tbuckley/cabot-search huggingface dataset:
Sequence-Based Analysis of Protein Energy Landscapes Reveals Nonuniform Thermal Adaptation within the Proteome
Authors: J. Gu, V. J. Hilser
Journal: Molecular Biology and Evolution (2009)

Thermal adaptation of individual proteins is often achieved through modulating protein stability, with proteins that are adapted to extreme cold environments having increased conformational flexibility when brought to mesophilic conditions. Conversely, proteins adapted to higher temperatures appear less dynamic and are found to be much more stable against thermal denaturation than their mesophilic counterparts. According to the current paradigm, the adaptation of an organism for survival at higher or lower temperatures is facilitated by the adaptation of the component proteins. We note, however, that these observations have been carried out on relatively few proteins. The extent to which the conformational stabilities of all members of the proteome have been modulated for thermal adaptation remains unclear, with no direct experimental strategies to address this issue. Adapted extremophilies are likely to use a multitude of molecular and biophysical strategies for survival and, therefore, evolution of specific biophysical properties of proteins for optimal function may not be necessary for all proteins in the proteome. Using a sequence-based predictor of protein stability, eScape, an in silico examination of several extremophilic proteomes shows a correlation between the collective stability of the proteins and the thermal range of survival for the organism as expected. Unexpectedly, however, the analysis shows that protein thermostability is modified to different extents across the proteome and depends on the functional role for which the protein is involved. Identification of these differences provides unique opportunities to study interdependence within the proteome as well as the role that the proteome plays in the process of evolutionary thermal adaptation.
The spliceosome, a potential Achilles heel of MYC-driven tumors
Authors: Olga Anczuków, Adrian R. Krainer
Journal: Genome Medicine (2015)

Alterations in RNA splicing are frequent in human tumors. Two recent studies of lymphoma and breast cancer have identified components of the spliceosome — the core splicing machinery — that are essential for malignant transformation driven by the transcription factor MYC. These findings provide a direct link between MYC and RNA splicing deregulation, and raise the exciting possibility of targeting spliceosome components in MYC-driven tumors.
Organic dust toxicity (pulmonary mycotoxicosis) associated with silo unloading.
Authors: J J May, L Stallones, D Darrow, D S Pratt
Journal: Thorax (1986)

An acute febrile illness associated with unloading silos occurs more frequently than any other farm associated respiratory illness in mid state New York. This report describes 29 cases of organic dust toxic syndrome (also known as pulmonary mycotoxicosis) occurring in 24 men and one woman with a mean age of 29 years. In 16 instances more than one worker was exposed to the dust, and in 12 of these shared exposures more than one worker became ill. Patients presented 5.3 (SD 3.3) hours after inhalation of organic dust and mould with fever (79%), myalgia (76%), chest tightness (72%), cough (66%), and headache (59%). The mean temperature was 38.7 degrees C and the mean white blood cell count 13.2 X 10(9)/l. In contrast to patients with allergic alveolitis, nearly all these patients had normal breath sounds, chest radiographs, and arterial oxygen saturation. Tests for precipitating antibodies to farmer's lung disease antigens gave negative results in all 26 episodes in which they were done; of these, 10 had no evidence of precipitating antibodies to an aqueous extract of the silage associated with their own illness. Organic dust toxic syndrome appears to be a common and substantial respiratory hazard to young farm workers. Despite being frequently mis-diagnosed as farmer's lung, organic dust toxic syndrome is clearly a distinctly different disease process.
Inhaled corticosteroid use is associated with lower mortality for subjects with COPD and hospitalised with pneumonia
Authors: R. Malo de Molina, E. M. Mortensen, M. I. Restrepo, L. A. Copeland, M. J. V. Pugh, A. Anzueto
Journal: European Respiratory Journal (2010)

