tbuckley/cabot-search huggingface dataset:
Internal and External Paralogy in the Evolution of Tropomyosin Genes in Metazoans
Authors: M. Irimia, I. Maeso, P. W. Gunning, J. Garcia-Fernandez, S. W. Roy
Journal: Molecular Biology and Evolution (2010)

Nature contains a tremendous diversity of forms both at the organismal and genomic levels. This diversity motivates the twin central questions of molecular evolution: what are the molecular mechanisms of adaptation, and what are the functional consequences of genomic diversity. We report a 22-species comparative analysis of tropomyosin (PPM) genes, which exist in a variety of forms and are implicated in the emergence of a wealth of cellular functions, including the novel muscle functions integral to the functional diversification of bilateral animals. TPM genes encode either or both of long-form [284 amino acid (aa)] and short-form (approximately 248 aa) proteins. Consistent with a role of TPM diversification in the origins and radiation of bilaterians, we find evidence that the muscle-specific long-form protein arose in proximal bilaterian ancestors (the bilaterian ‘stem’). Duplication of the 5′ end of the gene led to alternative promoters encoding long- and short-form transcripts with distinct functions. This dual-function gene then underwent strikingly parallel evolution in different bilaterian lineages. In each case, recurrent tandem exon duplication and mutually exclusive alternative splicing of the duplicates, with further association between these alternatively spliced exons along the gene, led to long- and short-form–specific exons, allowing for gradual emergence of alternative “internal paralogs” within the same gene. We term these Mutually exclusively Alternatively spliced Tandemly duplicated Exon sets “MATEs”. This emergence of internal paralogs in various bilaterians has employed every single TPM exon in at least one lineage and reaches striking levels of divergence with up to 77% of long- and short-form transcripts being transcribed from different genomic regions. Interestingly, in some lineages, these internal alternatively spliced paralogs have subsequently been “externalized” by full gene duplication and reciprocal retention/loss of the two transcript isoforms, a particularly clear case of evolution by subfunctionalization. This parallel evolution of TPM genes in diverse metazoans attests to common selective forces driving divergence of different gene transcripts and represents a striking case of emergence of evolutionary novelty by alternative splicing.
Similar antigen cross-presentation capacity and phagocytic functions in all freshly isolated human lymphoid organ–resident dendritic cells
Authors: Elodie Segura, Mélanie Durand, Sebastian Amigorena
Journal: The Journal of Experimental Medicine (2013)

Dendritic cells (DCs) represent a heterogeneous population of antigen-presenting cells that initiate and orient immune responses in secondary lymphoid organs. In mice, lymphoid organ–resident CD8+ DCs are specialized at cross-presentation and have developed specific adaptations of their endocytic pathway (high pH, low degradation, and high export to the cytosol). In humans, blood BDCA3+ DCs were recently shown to be the homologues of mouse CD8+ DCs. They were also proposed to cross-present antigens more efficiently than other blood DC subsets after in vitro activation, suggesting that in humans cross-presentation is restricted to certain DC subsets. The DCs that cross-present antigen physiologically, however, are the ones present in lymphoid organs. Here, we show that freshly isolated tonsil-resident BDCA1+ DCs, BDCA3+ DCs, and pDCs all cross-present soluble antigen efficiently, as compared to macrophages, in the absence of activation. In addition, BDCA1+ and BDCA3+ DCs display similar phagosomal pH and similar production of reactive oxygen species in their phagosomes. All three DC subsets, in contrast to macrophages, also efficiently export internalized proteins to the cytosol. We conclude that all freshly isolated lymphoid organ–resident human DCs, but not macrophages, display high intrinsic cross-presentation capacity.
Molecular Approaches to Analysis of X-Linked Immunodeficiencies
Authors: Mary Ellen Conley
Journal: Annual Review of Immunology (1992)

