tbuckley/cabot-search huggingface dataset:
Evolutionarily Conserved cox1Trans-Splicing Without cis-Motifs
Authors: Georgette N. Kiethega, Marcel Turcotte, Gertraud Burger
Journal: Molecular Biology and Evolution (2011)

In the protist Diplonema papillatum (Diplonemea, Euglenozoa), mitochondrial genes are systematically fragmented with each nonoverlapping piece (module) encoded individually on a distinct circular chromosome. Gene modules are transcribed separately, and precursor transcripts are assembled to mature mRNA by a trans-splicing process of yet unknown mechanism. Expression of the cox1 gene that consists of nine modules, also involves RNA editing by which six uridines are added between Modules 4 and 5. Here, we investigate whether the unusual features of cox1 are shared by all Diplonemea and what the mechanism of trans-splicing might be. We examine three additional species representing both Diplonemea genera, namely D. papillatum described before, and D. ambulator, Diplonema sp.2, and Rhynchopus euleeides and discover that in all Diplonemea, the cox1 gene is discontinuous and split up into nine modules that each reside on a distinct chromosome. Positions of gene breakpoints vary by up to two nucleotides. Further, all taxa have six nonencoded uridines inserted in cox1 mRNA at exactly the same position as D. papillatum. In silico searches do not detect signatures of introns known to engage in trans-splicing, in particular Group I, Group II, spliceosomal, and transfer RNA introns. Nor did we find statistically significant reverse-complementary motifs between adjacent modules and their flanking regions, or residues conserved within or across species. This provides compelling evidence that trans-splicing in Diplonemea mitochondria does not rely on sequence elements in cis but rather proceeds by a mechanism employing matchmaking trans factors, such as RNAs or proteins.
Apolipoprotein J, a glucose-upregulated molecular chaperone, stabilizes core and NS5A to promote infectious hepatitis C virus virion production
Authors: Chun-Chieh Lin, Peiju Tsai, Hung-Yu Sun, Mei-Chi Hsu, Jin-Ching Lee, I-Chin Wu, Chiung-Wen Tsao, Ting-Tsung Chang, Kung-Chia Young
Journal: Journal of Hepatology (2014)
Functional IRF3 deficiency in a patient with herpes simplex encephalitis
Authors: Line Lykke Andersen, Nanna Mørk, Line S. Reinert, Emil Kofod-Olsen, Ryo Narita, Sofie E. Jørgensen, Kristian A. Skipper, Klara Höning, Hans Henrik Gad, Lars Østergaard, Torben F. Ørntoft, Veit Hornung, Søren R. Paludan, Jacob Giehm Mikkelsen, Takashi Fujita, Mette Christiansen, Rune Hartmann, Trine H. Mogensen
Journal: The Journal of Experimental Medicine (2015)

Herpes simplex encephalitis (HSE) in children has previously been linked to defects in type I interferon (IFN) production downstream of Toll-like receptor 3. Here, we describe a novel genetic etiology of HSE by identifying a heterozygous loss-of-function mutation in the IFN regulatory factor 3 (IRF3) gene, leading to autosomal dominant (AD) IRF3 deficiency by haploinsufficiency, in an adolescent female patient with HSE. IRF3 is activated by most pattern recognition receptors recognizing viral infections and plays an essential role in induction of type I IFN. The identified IRF3 R285Q amino acid substitution results in impaired IFN responses to HSV-1 infection and particularly impairs signaling through the TLR3–TRIF pathway. In addition, the R285Q mutant of IRF3 fails to become phosphorylated at S386 and undergo dimerization, and thus has impaired ability to activate transcription. Finally, transduction with WT IRF3 rescues the ability of patient fibroblasts to express IFN in response to HSV-1 infection. The identification of IRF3 deficiency in HSE provides the first description of a defect in an IFN-regulating transcription factor conferring increased susceptibility to a viral infection in the CNS in humans.
MYELOPEROXIDASE AS EARLY DIAGNOSTIC AND PROGNOSTIC MARKER OF ACUTE CORONARY SYNDROME: A HEAD-TO-HEAD COMPARISON WITH HIGH SENSITIVE TROPONIN I
Authors: Volker Rudolph, Till Keller, Andreas Schulz, Francisco Ocheda Echevarria, Tanja Rudolph, Christoph Bickel, Thomas Meinertz, Thomas Münzel, Stefan Blankenberg, Stephan Baldus
Journal: Journal of the American College of Cardiology (2011)
Natural language and natural selection
Authors: Steven Pinker, Paul Bloom
Journal: Behavioral and Brain Sciences (1990)

