tbuckley/cabot-search huggingface dataset:
New Insights into Centromere Organization and Evolution from the White-Cheeked Gibbon and Marmoset
Authors: A. Cellamare, C.R. Catacchio, C. Alkan, G. Giannuzzi, F. Antonacci, M.F. Cardone, G. Della Valle, M. Malig, M. Rocchi, E.E. Eichler, M. Ventura
Journal: Molecular Biology and Evolution (2009)

The evolutionary history of α-satellite DNA, the major component of primate centromeres, is hardly defined because of the difficulty in its sequence assembly and its rapid evolution when compared with most genomic sequences. By using several approaches, we have cloned, sequenced, and characterized α-satellite sequences from two species representing critical nodes in the primate phylogeny: the white-cheeked gibbon, a lesser ape, and marmoset, a New World monkey. Sequence analyses demonstrate that white-cheeked gibbon and marmoset α-satellite sequences are formed by units of ∼171 and ∼342 bp, respectively, and they both lack the high-order structure found in humans and great apes. Fluorescent in situ hybridization characterization shows a broad dispersal of α-satellite in the white-cheeked gibbon genome including centromeric, telomeric, and chromosomal interstitial localizations. On the other hand, centromeres in marmoset appear organized in highly divergent dimers roughly of 342 bp that show a similarity between monomers much lower than previously reported dimers, thus representing an ancient dimeric structure. All these data shed light on the evolution of the centromeric sequences in Primates. Our results suggest radical differences in the structure, organization, and evolution of α-satellite DNA among different primate species, supporting the notion that 1) all the centromeric sequence in Primates evolved by genomic amplification, unequal crossover, and sequence homogenization using a 171 bp monomer as the basic seeding unit and 2) centromeric function is linked to relatively short repeated elements, more than higher-order structure. Moreover, our data indicate that complex higher-order repeat structures are a peculiarity of the hominid lineage, showing the more complex organization in humans.
Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease
Authors: Mike A Nalls, Nathan Pankratz, Christina M Lill, Chuong B Do, Dena G Hernandez, Mohamad Saad, Anita L DeStefano, Eleanna Kara, Jose Bras, Manu Sharma, Claudia Schulte, Margaux F Keller, Sampath Arepalli, Christopher Letson, Connor Edsall, Hreinn Stefansson, Xinmin Liu, Hannah Pliner, Joseph H Lee, Rong Cheng, M Arfan Ikram, John P A Ioannidis, Georgios M Hadjigeorgiou, Joshua C Bis, Maria Martinez, Joel S Perlmutter, Alison Goate, Karen Marder, Brian Fiske, Margaret Sutherland, Georgia Xiromerisiou, Richard H Myers, Lorraine N Clark, Kari Stefansson, John A Hardy, Peter Heutink, Honglei Chen, Nicholas W Wood, Henry Houlden, Haydeh Payami, Alexis Brice, William K Scott, Thomas Gasser, Lars Bertram, Nicholas Eriksson, Tatiana Foroud, Andrew B Singleton
Journal: Nature Genetics (2014)
Which Threshold to Detect Hypoglycemia?
Authors: Gérard Reach
Journal: Diabetes Care (2001)

The Diabetes Control and Complications Trial (DCCT) showed that the improvement of glycemic control by intensive insulin therapy resulted in a decrease in the risk of late diabetic complications. However, this effect was associated with an increase (by a factor of 3) in the risk of severe hypoglycemia (1). This explains the interest in the development of a hypoglycemic alarm that uses continuous glucose monitoring. Several approaches to this are possible.

Noninvasive methods have the benefit of measuring glucose without breaking the cutaneous barrier. Generally, these methods are based on the principle of the analysis of the absorption of the light in a zone of the spectrum close to the infrared, or of the diffraction of the light in the skin. These two parameters are indeed influenced by the level of glycemia, but sensitivity and specificity of these methods are far from providing sufficiently useful miniaturized systems that can be used in clinical practice (2). In invasive methods, the system of measurement (or a part of the system of measurement) is placed inside the body. The system can be totally implantable, requiring that both the sensor and the electronic control system are miniaturized, which is currently possible. In addition, the system must work for a time period sufficiently long to avoid the need for frequent implantations. The sensitive part of the system (the sensor) may be placed directly into a blood vessel (3) or in subcutaneous tissue (4). Nevertheless, for obvious reasons, most of the invasive systems that have been developed so far use transcutaneous access.