Although the X-linked immunodeficiencies—X-linked agammaglobulinemia (XLA), X-linked severe combined immunodeficiency (XSCID), Wiskott-Aldrich syndrome (WAS), X-linked lymphoproliferative syndrome and X-linked hyper IgM syndrome—have been mapped to loci distributed throughout the X chromosome, they have several features in common that suggest that they might be members of a gene family: (i) all are maintained in the population at approximately the same gene frequency; (ii) expression of each defect is limited to the hematopoieticsy stem; (iii) atypical forms of each disorder have been described; and (iv) obligate carriers of these disorders are normal by all immunologic criteria. The failure of carriers of XLA, XSCID, and WAS to show signs of their gene defects can be explained by the preferential use of the normal, nonmutant X as the active X in the cell lineages affected by the gene defects. These three disorders also share an additional feature; in boys with XLAX, SCID, or WAS there is asynchronous expression of cell surface markers of differentiation or activation. If some or all of the genes that are abnormal in the X-linked immunodeficiencies are members of a gene family, then isolation of one gene may lead to the others.
Homozygous Southeast Asian ovalocytosis is a severe dyserythropoietic anemia associated with distal renal tubular acidosis
Authors: Véronique Picard, Alexis Proust, Marion Eveillard, Joanna F. Flatt, Marie-Laure Couec, Gaêlle Caillaux, Madeleine Fénéant-Thibault, Arie Finkelstein, Martine Raphaël, Jean Delaunay, Lesley J. Bruce, Serge Pissard, Caroline Thomas
Journal: Blood (2014)
Senescent Stromal-Derived Osteopontin Promotes Preneoplastic Cell Growth
Authors: Ermira Pazolli, Xianmin Luo, Sarah Brehm, Kelly Carbery, Jun-Jae Chung, Julie L. Prior, Jason Doherty, Shadmehr Demehri, Lorena Salavaggione, David Piwnica-Worms, Sheila A. Stewart
Journal: Cancer Research (2009)

Alterations in the tissue microenvironment collaborate with cell autonomous genetic changes to contribute to neoplastic progression. The importance of the microenvironment in neoplastic progression is underscored by studies showing that fibroblasts isolated from a tumor stimulate the growth of preneoplastic and neoplastic cells in xenograft models. Similarly, senescent fibroblasts promote preneoplastic cell growth in vitro and in vivo. Because senescent cells accumulate with age, their presence is hypothesized to facilitate preneoplastic cell growth and tumor formation in older individuals. To identify senescent stromal factors directly responsible for stimulating preneoplastic cell growth, we carried out whole-genome transcriptional profiling and compared senescent fibroblasts with their younger counterparts. We identified osteopontin (OPN) as one of the most highly elevated transcripts in senescent fibroblasts. Importantly, reduction of OPN protein levels by RNA interference did not affect senescence induction in fibroblasts; however, it dramatically reduced the growth-promoting activities of senescent fibroblasts in vitro and in vivo, showing that OPN is necessary for paracrine stimulation of preneoplastic cell growth. In addition, we found that recombinant OPN was sufficient to stimulate preneoplastic cell growth. Finally, we show that OPN is expressed in senescent stroma within preneoplastic lesions that arise following 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate treatment of mice, suggesting that stromal-derived OPN-mediated signaling events affect neoplastic progression.
Altered Reward Processing in Women Recovered From Anorexia Nervosa
Authors: Angela Wagner, Howard Aizenstein, Vijay K. Venkatraman, Julie Fudge, J. Christopher May, Laura Mazurkewicz, Guido K. Frank, Ursula F. Bailer, Lorie Fischer, Van Nguyen, Cameron Carter, Karen Putnam, Walter H. Kaye
Journal: American Journal of Psychiatry (2007)