Abstract Many people have argued that the evolution of the human language faculty cannot be explained by Darwinian natural selection. Chomsky and Gould have suggested that language may have evolved as the by-product of selection for other abilities or as a consequence of as-yet unknown laws of growth and form. Others have argued that a biological specialization for grammar is incompatible with every tenet of Darwinian theory – that it shows no genetic variation, could not exist in any intermediate forms, confers no selective advantage, and would require more evolutionary time and genomic space than is available. We examine these arguments and show that they depend on inaccurate assumptions about biology or language or both. Evolutionary theory offers clear criteria for when a trait should be attributed to natural selection: complex design for some function, and the absence of alternative processes capable of explaining such complexity. Human language meets these criteria: Grammar is a complex mechanism tailored to the transmission of propositional structures through a serial interface. Autonomous and arbitrary grammatical phenomena have been offered as counterexamples to the position that language is an adaptation, but this reasoning is unsound: Communication protocols depend on arbitrary conventions that are adaptive as long as they are shared. Consequently, language acquisition in the child should systematically differ from language evolution in the species, and attempts to analogize them are misleading. Reviewing other arguments and data, we conclude that there is every reason to believe that a specialization for grammar evolved by a conventional neo-Darwinian process.
PAIN IN MUCOUS COLITIS AND IN IRRITABLE STATES OF THE COLON IN GENERAL
Authors: T. S. Wilson
Journal: BMJ (1909)

MUCOUS COLITIS.T [MEDICAL JOU1NAL 73 11907, when he had another attack of haematemesis, but not so -severe, and he soon resumed work.A third attack occurred in 'February, 1908, a fourth in April, 1908, and the last in November, 1908.Between these attacks he has been absolutely free from .allstomach trouble.His wife says that these attacks have -always been brought on by overwork, but admits that he drinks more than an ordinary amount of alcohol.Examination of his stomach contents after a test meal (toast and tea) shows the presence of free HCI.Lactic acid or other abnormal constituents are not present.Four hours after a test meal of beef, potatoes, and pudding a small amount of meat 'fibre was washed out of the stomach.Roentgen-ray Examintationt.-His stomach was first washed clean with water and the bowel emptied by an enema, which .acted well.Eight ounces of hot bread and milk thoroughly imixed with 1 oz. of bismuth carbonate was then given him to -eat.Ten minutes after the food had been taken, with the x-ray screen a distinct shadow was seen.The lower outline was definite, and the lowest point was 1J in.above the umbilicus.The thickest part of the shadow was towards the cardiac end of the stomach, and it gradually tapered towards the pyloric end (see Fig. 5); twenty-five minutes after food the upper outline, which was never as clear as the lower, showed less clearly, and the whole mass looked -narrower.In addition to the projection to the right of the midline and some increased darkening towards the pyloric end, there was a definite shadow leading vertically downwards from the lower border of the stomach shadow (see Figs. 6 and7).that this was not the spinal column was proved by the facts that it was not seen earlier and did not appear above the stomach shadow.The patient was standing up during each -examination.Our interpretation of the findings is that the projection to the right represents the pyloric antrum, and the vertical 'shadow food escaping through the artificial opening into ,the jejunum.For the laborious work of tracing these cases and collecting the notes we are indebted to Mr. Hamilton Drummond.
P07 Splanchnic steal in patients with liver disease: a 3T MRI study of visceral blood flow
Authors: N McAvoy, K A Leyland, J M J Richards, S I K Semple, D Patel, D E Newby, P C Hayes
Journal: Gut (2010)