Two basic approaches have been attempted. In the first approach, the glucose sensor has the shape of a needle that is implanted under the skin and is …
Dominant-negative effect of SCN5A N-terminal mutations through the interaction of Nav1.5 α-subunits
Authors: Jérôme Clatot, Azza Ziyadeh-Isleem, Svetlana Maugenre, Isabelle Denjoy, Haiyan Liu, Gilles Dilanian, Stéphane N. Hatem, Isabelle Deschênes, Alain Coulombe, Pascale Guicheney, Nathalie Neyroud
Journal: Cardiovascular Research (2012)

Brugada syndrome (BrS) is an autosomal-inherited cardiac arrhythmia characterized by an ST-segment elevation in the right precordial leads of the electrocardiogram and an increased risk of syncope and sudden death. SCN5A, encoding the cardiac sodium channel Nav1.5, is the main gene involved in BrS. Despite the fact that several mutations have been reported in the N-terminus of Nav1.5, the functional role of this region remains unknown. We aimed to characterize two BrS N-terminal mutations, R104W and R121W, a construct where this region was deleted, ΔNter, and a construct where only this region was present, Nter. Patch-clamp recordings in HEK293 cells demonstrated that R104W, R121W, and ΔNter abolished the sodium current INa. Moreover, R104W and R121W mutations exerted a strong dominant-negative effect on wild-type (WT) channels. Immunocytochemistry of rat neonatal cardiomyocytes revealed that both mutants were mostly retained in the endoplasmic reticulum and that their co-expression with WT channels led to WT channel retention. Furthermore, co-immunoprecipitation experiments showed that Nav1.5-subunits were interacting with each other, even when mutated, deciphering the mutation dominant-negative effect. Both mutants were mostly degraded by the ubiquitin–proteasome system, while ΔNter was addressed to the membrane, and Nter expression induced a two-fold increase in INa. In addition, the co-expression of N-terminal mutants with the gating-defective but trafficking-competent R878C-Nav1.5 mutant gave rise to a small INa. This study reports for the first time the critical role of the Nav1.5 N-terminal region in channel function and the dominant-negative effect of trafficking-defective channels occurring through α-subunit interaction.
Are the take-off and landing phase dynamics of the volleyball spike jump related to patellar tendinopathy?
Authors: R W Bisseling, A L Hof, S W Bredeweg, J Zwerver, T Mulder
Journal: British Journal of Sports Medicine (2008)

Objective: The causal mechanism of the chronic sports injury patellar tendinopathy is not well understood. The aim of the present study was to compare ankle and knee joint dynamics during the performance of the volleyball spike jump between healthy volleyball players (n = 8) and asymptomatic volleyball players with previous patellar tendinopathy (n = 7). Design: Cross-sectional. Methods: Inverse dynamics were used to estimate ankle and knee joint dynamics. From these multiple biomechanical variables, a logistic regression was performed to estimate the probability of the presence or absence of previous patellar tendinopathy among the volleyball players studied. Results: Several biomechanical variables improved the prediction of the presence or absence of previous patellar tendinopathy. For landing, ankle plantar flexion at the time of touch-down, and knee range of motion during the first part of impact, and for take-off, loading rate of the knee extensor moment during the eccentric countermovement phase of take-off were predictive. As interaction effects, the presence or absence of previous patellar tendinopathy were correctly predicted by ankle and knee range of motion during the first part of impact, by loading rate of the knee extensor moment during the eccentric phases of take-off and landing, and by knee angular velocity during the eccentric phases of take-off and landing. Conclusion: Smaller joint flexion during the first part of landing impact , and higher rate of knee moment development during the eccentric phases of the spike-jump landing sequence, together with higher knee angular velocities, might be risk factors in the development of patellar tendinopathy in volleyball players.
Langerhans cells in the epidermis of athymic mice
Authors: J.A.A. HUNTER, D.J. FAIRLEY, G.C. PRIESTLEY, H.A. CUBIE
Journal: British Journal of Dermatology (1976)