Objective: Individuals with anorexia nervosa are known to be ascetic and able to sustain self-denial of food as well as most comforts and pleasures in life. Building on previous findings of altered striatal dopamine binding in anorexia nervosa, the authors sought to assess the response of the anterior ventral striatum to reward and loss in this disorder. Method: Striatal responses to a simple monetary reward task were investigated using event-related functional magnetic resonance imaging. To avoid the confounding effects of malnutrition, the authors compared 13 healthy comparison women and 13 women who had recovered from restricting-type anorexia nervosa and had 1 year of normal weight and regular menstrual cycles, without binge eating or purging. Results: Recovered women showed greater hemodynamic activation in the caudate than comparison women. Only the recovered women showed a significant positive relationship between trait anxiety and the percentage change in hemodynamic signal in the caudate during either wins or losses. In contrast, in the anterior ventral striatum, comparison women distinguished positive and negative feedback, whereas recovered women had similar responses to both conditions. Conclusions: Individuals who have recovered from anorexia nervosa may have difficulties in differentiating positive and negative feedback. The exaggerated activation of the caudate, a region involved in linking action to outcome, may constitute an attempt at “strategic” (as opposed to hedonic) means of responding to reward stimuli. The authors hypothesize that individuals with anorexia nervosa have an imbalance in information processing, with impaired ability to identify the emotional significance of a stimulus but increased traffic in neurocircuits concerned with planning and consequences.
Interplay of IKK/NF-κB signaling in macrophages and myofibers promotes muscle degeneration in Duchenne muscular dystrophy
Authors: Swarnali Acharyya, S. Armando Villalta, Nadine Bakkar, Tepmanas Bupha-Intr, Paul M.L. Janssen, Micheal Carathers, Zhi-Wei Li, Amer A. Beg, Sankar Ghosh, Zarife Sahenk, Michael Weinstein, Katherine L. Gardner, Jill A. Rafael-Fortney, Michael Karin, James G. Tidball, Albert S. Baldwin, Denis C. Guttridge
Journal: Journal of Clinical Investigation (2007)

Duchenne muscular dystrophy (DMD) is a lethal X-linked disorder associated with dystrophin deficiency that results in chronic inflammation and severe skeletal muscle degeneration. In DMD mouse models and patients, we find that IkappaB kinase/NF-kappaB (IKK/NF-kappaB) signaling is persistently elevated in immune cells and regenerative muscle fibers. Ablation of 1 allele of the p65 subunit of NF-kappaB was sufficient to improve pathology in mdx mice, a model of DMD. In addition, conditional deletion of IKKbeta in mdx mice elucidated that NF-kappaB functions in activated macrophages to promote inflammation and muscle necrosis and in skeletal muscle fibers to limit regeneration through the inhibition of muscle progenitor cells. Furthermore, specific pharmacological inhibition of IKK resulted in improved pathology and muscle function in mdx mice. Collectively, these results underscore the critical role of NF-kappaB in the progression of muscular dystrophy and suggest the IKK/NF-kappaB signaling pathway as a potential therapeutic target for DMD.
The novel cytokine interleukin-36α is expressed in psoriatic and rheumatoid arthritis synovium
Authors: Silke Frey, Anja Derer, Maria-Elena Messbacher, Dominique L P Baeten, Serena Bugatti, Carlomaurizio Montecucco, Georg Schett, Axel J Hueber
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Abstract</h3> Previously, we classified colorectal cancers (CRCs) into five CRCA subtypes with different prognoses and potential treatment responses, using a 786-gene signature. We merged our subtypes and those described by five other groups into four consensus molecular subtypes (CMS) that are similar to CRCA subtypes. Here we demonstrate the analytical development and application of a custom NanoString platform-based biomarker assay to stratify CRC into subtypes. To reduce costs, we switched from the standard protocol to a custom modified protocol (NanoCRCA) with a high Pearson correlation coefficient (&gt;0.88) between protocols. Technical replicates were highly correlated (&gt;0.96). The assay included a reduced robust 38-gene panel from the 786-gene signature that was selected using an in-laboratory developed computational pipeline of class prediction methods. We applied our NanoCRCA assay to untreated CRCs including fresh-frozen and formalin-fixed paraffin-embedded (FFPE) samples (n=81) with matched microarray or RNA-Seq profiles. We further compared the assay results with CMS classification, different platforms (microarrays/RNA-Seq) and gene-set classifiers (38 and 786 genes). NanoCRCA classified fresh-frozen samples (n=39; not including those showing a mixture of subtypes) into all five CRCA subtypes with overall high concordance across platforms (89.7%) and with CMS subtypes (84.6%), independent of tumour cellularity. This analytical validation of the assay shows the association of subtypes with their known molecular, mutational and clinical characteristics. Overall, our modified NanoCRCA assay with further clinical assessment may facilitate prospective validation of CRC subtypes in clinical trials and beyond. <h3>Novelty and Impact</h3> We previously identified five gene expression-based CRC subtypes with prognostic and potential predictive differences using a 786-gene signature and microarray platform. Subtype-driven clinical trials require a validated assay suitable for routine clinical use. This study demonstrates, for the first time, how molecular CRCA subtype can be detected using NanoString Technology-based biomarker assay (NanoCRCA) suitable for clinical validation. NanoCRCA is suitable for analysing FFPE samples, and this assay may facilitate patient stratification within clinical trials.
Prevalence of &lt;EMPH TYPE="ITAL"&gt;BRCA1&lt;/EMPH&gt; and &lt;EMPH TYPE="ITAL"&gt;BRCA2&lt;/EMPH&gt; Mutations in Women Diagnosed With Ductal Carcinoma In Situ
Authors: Elizabeth B. Claus, Stacey Petruzella, Ellen Matloff, Darryl Carter
Journal: JAMA (2005)