Recent studies suggest that use of inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD) may be associated with a higher incidence of pneumonia. However, it is unclear whether COPD subjects on ICS who develop pneumonia have worse outcomes. Therefore, our aim was to examine the association of prior outpatient ICS therapy with mortality in hospitalised COPD subjects with pneumonia. We included subjects ≥64 yrs of age, hospitalised with pneumonia in US Veterans Affairs hospitals, and assessed the association of ICS exposure with mortality for hospitalised COPD subjects with pneumonia in a covariate-adjusted regression model. We identified 6,353 subjects with a diagnosis of pneumonia and prior COPD, of whom 38% were on ICS. Mortality was 9% at 30 days and 16% at 90 days. In regression analyses, outpatient ICS therapy was associated with lower mortality at both 30 days (OR 0.76, 95% CI 0.70–0.83), and 90 days (OR 0.80, 95% CI 0.75–0.86). Outpatient therapy with ICS was associated with a significantly lower 30- and 90-day mortality in hospitalised COPD patients with pneumonia.
Second pregnancy outcomes for women with systemic lupus erythematosus
Authors: Antonia W Shand, Charles S Algert, Lyn March, Christine L Roberts
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> Systemic lupus erythematosus (SLE) is associated with adverse pregnancy outcomes overall. <h3>Objective</h3> To examine the outcomes for women with SLE in a pregnancy subsequent to a first birth with an adverse outcome. <h3>Methods</h3> A population-based cohort study was carried out of 794 577 deliveries to 532 612 women giving birth in New South Wales, Australia from 2001 to 2009. Data were obtained from longitudinally linked birth records and hospital records. <h3>Results</h3> 675 women had a diagnosis of SLE in the study period (prevalence 127 per 100 000 childbearing women). Of 177 women who had a first nulliparous birth and subsequent pregnancy, 10 (5.6%) had a perinatal death in the first pregnancy, and of these women, 9 (90%) had a baby discharged home alive in the second pregnancy. Of the 167 women whose first-birth infants survived, second pregnancy outcomes included: 18 (11%) admission for spontaneous abortion, 1 perinatal death (0.6%) and 148 (89%) infants discharged home. Two women had a thromboembolic event in their first pregnancy but had no thromboembolic event in the second. Two women had thromboembolic events in second pregnancies only. <h3>Conclusion</h3> Women with SLE are at high risk of adverse pregnancy outcomes. However, those who have a perinatal death in their first pregnancy can expect a live birth for a subsequent pregnancy.
European expert opinion on the management of invasive candidiasis in adults
Authors: B.J. Kullberg, P.E. Verweij, M. Akova, M.C. Arendrup, J. Bille, T. Calandra, M. Cuenca-Estrella, R. Herbrecht, F. Jacobs, M. Kalin, C.C. Kibbler, O. Lortholary, P. Martino, J.F. Meis, P. Muñoz, F.C. Odds, B.E. De Pauw, J.H. Rex, E. Roilides, T.R. Rogers, M. Ruhnke, A.J. Ullmann, Ö. Uzun, K. Vandewoude, J.-L. Vincent, J.P. Donnelly
Journal: Clinical Microbiology and Infection (2011)
IL18 and IL18R1 polymorphisms, lung CT and fibrosis: a longitudinal study in coal miners
Authors: R. Nadif, M. Mintz, J. Marzec, A. Jedlicka, F. Kauffmann, S. R. Kleeberger
Journal: European Respiratory Journal (2006)

It has been suggested that interleukin (IL)-18 plays a role in the development of inflammatory and fibrosing lung diseases. Associations of polymorphisms in the genes coding for IL-18 ( IL18 /G-656T, C-607A, G-137C, T113G, C127T) and its receptor ( IL18R1 /C-69T) with coal workers' pneumoconiosis (CWP) were studied in 200 miners who were examined in 1990, 1994 and 1999. Coal-dust exposure was assessed according to job history and ambient measures. The main health outcome was lung computed tomography (CT) score in 1990. Internal coherence was assessed by studying CT score in 1994, 4-yr change in CT score and CWP incidence and prevalence. CT score in 1990 was a good predictor of radiographic grade in 1999 and, therefore, an appropriate subclinical quantitative trait. The IL18 -137C allele was associated with lower CT score in 1990 and 1994 (1.24 versus 1.69 and 1.57 versus 2.46, respectively), slower progression of CT score between 1990 and 1994 and lower pneumoconiosis prevalence in 1999 relative to the G allele (0.33 versus 0.77 and 8.2 versus 19.6%, respectively). Smoking- or dust-adjustment, and stratification on IL18R1 genotype and adjustment for haplotype effects did not change the conclusions. In conclusion, the results of the present study suggest a role for IL18 in reducing the development of this fibrosing lung disease.
Significance of Suppressor Macrophages for Immunosurveillance of Tumor-Bearing Mice&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: T Fujii, T Igarashi, S Kishimoto
Journal: JNCI Journal of the National Cancer Institute (1987)