Langerhans cells were identified with the electron microscope in the epidermis of six athymic nu/nu mice. Their origin in the thymus is ruled out and their functional dependence on either the thymus or T lymphocytes seems improbable.
EFFECTS OF CHRONIC EXCESS SALT INGESTION
Authors: Lewis K. Dahl, Knud D. Knudsen, Martha Heine, George Leitl
Journal: The Journal of Experimental Medicine (1967)

Parabiosis has been found to modify the expected blood pressure response of rats from two strains with opposite genetic propensities for experimental hypertension. When a member from one strain was united in parabiosis with a member from the other and both were maintained on high NaCl diet, the rat from the strain ordinarily resistant to it rapidly developed hypertension, in contrast to appropriate controls from this strain. The development of hypertension in this resistant animal preceded that in its mate from the strain highly sensitive to hypertension. In the latter, both the level of hypertension and mortality were significantly less than in its control. It seems likely that the hypertension observed is the resistant parabiont was initiated in its partner from the sensitive strain. This modification in blood pressures was not observed in the absence of a high NaCl diet. Parabiosis between animals from the same strain did not alter their response. Thus, as in earlier experiences (1-4) the interaction of a nongenetic factor (NaCl) with the appropriate genetic substrate appeared to be necessary for the development of hypertension. The findings are interpreted as evidence that a transmittable humoral influence plays an important role in the pathogenesis of rat hypertension. The presence of this agent is genetically determined but, under the conditions of these experiments, it took the added stimulus of dietary NaCl to demonstrate its existence.
EBV-Induced Human CD8+ NKT Cells Suppress Tumorigenesis by EBV-Associated Malignancies
Authors: He Yuling, Xiao Ruijing, Li Li, Ji Xiang, Zhou Rui, Wang Yujuan, Zhang Lijun, Du Chunxian, Tan Xinti, Xiao Wei, Chen Lang, Jiang Yanping, Xiong Tao, Wu Mengjun, Xiong Jie, Jin Youxin, Tan Jinquan
Journal: Cancer Research (2009)

Abstract The underlying mechanism of the protective and suppressive role of NKT cells in human tumor immunosurveillance remains to be fully elucidated. We show that the frequencies of CD8+ NKT cells in patients with EBV-associated Hodgkin's lymphoma or nasopharyngeal carcinoma are significantly lower than those in healthy EBV carriers. These CD8+ NKT cells in tumor patients are also functionally impaired. In human-thymus-severe combined immunodeficient (hu-thym-SCID) chimeras, EBV challenge efficiently promotes the generation of IFN-γ–biased CD8+ NKT cells. These cells are strongly cytotoxic, drive syngeneic T cells into a Th1 bias, and enhance T-cell cytotoxicity to EBV-associated tumor cells. Interleukin-4–biased CD4+ NKT cells are predominately generated in unchallenged chimeras. These cells are noncytotoxic, drive syngeneic T cells into a Th2 bias, and do not affect T-cell cytotoxicity. In humanized xenogeneic tumor-transplanted hu-thym-SCID chimeras, adoptive transfer with EBV-induced CD8+ NKT cells significantly suppresses tumorigenesis by EBV-associated malignancies. EBV-induced CD8+ NKT cells are necessary and sufficient to enhance the T-cell immunity to EBV-associated malignancies in the hu-thym-SCID chimeras. CD4+ NKT cells are synergetic with CD8+ NKT cells, leading to a more pronounced T-cell antitumor response in the chimeras cotransferred with CD4+ and CD8+ NKT cells. Thus, immune reconstitution with EBV-induced CD8+ NKT cells could be a useful strategy in management of EBV-associated malignancies. [Cancer Res 2009;69(20):7935–44]
Cortisol levels during human aging predict hippocampal atrophy and memory deficits
Authors: Sonia J. Lupien, Mony de Leon, Susan de Santi, Antonio Convit, Chaim Tarshish, N. P. V. Nair, Mira Thakur, Bruce S. McEwen, Richard L. Hauger, Michael J. Meaney
Journal: Nature Neuroscience (1998)
Tissue Factor and Factor VIIa as Therapeutic Targets in Disorders of Hemostasis
Authors: Ulla Hedner, Mirella Ezban
Journal: Annual Review of Medicine (2007)