The distribution of BRCA1 and BRCA2 mutations in women diagnosed with noninvasive breast carcinoma is unknown.To estimate the BRCA1 and BRCA2 mutation prevalence in women with ductal carcinoma in situ (DCIS), unselected for age, family history, or ethnicity.The data were 369 DCIS cases diagnosed among female residents aged 20 to 79 years from the state of Connecticut between September 15, 1994, and March 14, 1998. These women were participants in a large population-based case-control study of breast carcinoma in situ. Telephone interviews were used to collect risk factor information and blood or buccal specimens were collected for BRCA1 and BRCA2 mutation testing.Prevalence of disease-associated mutations of BRCA1 and BRCA2 in women diagnosed with DCIS.Three (0.8%) and 9 (2.4%) of 369 DCIS cases had disease-associated mutations in BRCA1 or BRCA2, respectively. One woman had a mutation in both genes (BRCA1 W321X and BRCA2 3398del5). Carriers were significantly more likely than noncarriers to report a first-degree (mother, sister, or daughter) family history of breast cancer (odds ratio [OR], 3.7; 95% confidence interval [CI], 1.1-12.4), as well as a personal history of ovarian cancer. In addition, carriers were more likely than noncarriers to be diagnosed at an early age (<50 years) (OR, 3.4; 95% CI, 1.0-11.7), as well as to report at least 1 first-degree relative diagnosed with breast cancer before 50 years (OR, 10.6; 95% CI, 3.0-37.0).Ductal carcinoma in situ is a part of the breast/ovarian cancer syndromes defined by BRCA1 and BRCA2, with mutation rates similar to those found for invasive breast cancer. These findings suggest that patients with breast cancer with an appropriate personal or family history of breast and/or ovarian cancer should be screened and followed according to high-risk protocols, regardless of whether they are diagnosed with in situ or invasive breast cancer.
Use of ramipril in preventing stroke: double blind randomised trial
Authors: J. Bosch
Journal: BMJ (2002)

