed at high levels in leukemic cells carrying a t(14;14)(q11;q32) chromosome translocation or a inv(14)(q11;q32) chromosome inversion. The cognate cDNA sequence reveals an open reading frame of 342 nt encoding a protein of 14 kDa. The TCL1 gene sequence, which, to our knowledge, shows no sequence homology with other human genes, is preferentially expressed early in T- and B-lymphocyte differentiation.
Organization of the replication control region of plasmid ColIb-P9 (1990)

We identified a 1,845-base-pair sequence that contains essential information for the autonomous replication and regulation of the 93-kilobase-pair IncI alpha group ColIb-P9 plasmid. Biochemical and genetic analyses revealed that this sequence specifies at least two structural genes, designated repZ and inc. The repZ gene encodes a protein with a molecular weight of 39,000, which probably functions as an initiator for the ColIb-P9 replicon. The inc gene that phenotypically governs the incompatibility encodes an RNA with a size of about 70 bases. This small RNA acts in trans to repress the expression of repZ, thereby functioning to maintain a constant copy number of the ColIb-P9 replicon in host cells.
A microfluidic chip based sequential injection system with trapped droplet liquid–liquid extraction and chemiluminescence detection (2006)

A microfluidic chip-based sequential injection system with trapped droplet liquid-liquid extraction preconcentration and chemiluminescence detection was developed for achieving high sensitivity with low reagent and sample consumption. The microfabricated glass lab-chip had a 35 mm long extraction channel, with 134 shrunken opening rectangular recesses (L 100 microm x W 50 microm x D 25 microm) arrayed within a 1 mm length on both sides of the middle section of the channel. Ketonic peroxyoxalate ester solution was filled in the recesses forming organic droplets, and keeping the aqueous sample solution flowing continuously in the extraction channel; analytes were transferred from the aqueous phase into the droplets through molecular diffusion. After liquid-liquid extraction preconcentration, catalyst and hydrogen peroxide solutions were introduced into the channel, and mixed with analytes and peroxyoxalate ester to emit chemiluminescence light. The performance of the system was tested using butyl rhodamine B, yielding a precision of 4% RSD (n = 5) and a detection limit of 10(-9) M. Within a 17 min analytical cycle, the consumptions of sample and peroxyoxalate solutions were 2.7 microL and 160 nL, respectively.
Myostatin, insulin‐like growth factor‐1, and leukemia inhibitory factor mRNAs are upregulated in chronic human disuse muscle atrophy (2001)

Human disuse muscle atrophy frequently accompanies orthopedic injury, arthritis, or bed rest, and recovery is often incomplete despite current rehabilitation programs. We have studied the vastus lateralis muscle in 12 patients with chronic disuse atrophy associated with chronic osteoarthritis of the hip both preoperatively and after total hip arthroplasty. Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated an increase in the level of expression of myostatin, insulin-like growth factor-1 (IGF-1) and leukemia inhibitory factor (LIF) mRNAs compared to healthy control muscle. In all patients there was a significant correlation preoperatively between increasing myostatin mRNA expression and reduction in type 2A and 2B fiber area. In the 8 female patients there was a significant correlation between increased myostatin mRNA expression and the atrophy factor calculated for 2A and 2B fiber types preoperatively. We hypothesize that a complex interaction occurs between muscle growth regulating factors in the genesis of muscle wasting. Our results indicate that myostatin is a muscle-wasting factor contributing to type 2B and 2A atrophy. Other muscle growth factors, such as IGF-1 and LIF, may be upregulated in a counterregulatory fashion or may be involved in the fiber type switching seen in disuse muscle wasting.
Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients (2015)

Enhancing immune responses with immune-modulatory monoclonal antibodies directed to inhibitory immune receptors is a promising modality in cancer therapy. Clinical efficacy has been demonstrated with antibodies blocking inhibitory immune checkpoints such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) or PD-1/PD-L1. Treatment with ipilimumab, a fully human CTLA-4-specific mAb, showed durable clinical efficacy in metastatic melanoma; its mechanism of action is, however, only partially understood. This is a study of 29 patients with advanced cutaneous melanoma treated with ipilimumab. We analyzed peripheral blood mononuclear cells (PBMCs) and matched melanoma metastases from 15 patients responding and 14 not responding to ipilimumab by multicolor flow cytometry, antibody-dependent cell-mediated cytotoxicity (ADCC) assay, and immunohistochemistry. PBMCs and matched tumor biopsies were collected 24 h before (i.e., baseline) and up to 4 wk after ipilimumab. Our findings show, to our knowledge for the first time, that ipilimumab can engage ex vivo FcγRIIIA (CD16)-expressing, nonclassical monocytes resulting in ADCC-mediated lysis of regulatory T cells (Tregs). In contrast, classical CD14(++)CD16(-) monocytes are unable to do so. Moreover, we show that patients responding to ipilimumab display significantly higher baseline peripheral frequencies of nonclassical monocytes compared with nonresponder patients. In the tumor microenvironment, responders have higher CD68(+)/CD163(+) macrophage ratios at baseline and show decreased Treg infiltration after treatment. Together, our results suggest that anti-CTLA-4 therapy may target Tregs in vivo. Larger translational studies are, however, warranted to substantiate this mechanism of action of ipilimumab in patients.
Pharmacokinetic and Pharmacodynamic Evaluation of a Novel Proton Pump Inhibitor, YH1885, in Healthy Volunteers (2003)