The in vivo significance of suppressor macrophages for antitumor immunity was investigated in a syngeneic tumor system. The presence of suppressor macrophages in the spleens of X5563 C3H/HeN tumor-bearing mice (TBM) was directly shown in vitro. Thus the addition of splenic macrophages of TBM suppressed the in vitro secondary induction of both tumor-specific cytotoxic T-cells and effector cells of the delayed-type hypersensitivity reaction. Splenic macrophages of TBM exerted suppression on tumor-specific T-cell-mediated cytotoxicity in the effector phase as well. Prostaglandin production was found to be one of the major mechanisms involved in macrophage-induced suppression. In vivo treatment of TBM with carrageenan and/or indomethacin retarded tumor growth and in parallel augmented cell-mediated cytotoxicity against X5563 cells, probably by affecting suppressor macrophages in vivo. The suppressive effect of splenic macrophages from TBM was clearly demonstrated in a tumor-neutralization test indicating that suppressor macrophages were able to exert their function in vivo as well as in vitro. All these results suggested that suppressor macrophages had in vivo significance for the suppression of the immunosurveillance of the hosts.
The Long Noncoding RNA CHRF Regulates Cardiac Hypertrophy by Targeting miR-489
Authors: Kun Wang, Fang Liu, Lu-Yu Zhou, Bo Long, Shu-Min Yuan, Yin Wang, Cui-Yun Liu, Teng Sun, Xiao-Jie Zhang, Pei-Feng Li
Journal: Circulation Research (2014)

Sustained cardiac hypertrophy is often accompanied by maladaptive cardiac remodeling leading to decreased compliance and increased risk for heart failure. Maladaptive hypertrophy is considered to be a therapeutic target for heart failure. MicroRNAs (miRNAs) and long noncoding RNAs (lncRNAs) have various biological functions and have been extensively investigated in past years.We identified miR-489 and lncRNAs (cardiac hypertrophy related factor, CHRF) from hypertrophic cardiomyocytes. Here, we tested the hypothesis that miR-489 and CHRF can participate in the regulation of cardiac hypertrophy in vivo and in vitro.A microarray was performed to analyze miRNAs in response to angiotensin II treatment, and we found miR-489 was substantially reduced. Enforced expression of miR-489 in cardiomyocytes and transgenic overexpression of miR-489 both exhibited reduced hypertrophic response on angiotensin II treatment. We identified myeloid differentiation primary response gene 88 (Myd88) as a miR-489 target to mediate the function of miR-489 in cardiac hypertrophy. Knockdown of Myd88 in cardiomyocytes and Myd88-knockout mice both showed attenuated hypertrophic responses. Furthermore, we explored the molecular mechanism by which miR-489 expression is regulated and found that an lncRNA that we named CHRF acts as an endogenous sponge of miR-489, which downregulates miR-489 expression levels. CHRF is able to directly bind to miR-489 and regulate Myd88 expression and hypertrophy.Our present study reveals a novel cardiac hypertrophy regulating model that is composed of CHRF, miR-489, and Myd88. The modulation of their levels may provide a new approach for tackling cardiac hypertrophy.
Evaluation of the THRESHOLD trainer for inspiratory muscle endurance training: comparison with the weighted plunger method
Authors: P H Johnson, A J Cowley, W J Kinnear
Journal: European Respiratory Journal (1996)

Inspiratory muscle training (IMT) has been shown to enhance exercise performance. The weighted plunger (WP) system of inspiratory threshold loading is the most commonly used method of IMT, but is expensive and cumbersome. We have evaluated a commercially available portable spring-loaded IMT device, the THRESHOLD trainer. The WP and THRESHOLD trainer devices were evaluated with their opening pressures set, in random order, at 10, 20, 30 and 40 cmH2O. Using an airpump, pressure at the valve inlet was recorded at the point at which the valve opened, and at airflow rates of 20, 40, 60, 80 and 100 L.min-1.Ten THRESHOLD trainers were then compared using the same opening pressures and airflow rates. Finally, 10 patients with stable chronic heart failure (CHF) inspired, in random order, through the WP and THRESHOLD trainer for 4 min each. The pressure-time product (PTP) was calculated for each 4 min period, to compare the work performed on inspiring through each device. The mean measured opening pressures for the WP set at 10, 20, 30 and 40 cmH2O, were 9.0, 19.3, 27.9 and 39.2 cmH2O, respectively, and there was little change over the range of flow tested. Corresponding values for the THRESHOLD trainer were 7.5, 16.9, 26.2 and 39.1 cmH2O, with the pressure being closer to the set pressure as flow increased to that seen in clinical practice. The 10 different trainers tested performed very similarly to one another. Work performed (as measured by PTP) on inspiring through the WP and THRESHOLD trainer was not significantly different. Although less accurate than the weighted plunger, the THRESHOLD trainer is an inexpensive device of consistent quality. In a clinical setting it would be a satisfactory option for inspiratory muscle training in most patients, but less so in patients with very low inspiratory flow rates.
Gait speed and readmission following hospitalisation for acute exacerbations of COPD: a prospective study
Authors: Samantha S C Kon, Sarah E Jones, Susie J Schofield, Winston Banya, Mandy J Dickson, Jane L Canavan, Claire M Nolan, Brigitte M Haselden, Michael I Polkey, Paul Cullinan, William D-C Man
Journal: Thorax (2015)