<h3>Abstract</h3> <b>Objective:</b> To determine the effect of the angiotensin converting enzyme inhibitor ramipril on the secondary prevention of stroke. <b>Design:</b> Randomised controlled trial with 2×2 factorial design. <b>Setting:</b> 267 hospitals in 19 countries. <b>Participants:</b> 9297 patients with vascular disease or diabetes plus an additional risk factor, followed for 4.5 years as part of the HOPE study. <b>Outcome measures:</b> Stroke (confirmed by computed tomography or magnetic resonance imaging when available), transient ischaemic attack, and cognitive function. Blood pressure was recorded at entry to the study, after 2 years, and at the end of the study. <b>Results:</b> Reduction in blood pressure was modest (3.8 mm Hg systolic and 2.8 mm Hg diastolic). The relative risk of any stroke was reduced by 32% (156 <i>v</i> 226) in the ramipril group compared with the placebo group, and the relative risk of fatal stroke was reduced by 61% (17 <i>v</i> 44). Benefits were consistent across baseline blood pressures, drugs used, and subgroups defined by the presence or absence of previous stroke, coronary artery disease, peripheral arterial disease, diabetes, or hypertension. Significantly fewer patients on ramipril had cognitive or functional impairment. <b>Conclusion:</b> Ramipril reduces the incidence of stroke in patients at high risk, despite a modest reduction in blood pressure. <h3>What is already known on this topic</h3> Treatment with aspirin and lowering blood pressure reduce the incidence of stroke <h3>What this study adds</h3> Ramipril, an angiotensin converting enzyme inhibitor, reduces strokes in patients at high risk whose blood pressure is not elevated, despite only a modest lowering of blood pressure The benefits are observed even when patients receive aspirin and other blood pressure lowering treatments
CARDIOVASCULAR SCREENING IN NCAA ATHLETES: FINDINGS FROM A MULTICENTER ECG-INCLUSIVE PROGRAM
Authors: I Asif, D Hadley, K Harmon, D Owens, J Prutkin, J Salerno, J Drezner
Journal: British Journal of Sports Medicine (2014)

Background The optimal pre-participation screening strategy in competitive athletes is debated. Objective To evaluate the accuracy of cardiovascular screening in NCAA athletes using a standardized history, physical exam (PE), and electrocardiogram (ECG). Design Prospective multi-center trial. Setting Competitive US collegiate athletes from 17 schools. Participants 3 284 athletes (56% male; 73% Caucasian; 15% African-American; mean age 19.8 years) from 17 sports were screened from July 2012 to October 2013. Assessment of risk factors Screening included a standardized history and PE based on recommendations from the American Heart Association (AHA), and a resting 12-lead ECG interpreted using 2013 international consensus standards (Seattle Criteria). Main outcome measurements Abnormalities detected by history, PE, and ECG. Results 1 022 (31.1%) athletes had &gt; 1 positive history response with SOB (11.6%%), syncope/near-syncope (11.0%), and exertional chest pain (6.5%) most common. PE was abnormal in 72 (2.2%) athletes. Overall, 123 (3.7%) ECGs were classified as abnormal (67.5% male, 32.5% female). The rate of abnormal ECGs was higher in men compared to women (4.5% vs 2.6%), African-Americans compared to Caucasians (5.3% vs. 3.6%), and most common in basketball players. A total of 133 ECG abnormalities were detected, including Q waves 36.8%, T wave inversion 22.6%, left axis deviation 9.8%, ST depression 7.5%, ventricular pre-excitation 6.8%, PVCs 5.3%, left atrial enlargement 4.5%, right ventricular hypertrophy 3.0%, prolonged QRS 2.3%, and prolonged QTc 1.5%. Eleven (0.3%) potentially lethal cardiac disorders were discovered. All 11 had abnormal ECGs, and only 2 cases had abnormal history or PE. Conclusions The current AHA strategy for pre-participation screening generates a high number of false-positive responses in college athletes. ECG screening using modern standards for interpretation provides a low and acceptable rate of abnormal findings and greatly increases the identification of serious cardiac disorders in US collegiate athletes.
Non-self recognition by monocytes initiates allograft rejection
Authors: Martin H. Oberbarnscheidt, Qiang Zeng, Qi Li, Hehua Dai, Amanda L. Williams, Warren D. Shlomchik, David M. Rothstein, Fadi G. Lakkis
Journal: Journal of Clinical Investigation (2014)