Introduction  Liver cirrhosis and the development of portal hypertension is associated with significant morbidity and mortality. It is widely accepted that patients with liver disease have a hyperdynamic circulation that is associated with an increased cardiac output. We have previously proposed that, rather than a generalised systemic vasodilatation, there is selective splanchnic vasodilatation with concomitant vasoconstriction in other vascular beds: the so-called “splanchnic steal” phenomenon.  Aim  To measure regional visceral blood flow using 3T magnetic resonance imaging in patients with liver disease.  Method  Single centre pilot study of 19 subjects (10 healthy controls, nine patients with liver disease). Arterial and venous phase magnetic resonance angiograms were obtained using a Siemens 3T Verio MR scanner with gadolinium contrast. From these MRA9s, ECG-gated phase contrast flow measurement MR data were then positioned and measured in the hepatic artery, portal vein, superior mesenteric artery, descending thoracic aorta, distal abdominal aorta, and the renal and carotid arteries.  Results  Mean MELD score in patient group was 14 (range 7–21) with a range of aetiologies: alcoholic (6), non-alcoholic fatty (1), autoimmune (1), hepatitis C virus (1). In comparison to controls, flow in the descending thoracic aorta was increased by 43% in patients with liver disease (4.74 vs 3.32 L/min; p=0.021) consistent with an increased cardiac output. Hepatic artery flow showed a trend towards increase in patients (0.47 vs 0.27 L/min; p=0.11) whereas portal vein flow decreased dramatically (0.20 vs 1.20 L/min; p=0.006). Overall, in patients with liver disease, there was a 46% reduction in total liver blood flow (0.67 vs 1.47 L/min; p=0.037) and a reversal of hepatic artery/portal vein flow ratio (4.15 vs 0.33 L/min; p=0.009). Although superior mesenteric artery flow was three times greater in patients (0.54 vs 0.15 L/min; p=0.001), renal blood flow showed a trend towards reduction of 32% (0.42 vs 0.62 L/min; p=0.053), no change in carotid blood flow (0.75 vs 0.62 L/min; p=0.129) and no change in inferior aortic flow (1.45 vs 1.12 L/min; p=0.28).  Conclusion  There are marked derangements in regional visceral blood flow in patients with liver cirrhosis. Our findings strongly support the splanchnic steal hypothesis that dysregulated splanchnic vasodilatation and porto-systemic shunting induce a high cardiac output state associated with extra-splanchnic vasoconstriction including the renal circulation.
Epitope-specific regulation. II. A bistable, Igh-restricted regulatory mechanism central to immunologic memory
Authors: LA Herzenberg, T Tokuhisa, DR Parks, LA Herzenberg
Journal: The Journal of Experimental Medicine (1982)

Antibody responses to commonly used antigens are regulated by an epitope- specific system composed of Igh-restricted elements responsible for controlling the isotype and allotype responses mounted to each of the epitopes on the antigen. Because these elements can be independently induced to either suppress or support antibody production, this system as a whole provides an effector mechanism capable of selectively controlling the amount, affinity, isotype representation, and epitope-specificity of an antibody response. Sequential immunizations with a carrier molecule and a hapten conjugated to that carrier (carrier/hapten-carrier immunization) induce suppression for IgG responses to the hapten. IgG(2a), IgG(2b), and IgG(3) responses are easily suppressed, whereas IgG(1) responses tend to be more resistant. Once induced, suppression tends to be maintained; however, repeated stimulation with the hapten (on any carrier) eventually induces antibody production, first for IgG(1) and later for the more suppressible isotypes (IgG(2a), IgG(2b), IgG(3)). Antibody production, once initiated, also tends to be maintained. Ongoing IgG antihapten responses in animals primed with a hapten-carrier conjugate can be suppressed by subsequent carrier/hapten-carrier immunization (using a different carrier molecule); however, the suppression induced under these circumstances is substantially weaker, i.e., it mainly affects the more suppressible isotypes and is only strong enough to detect clearly in about one-half the immunized animals. Thus, the initiation of antibody production impairs the subsequent induction of suppression, and the initial induction of suppression tends to prevent subsequent initiation of antibody production. This reciprocal relationship defines a bistable regulatory mechanism, i.e., one that tends to maintain its initially induced state but is capable of shifting to the alternate state when stimulatory conditions so dictate. The operation of such a mechanism permits conditions surrounding the first immunization with an epitope (hapten) to strongly influence but not absolutely determine which and how many of the anti-epitope memory B cells generated by that immunization will subsequently be expressed. Thus, epitope- specific regulation, although subordinate to mechanisms that control memory B cell development (as opposed to expression), plays a key role in determining the magnitude, affinity, and isotype representation of anamnestic (memory) responses produced in response to previously encountered epitopes.
Critical Contribution of Ox40 Ligand to T Helper Cell Type 2 Differentiation in Experimental Leishmaniasis
Authors: Hisaya Akiba, Yasushi Miyahira, Machiko Atsuta, Kazuyoshi Takeda, Chiyoko Nohara, Toshiro Futagawa, Hironori Matsuda, Takashi Aoki, Hideo Yagita, Ko Okumura
Journal: The Journal of Experimental Medicine (2000)