For hemophilia patients with inhibitors against FVIII or FIX, the development of recombinant factor VIIa (rFVIIa) raises the possibility of a therapeutic alternative whose availability and convenience of treatment are comparable to those of FVIII or FIX. In support of this new concept for the treatment of bleeding episodes, pharmacological doses of FVIIa have been shown to induce hemostasis. Pharmacological doses of rFVIIa enhance thrombin generation on thrombin-activated platelets, thereby facilitating the formation of strong, well-structured fibrin plugs resistant to premature proteolysis. Modified rFVIIa molecules with a stronger hemostatic potential have been produced. Inhibition of the FVII-TF-dependent pathway (TFPI and rFVIIai) has been tried in attempts to prevent thrombosis, with promising results in animal models so far not confirmed in clinical trials.
Role of Telomerase in Cell Senescence and Oncogenesis
Authors: Virginia Urquidi, David Tarin, Steve Goodison
Journal: Annual Review of Medicine (2000)

The ends of linear chromosomes are capped by specialized nucleoprotein structures termed telomeres. Telomeres comprise tracts of noncoding hexanucleotide repeat sequences that, in combination with specific proteins, protect against degradation, rearrangement, and chromosomal fusion events. Due to the polarity of conventional DNA synthesis, a net loss of telomeric sequences occurs at each cell division. It has been proposed that this cumulative telomeric erosion is a limiting factor in replicative capacity and elicits a signal for the onset of cellular senescence. To proliferate beyond the senescent checkpoint, cells must restore telomere length. This can be achieved by telomerase, an enzyme with reverse-transcriptase activity. This enzyme is absent in differentiated somatic tissues, but telomerase reactivation has been detected in most tumors. Much investigative effort is focusing on telomere dynamics with a view to possible manipulation of cellular proliferative potential. In this article, we review the role of telomeres and telomerase in senescence and tumor progression, and we discuss the potential use of telomerase in diagnosis and treatment.
The Application of Psychodynamics to Behavior Therapy
Authors: JOHN M. RHOADS, BEN W. FEATHER
Journal: American Journal of Psychiatry (1974)

The authors describe a modification of systematic desensitization that they developed which uses a psychodynamic formulation as the basis for treatment along behavioral lines. The technique, illustrated by the authors through case reports, involves efforts to relieve the patient's anxiety arising in connection with unacceptable impulses or with irrational prohibitions against these impulses.
Tumour microembolism presenting as "primary pulmonary hypertension"
Authors: M. Hibbert, S. Braude
Journal: Thorax (1997)

Pulmonary tumour microembolism is a rare cause of pulmonary hypertension. A case of rapidly progressive pulmonary hypertension in a patient with a past history of breast carcinoma is presented. Despite active consideration and investigation for malignancy as a cause, correct diagnosis was only made at necropsy.
Multivitamins, Individual Vitamin and Mineral Supplements, and Risk of Diabetes Among Older U.S. Adults
Authors: Yiqing Song, Qun Xu, Yikyung Park, Albert Hollenbeck, Arthur Schatzkin, Honglei Chen
Journal: Diabetes Care (2010)