To evaluate the pharmacokinetic and pharmacodynamic characteristics of YH1885, a novel proton pump inhibitor, a single-blind, randomized, placebo-controlled, dose-rising, parallel-group study was conducted in 46 healthy volunteers. The volunteers were randomly allocated to single dose groups of 60 mg, 100 mg, 150 mg, 200 mg, and 300 mg (6 subjects per dose, including 2 placebos) or to multiple-dose groups of 150 mg and 300 mg (once-daily dosing for 7 days; 8 subjects per dose, including 2 placebos). The multiple-dose study was conducted separately after the single-dose study. YH1885 was administered orally after overnight fasting. Serial blood samples, urine samples, and pharmacodynamic measurements were taken. Drug concentrations in plasma and urine were determined by liquid chromatography/mass spectrometry (LC/MS). Pharmacodynamic changes were evaluated by ambulatory intragastric pH monitoring and by serial measurements of serum gastrin concentrations. Assessments of safety and tolerability also were made. Plasma concentrations of YH1885 reached peak levels 1.3 to 2.5 hours after single-dose administration and then declined monoexponentially with a terminal half-life (t(1/2)) of 2.2 to 2.4 hours in dosage groups up to 200 mg in the single-dose study. YH1885 showed linear pharmacokinetic characteristics, and little accumulation occurred after multiple administrations. The parent drug was not detected in urine. Dose-related pharmacological effects were obvious for dose groups of 150 mg and higher in the single-dose study. The mean intragastric pH and the percentage of time at pH>4 were significantly increased. The onset of drug effect was rapid, and maximal effects were observed on the first day of administration during multiple dosing. Serum gastrin levels also showed rapid increases during dosing but with a weak dose-effect relationship. Neither serious nor dose-limiting adverse effects were observed. YH1885 was found to be safe and well tolerated and effectively inhibited acid secretion with dose-dependent increases in intragastric pH. The acid-suppressing efficacy of YH1885 needs to be further evaluated in patients with gastric acid-related diseases.
The structure of the ankyrin-binding site of β-spectrin reveals how tandem spectrin-repeats generate unique ligand-binding properties (2009)

Spectrin and ankyrin participate in membrane organization, stability, signal transduction, and protein targeting; their interaction is critical for erythrocyte stability. Repeats 14 and 15 of betaI-spectrin are crucial for ankyrin recognition, yet the way spectrin binds ankyrin while preserving its repeat structure is unknown. We have solved the crystal structure of the betaI-spectrin 14,15 di-repeat unit to 2.1 A resolution and found 14 residues critical for ankyrin binding that map to the end of the helix C of repeat 14, the linker region, and the B-C loop of repeat 15. The tilt (64 degrees) across the 14,15 linker is greater than in any published di-repeat structure, suggesting that the relative positioning of the two repeats is important for ankyrin binding. We propose that a lack of structural constraints on linker and inter-helix loops allows proteins containing spectrin-like di-repeats to evolve diverse but specific ligand-recognition sites without compromising the structure of the repeat unit. The linker regions between repeats are thus critical determinants of both spectrin's flexibility and polyfunctionality. The putative coupling of flexibility and ligand binding suggests a mechanism by which spectrin might participate in mechanosensory regulation.
A Convenient Synthesis of α,α′-Bis(substitutedbenzylidene)cycloalkanones (1993)