Infection of inbred mouse strains with Leishmania major is a well characterized model for analysis of T helper (Th)1 and Th2 cell development in vivo. In this study, to address the role of costimulatory molecules CD27, CD30, 4-1BB, and OX40, which belong to the tumor necrosis factor receptor superfamily, in the development of Th1 and Th2 cells in vivo, we administered monoclonal antibody (mAb) against their ligands, CD70, CD30 ligand (L), 4-1BBL, and OX40L, to mice infected with L. major. Whereas anti-CD70, anti-CD30L, and anti–4-1BBL mAb exhibited no effect in either susceptible BALB/c or resistant C57BL/6 mice, the administration of anti-OX40L mAb abrogated progressive disease in BALB/c mice. Flow cytometric analysis indicated that OX40 was expressed on CD4+ T cells and OX40L was expressed on CD11c+ dendritic cells in the popliteal lymph nodes of L. major–infected BALB/c mice. In vitro stimulation of these CD4+ T cells showed that anti-OX40L mAb treatment resulted in substantially reduced production of Th2 cytokines. Moreover, this change in cytokine levels was associated with reduced levels of anti–L. major immunoglobulin (Ig)G1 and serum IgE. These results indicate that anti-OX40L mAb abrogated progressive leishmaniasis in BALB/c mice by suppressing the development of Th2 responses, substantiating a critical role of OX40–OX40L interaction in Th2 development in vivo.
Constitutive CD27/CD70 Interaction Induces Expansion of Effector-Type T Cells and Results in IFNγ-Mediated B Cell Depletion
Authors: Ramon Arens, Kiki Tesselaar, Paul A Baars, Gijs M.W van Schijndel, Jenny Hendriks, Steven T Pals, Paul Krimpenfort, Jannie Borst, Marinus H.J van Oers, René A.W van Lier
Journal: Immunity (2001)
Lung transplantation for silicosis, report of 17 patients
Authors: Dror Rosengarten, Viktoria Rusanov, Oren Fruchter, Yael Raviv, Mordechai Kramer
Journal: European Respiratory Journal (2014)

Silicosis is a progressive, fibrotic lung disease resulting from inhalation of respirable crystalline silica. Silicosis is one of the most important occupational lung diseases worldwide and is associated with a high morbidity and mortality. Unfortunately, there is no medical treatment available for end-stage silicosis other than lung transplantation (LT). Nevertheless, Silicosis is a rare indication for LT which has been previously reported to result in poor outcome. Recently, a Silicosis outbreak reported in Israel, which has been attributed to exposure to artificial stone with high-silica-content. During the last 7 years, 60 patients with silicosis were referred for evaluation, among them, 17 patients underwent LT in the Rabin medical center. All patients were male and average age was 50.3 years. Average FEV1 was 31.6% and average DLCO was 34.8%. Average lung allocation score was 45.9. Single lung transplantation was performed in 82% and 29% were done with extracorporeal membrane oxygenation support. One year survival was 87.5% and two years survival was 75%, which is similar to the outcome of other transplantations in our center. Mean follow-up was 21.6±18.3 months. Silicosis patients represent 5% of all patients transplanted in our center. This rate is extremely high comparing to the rate reported in the United Network of Organ Sharing which was only 0.43%. This tenfold increase in the rate of Silicosis patients transplanted in Israel represents the severity of the artificial stone silicosis outbreak.  Conclusion:  Artificial stone silicosis outbreak in Israel presents a challenge with increased rate of patients with severe Silicosis who required LT.  LT offers an effective therapy for patients with end-stage silicosis.
Asbestos induced diffuse pleural fibrosis: pathology and mineralogy.
Authors: M Stephens, A R Gibbs, F D Pooley, J C Wagner
Journal: Thorax (1987)