Maturation of T cell–activating APCs directly links innate and adaptive immunity and is typically triggered by microbial infection. Transplantation of allografts, which are sterile, generates strong T cell responses; however, it is unclear how grafts induce APC maturation in the absence of microbial-derived signals. A widely accepted hypothesis is that dying cells in the graft release “danger” molecules that induce APC maturation and initiate the adaptive alloimmune response. Here, we demonstrated that danger signals associated with dying cells are not sufficient to initiate alloimmunity, but that recognition of allogeneic non-self by the innate immune system is required. In WT as well as in T cell–, B cell–, and innate lymphoid cell–deficient mice, allogeneic grafts elicited persistent differentiation of monocytes into mature DCs that expressed IL-12 and stimulated T cell proliferation and IFN-γ production. In contrast, syngeneic grafts in the same mice elicited transient and less pronounced differentiation of monocytes into DCs, which neither expressed IL-12 nor stimulated IFN-γ production. In a model in which T cell recognition is restricted to a single foreign antigen on the graft, rejection occurred only if the allogeneic non-self signal was also sensed by the host’s innate immune system. These findings underscore the importance of innate recognition of allogeneic non-self by monocytes in initiating graft rejection.
Phosphodiesterase Type 3A Regulates Basal Myocardial Contractility Through Interacting With Sarcoplasmic Reticulum Calcium ATPase Type 2a Signaling Complexes in Mouse Heart
Authors: Sanja Beca, Faiyaz Ahmad, Weixing Shen, Jie Liu, Samy Makary, Nazari Polidovitch, Junhui Sun, Steven Hockman, Youn Wook Chung, Matthew Movsesian, Elizabeth Murphy, Vincent Manganiello, Peter H. Backx
Journal: Circulation Research (2012)

cAMP is an important regulator of myocardial function, and regulation of cAMP hydrolysis by cyclic nucleotide phosphodiesterases (PDEs) is a critical determinant of the amplitude, duration, and compartmentation of cAMP-mediated signaling. The role of different PDE isozymes, particularly PDE3A vs PDE3B, in the regulation of heart function remains unclear.
CYLD Regulates Noscapine Activity in Acute Lymphoblastic Leukemia via a Microtubule-Dependent Mechanism
Authors: Yunfan Yang, Jie Ran, Lei Sun, Xiaodong Sun, Youguang Luo, Bing Yan, None Tala, Min Liu, Dengwen Li, Lei Zhang, Gang Bao, Jun Zhou
Journal: Theranostics (2015)

Noscapine is an orally administrable drug used worldwide for cough suppression and has recently been demonstrated to disrupt microtubule dynamics and possess anticancer activity.However, the molecular mechanisms regulating noscapine activity remain poorly defined.Here we demonstrate that cylindromatosis (CYLD), a microtubule-associated tumor suppressor protein, modulates the activity of noscapine both in cell lines and in primary cells of acute lymphoblastic leukemia (ALL).Flow cytometry and immunofluorescence microscopy reveal that CYLD increases the ability of noscapine to induce mitotic arrest and apoptosis.Examination of cellular microtubules as well as in vitro assembled microtubules shows that CYLD enhances the effect of noscapine on microtubule polymerization.Microtubule cosedimentation and fluorescence titration assays further reveal that CYLD interacts with microtubule outer surface and promotes noscapine binding to microtubules.These findings thus demonstrate CYLD as a critical regulator of noscapine activity and have important implications for ALL treatment.