<h3>Background</h3> Hospitalisation for acute exacerbations of COPD is associated with high risk of readmission. However, no tool has been validated to stratify patients at discharge for risk of readmission. <h3>Aim</h3> To evaluate the ability of the 4 m gait speed (4MGS), a surrogate marker of frailty, to predict risk of future readmission in hospitalised patients with an acute exacerbation of COPD (AECOPD). <h3>Methods</h3> 213 patients hospitalised with an AECOPD were recruited prospectively. 4MGS was measured on day of discharge. Logistic regression models were used to assess the association between 4MGS and readmission at 90 days after discharge. <h3>Results</h3> Baseline characteristics of the cohort: 52% men; mean age 72 years; median FEV<sub>1</sub> 35%predicted. Mean (SD) 4MGS at hospital discharge was 0.61 (0.26) ms<sup>−1</sup>. Significant increased rates of all-cause readmission at 90 days were seen across quartiles of decreasing 4MGS (Q4 fastest: 11.5%; Q3: 20.4%; Q2: 30.2%; Q1 slowest: 48.2%; p<sub>trend</sub>&lt;0.001). Compared with Q4, those in the slowest 4MGS quartile had unadjusted ORs (95% CIs) for 90-day readmission of 7.12 (2.61 to 19.44) for the whole cohort and 11.56 (3.08 to 43.35) in those aged 65 or over. A multivariate model incorporating 4MGS, Charlson Index, hospital admission in past year, FEV<sub>1</sub>%predicted and number of exacerbations in past year in those aged 65 or over predicted 90-day readmission with a C-statistic of 0.86. <h3>Conclusions</h3> The 4MGS, a surrogate marker of physical frailty, independently predicts the risk of readmission in older patients hospitalised for acute exacerbation of COPD. <h3>Trial registration number</h3> NCT01507415.
A polymorphism in the XPD gene predisposes to leukemic transformation and new nonmyeloid malignancies in essential thrombocythemia and polycythemia vera
Authors: Juan-Carlos Hernández-Boluda, Arturo Pereira, Francisco Cervantes, Alberto Alvarez-Larrán, María Collado, Esperanza Such, M. Jesús Arilla, Concepción Boqué, Blanca Xicoy, Margherita Maffioli, Beatriz Bellosillo, Isabel Marugán, Paula Amat, Carles Besses, Vicent Guillem
Journal: Blood (2012)
Evaluating Risk of ESRD in the Urban Poor
Authors: Marlena Maziarz, R. Anthony Black, Christine T. Fong, Jonathan Himmelfarb, Glenn M. Chertow, Yoshio N. Hall
Journal: Journal of the American Society of Nephrology (2014)

The capacity of risk prediction to guide management of CKD in underserved health settings is unknown. We conducted a retrospective cohort study of 28,779 adults with nondialysis-requiring CKD who received health care in two large safety net health systems during 1996-2009 and were followed for ESRD through September of 2011. We developed and evaluated the performance of ESRD risk prediction models using recently proposed criteria designed to inform population health approaches to disease management: proportion of cases followed and proportion that needs to be followed. Overall, 1730 persons progressed to ESRD during follow-up (median follow-up=6.6 years). ESRD risk for time frames up to 5 years was highly concentrated among relatively few individuals. A predictive model using five common variables (age, sex, race, eGFR, and dipstick proteinuria) performed similarly to more complex models incorporating extensive sociodemographic and clinical data. Using this model, 80% of individuals who eventually developed ESRD were among the 5% of cohort members at the highest estimated risk for ESRD at 1 year. Similarly, a program that followed 8% and 13% of individuals at the highest ESRD risk would have included 80% of those who eventually progressed to ESRD at 3 and 5 years, respectively. In this underserved health setting, a simple five-variable model accurately predicts most cases of ESRD that develop within 5 years. Applying risk prediction using a population health approach may improve CKD surveillance and management of vulnerable groups by directing resources to a small subpopulation at highest risk for progressing to ESRD.
Doctors should care for people who choose to die by starvation, says Dutch Medical Association
Authors: T. Sheldon
Journal: BMJ (2014)