Lungs from seven cases of diffuse pleural fibrosis with known asbestos exposure were studied to determine the gross and microscopic pathological features and relate these to the analysed mineral fibre content of the lung. All seven individuals had had substantial exposure, ranging from two to 25 years, and chronic chest problems and at necropsy all cases met the criteria for compensatable disease. Macroscopically, all had extensive visceral pleural fibrosis and extensive areas of adhesions, and four also had discrete parietal pleural plaques. The histological features were similar in all the cases--most strikingly the basket weave pattern of the thickened pleura and a dense subpleural parenchymal interstitial fibrosis with fine honeycombing, extending up to 1 cm into the underlying lung. The similar histological appearances raise the possibility that diffuse pleural fibrosis and pleural plaques have a similar pathogenesis. Amphibole asbestos (crocidolite and amosite) counts were high in six of the seven cases and chrysotile counts in four; four cases had high mullite counts, but the importance of this is not known. It is concluded that diffuse pleural fibrosis is a specific asbestos associated entity, of uncertain pathogenesis, with mineral fibre counts falling between those found with plaques and those in minimal asbestosis.
Effects of Parenteral Hydration in Terminally Ill Cancer Patients: A Preliminary Study
Authors: Eduardo Bruera, Raul Sala, Maria Antonieta Rico, Jairo Moyano, Carlos Centeno, Jie Willey, J. Lynn Palmer
Journal: Journal of Clinical Oncology (2005)

Most patients with cancer develop decreased oral intake and dehydration before death. This study aimed to determine the effect of parenteral hydration on overall symptom control in terminally ill cancer patients with dehydration.Patients with clinical evidence of mild to moderate dehydration and a liquid oral intake less than 1,000 mL/day were randomly assigned to receive either parenteral hydration with 1,000 mL (treatment group) or placebo with 100 mL normal saline administered over 4 hours for 2 days. Patients were evaluated for target symptoms (hallucinations, myoclonus, fatigue, and sedation), global well-being, and overall benefit.Twenty-seven patients randomly assigned to the treatment group had improvement in 53 (73%) of their 73 target symptoms versus 33 (49%) of 67 target symptoms in the placebo group (n=22; P = .005). Fifteen (83%) of 18 and 15 (83%) of 18 patients had improved myoclonus and sedation after hydration versus eight (47%) of 17 and five (33%) of 15 patients after placebo (P = .035 and P = .005, respectively). There were no significant differences of improvement in hallucinations or fatigue between groups. When blinded to treatment, patients (17 [63%] of 77) and investigators (20 [74%] of 27) perceived hydration as effective compared with placebo in nine (41%) of 22 patients (P = .78) and 12 (54%) of 22 investigators (P = .15), respectively. The intensity of pain and swelling at the injection site were not significantly different between groups.Parenteral hydration decreased symptoms of dehydration in terminally ill cancer patients who had decreased fluid intake. Hydration was well tolerated, and a placebo effect was observed. Studies with larger samples and a longer follow-up period are justified.
Maximum-Likelihood Phylogenetic Inference with Selection on Protein Folding Stability
Authors: Miguel Arenas, Agustin Sánchez-Cobos, Ugo Bastolla
Journal: Molecular Biology and Evolution (2015)

Despite intense work, incorporating constraints on protein native structures into the mathematical models of molecular evolution remains difficult, because most models and programs assume that protein sites evolve independently, whereas protein stability is maintained by interactions between sites. Here, we address this problem by developing a new mean-field substitution model that generates independent site-specific amino acid distributions with constraints on the stability of the native state against both unfolding and misfolding. The model depends on a background distribution of amino acids and one selection parameter that we fix maximizing the likelihood of the observed protein sequence. The analytic solution of the model shows that the main determinant of the site-specific distributions is the number of native contacts of the site and that the most variable sites are those with an intermediate number of native contacts. The mean-field models obtained, taking into account misfolded conformations, yield larger likelihood than models that only consider the native state, because their average hydrophobicity is more realistic, and they produce on the average stable sequences for most proteins. We evaluated the mean-field model with respect to empirical substitution models on 12 test data sets of different protein families. In all cases, the observed site-specific sequence profiles presented smaller Kullback–Leibler divergence from the mean-field distributions than from the empirical substitution model. Next, we obtained substitution rates combining the mean-field frequencies with an empirical substitution model. The resulting mean-field substitution model assigns larger likelihood than the empirical model to all studied families when we consider sequences with identity larger than 0.35, plausibly a condition that enforces conservation of the native structure across the family. We found that the mean-field model performs better than other structurally constrained models with similar or higher complexity. With respect to the much more complex model recently developed by Bordner and Mittelmann, which takes into account pairwise terms in the amino acid distributions and also optimizes the exchangeability matrix, our model performed worse for data with small sequence divergence but better for data with larger sequence divergence. The mean-field model has been implemented into the computer program Prot_Evol that is freely available at http://ub.cbm.uam.es/software/Prot_Evol.php.