Abstract The Cp2TiPh2-catalyzed reaction of cyclopentanone or cyclohexanones with benzaldehydes brought about the cross-aldol condensation to give the corresponding 2,5-bis(substitutedbenzylidene)cyclopentanones or 2,6-bis(substitutedbenzylidene)cyclohexanones in good yields under milder conditions than those previouly reported.
A Novel Class of Oligonucleotide Analogues Containing 2‘-O,3‘-C-Linked [3.2.0]Bicycloarabinonucleoside Monomers:  Synthesis, Thermal Affinity Studies, and Molecular Modeling (1998)

Oligonucleotide analogues containing a novel 2‘-O,3‘-C-linked [3.2.0]bicyclonucleoside have been efficiently synthesized. Enhanced thermal stabilities of duplexes toward both RNA and DNA are reported for a 14-mer oligothymidylate containing 13 modifications and for a nonamer mixed sequence containing three modifications. These results and the results from molecular modeling reveal that strong conformational restriction of a monomer can be important for favorable duplex formation though the fixed conformation of the pentofuranose ring deviates from a North or South conformation.
Preferential Development of CD4 and CD8 T Regulatory Cells in RasGRP1-Deficient Mice (2008)

RasGRP1 and Sos are two Ras-guanyl-nucleotide exchange factors that link TCR signal transduction to Ras and MAPK activation. Recent studies demonstrate positive selection of developing thymocytes is crucially dependent on RasGRP1, whereas negative selection of autoreactive thymocytes appears to be RasGRP1 independent. However, the role of RasGRP1 in T regulatory (Treg) cell development and function is unknown. In this study, we characterized the development and function of CD4(+)CD25(+)Foxp3(+) and CD8(+)CD44(high)CD122(+) Treg lineages in RasGRP1(-/-) mice. Despite impaired CD4 Treg cell development in the thymus, the periphery of RasGRP1(-/-) mice contained significantly increased frequencies of CD4(+)Foxp3(+) Treg cells that possessed a more activated cell surface phenotype. Furthermore, on a per cell basis, CD4(+)Foxp3(+) Treg cells from mutant mice are more suppressive than their wild-type counterparts. Our data also suggest that the lymphopenic environment in the mutant mice plays a dominant role of favored peripheral development of CD4 Treg cells. These studies suggest that whereas RasGRP1 is crucial for the intrathymic development of CD4 Treg cells, it is not required for their peripheral expansion and function. By contrast to CD4(+)CD25(+)Foxp3(+) T cells, intrathymic development of CD8(+)CD44(high)CD122(+) Treg cells is unaffected by the RasGRP1(-/-) mutation. Moreover, RasGRP1(-/-) mice contained greater numbers of CD8(+)CD44(high)CD122(+) T cells in the spleen, relative to wild-type mice. Activated CD8 Treg cells from RasGRP1(-/-) mice retained their ability to synthesize IL-10 and suppress the proliferation of wild-type CD8(+)CD122(-) T cells, albeit at a much lower efficiency than wild-type CD8 Treg cells.
A Memory Allocation Profiler for C and Lisp Programs (1988)

This paper describes mprof, a tool used to study the dynamic memory allocation behavior of programs. Mprof records the amount of memory that a function allocates, breaks down allocation information by type and size, and displays a program’s dynamic call graph so that functions indirectly responsible for memory allocation are easy to identify. Mprof is a two-phase tool. The monitor phase is linked into executing programs and records information each time memory is allocated. The display phase reduces the data generated by the monitor and presents the information to a user in several tables. Mprof has been implemented for C and Kyoto Common Lisp. Measurements of these implementations are presented. 1
Increased Incidence of Cholestasis during Total Parenteral Nutrition in Children. Factors Affecting Stone Formation. (1993)

Cholelithiasis is extremely unusual in infants and children. Recently, some cases of cholelithiasis associated with total parenteral nutrition (TPN) have been reported. A group of 400 children receiving TPN were evaluated prospectively for the presence of gallstones and sludge in this report. Eight children (2%) were determined by ultrasonography to have developed cholelithiasis. All of these patients had received large amounts of amino acids (> or = 1.8g/kg/day) and relatively low amounts of fat (< or = 1.7g/kg/day) with a high ratio of non-protein: kcal/ml (> 0.8). It was concluded that the administration of large amounts of amino acids and a high ratio of non-protein: kcal/ml enhanced the risk for formation of gallstones and sludge. Conversely, these are prevented by the administration of appropriate amounts of fat.
Combination Therapy (Intratympanic Dexamethasone + High-Dose Prednisone Taper) for the Treatment of Idiopathic Sudden Sensorineural Hearing Loss (2008)

The results of this study suggest that ISSNHL patients treated with IT-Dex + HDPT (combination therapy) have a higher likelihood of hearing recovery than those treated with HDPT alone.