Elderly people who deliberately choose to stop eating and drinking in order to die more quickly have a right to the appropriate care from their doctor, say new professional guidelines from the Dutch Medical Association.

The association said that only on limited occasions may doctors refer such patients to other carers on the grounds of conscience. It said that treatment must then continue until the referral.

The “concept guidelines” currently being considered by the association’s members accepted that the withdrawal of food and fluids could be a humane way to die, on the basis of scientific literature. They did not regard these cases as assisted suicide but more akin to patients exercising their right to refuse life prolonging …
Phase I Clinical Investigation of Fludarabine Phosphate by a Loading-Dose and Continuous-Infusion Schedule
Authors: J. M. Leiby, M. R. Grever, A. E. Staubus, J. A. Neidhart, L. Malspeis
Journal: JNCI Journal of the National Cancer Institute (1988)

Fludarabine phosphate was studied in a phase I trial of a loading dose/continuous-infusion schedule. The schedule was chosen to rapidly achieve and maintain concentrations that have been shown in vitro to achieve maximal inhibition of cell growth. The initial level was a loading dose of 20 mg/m2 followed by a 48-hour continuous iv (CIV) infusion of 30 mg/m2 every 24 hours. For the single-dose escalation, the loading dose was held constant while the CIV dose was increased to 45 mg/m2/24 hours for 48 hours. The dose-limiting toxicity was myelosuppression, especially leukopenia. No other significant toxicity was encountered. The maximum tolerated dose was 20 mg/m2 by iv push followed by a 48-hour CIV infusion of 30 mg/m2/24 hours for 48 hours. The recommended starting dose for phase II trials is 20 mg/m2 by iv push followed by a 48-hour CIV infusion of 30 mg/m2/24 hours. This dose level achieved the target plasma levels in the 2 patients studied. [J Natl Cancer Inst 1988;80:447–449]
Evolution of the Toxoglossa Venom Apparatus as Inferred by Molecular Phylogeny of the Terebridae
Authors: M. Holford, N. Puillandre, Y. Terryn, C. Cruaud, B. Olivera, P. Bouchet
Journal: Molecular Biology and Evolution (2008)

Toxoglossate marine gastropods, traditionally assigned to the families Conidae, Terebridae, and Turridae, are one of the most populous animal groups that use venom to capture their prey. These marine animals are generally characterized by a venom apparatus that consists of a muscular venom bulb and a tubular venom gland. The toxoglossan radula, often compared with a hypodermic needle for its use as a conduit to inject toxins into prey, is considered a major anatomical breakthrough that assisted in the successful initial radiation of these animals in the Cretaceous and early Tertiary. The pharmacological success of toxins from cone snails has made this group a star among biochemists and neuroscientists, but very little is known about toxins from the other Toxoglossa, and the phylogeny of these families is largely in doubt. Here we report the first molecular phylogeny for the Terebridae and use the results to infer the evolution of the venom apparatus for this group. Our findings indicate that most of the genera of terebrids are polyphyletic, and one species ("Terebra" (s.l.) jungi) is the sister group to all other terebrids. Molecular analyses combined with mapping of venom apparatus morphology indicate that the Terebridae have lost the venom apparatus at least twice during their evolution. Species in the genera Terebra and Hastula have the typical venom apparatus found in most toxoglossate gastropods, but all other terebrid species do not. For venomous organisms, the dual analysis of molecular phylogeny and toxin function is an instructive combination for unraveling the larger questions of phylogeny and speciation. The results presented here suggest a paradigm shift in the current understanding of terebrid evolution, while presenting a road map for discovering novel terebrid toxins, a largely unexplored resource for biomedical research and potential therapeutic drug development.