OBJECTIVE Understanding the relationship between multivitamin use and diabetes risk is important given the wide use of multivitamin supplements among U.S. adults. RESEARCH DESIGN AND METHODS We prospectively examined supplemental use of multivitamins and individual vitamins and minerals assessed in 1995–1996 in relation to self-reported diabetes diagnosed after 2000 among 232,007 participants in the National Institutes of Health–American Association of Retired Persons Diet and Health Study. Multivitamin use was assessed by a food-frequency questionnaire at baseline. Odds ratios (ORs) and 95% CIs were calculated by logistic regression models, adjusted for potential confounders. In total, 14,130 cases of diabetes diagnosed after 2000 were included in the analysis. RESULTS Frequent use of any multivitamins was not associated with risk of diabetes after adjustment for potential confounders and uses of individual supplements. Compared with nonusers of any multivitamins, the multivariate ORs among users were 1.07 (95% CI 0.94–1.21) for taking vitamins less than once per week, 0.97 (0.88–1.06) for one to three times per week, 0.92 (0.84–1.00) for four to six times per week, and 1.02 (0.98–1.06) for seven or more times per week (P for trend = 0.64). Significantly lower risk of diabetes was associated with the use of vitamin C or calcium supplements. The multivariate ORs comparing daily users with nonusers were 0.91 (0.86–0.97) for vitamin C supplements and 0.85 (0.80–0.90) for calcium supplements. Use of vitamin E or other individual vitamin and mineral supplements were not associated with diabetes risk. CONCLUSIONS In this large cohort of U.S. older adults, multivitamin use was not associated with diabetes risk. The findings of lower diabetes risk among frequent users of vitamin C or calcium supplements warrant further evaluations.
Lack of relevant pharmacokinetic and pharmacodynamic interactions between the new dual endothelin receptor antagonist macitentan and warfarin in healthy subjects
Authors: Patricia Sidharta, Hartmut Dietrich, Jasper Dingemanse
Journal: European Respiratory Journal (2012)

Macitentan, a new, potent, dual endothelin receptor antagonist (ERA), is a potential treatment for pulmonary arterial hypertension (PAH). In this study (AC-055-105), the effect of macitentan on the pharmacokinetics (PK) and pharmacodynamics (PD) of a single dose of warfarin was investigated in 14 healthy male subjects. Subjects received treatment sequence A/B or B/A separated by a 2-week washout. Treatment A: macitentan for 8 days (loading dose of 30 mg, thereafter 10 mg o.d.). On Day 4, a single dose of 25 mg warfarin was given with macitentan. Treatment B: A single dose of 25 mg warfarin on Day 1. Blood samples were assessed for warfarin PK (R- and S-warfarin) and PD (INR and Factor VII). Plasma trough levels of macitentan and its active metabolite, ACT-132577, were determined. Twelve subjects were included in the PK/PD analysis. The plasma concentration-time profiles of R- and S-Warfarin (Figure 1) and PD parameters of INR and Factor VII were comparable between treatments. Warfarin did not impact the trough levels of macitentan and ACT-132577. Both treatments were well tolerated. Based on these results, no dose correction of macitentan or warfarin is needed when using these drugs together.

Figure: Plasma concentration-time profile of R- and S-warfarin with and without macitentan (mean ± SD, n=12).

![Figure][1]  [1]: pending:yes
Efficient Inference of Recombination Hot Regions in Bacterial Genomes
Authors: Koji Yahara, Xavier Didelot, M. Azim Ansari, Samuel K. Sheppard, Daniel Falush
Journal: Molecular Biology and Evolution (2014)

In eukaryotes, detailed surveys of recombination rates have shown variation at multiple genomic scales and the presence of "hotspots" of highly elevated recombination. In bacteria, studies of recombination rate variation are less developed, in part because there are few analysis methods that take into account the clonal context within which bacterial evolution occurs. Here, we focus in particular on identifying "hot regions" of the genome where DNA is transferred frequently between isolates. We present a computationally efficient algorithm based on the recently developed "chromosome painting" algorithm, which characterizes patterns of haplotype sharing across a genome. We compare the average genome wide painting, which principally reflects clonal descent, with the painting for each site which additionally reflects the specific deviations at the site due to recombination. Using simulated data, we show that hot regions have consistently higher deviations from the genome wide average than normal regions. We applied our approach to previously analyzed Escherichia coli genomes and revealed that the new method is highly correlated with the number of recombination events affecting each site inferred by ClonalOrigin, a method that is only applicable to small numbers of genomes. Furthermore, we analyzed recombination hot regions in Campylobacter jejuni by using 200 genomes. We identified three recombination hot regions, which are enriched for genes related to membrane proteins. Our approach and its implementation, which is downloadable from https://github.com/bioprojects/orderedPainting, will help to develop a new phase of population genomic studies of recombination in prokaryotes.
Serum levels of tumour necrosis factor family members a proliferation-inducing ligand (APRIL) and B lymphocyte stimulator (BLyS) are inversely correlated in systemic lupus erythematosus
Authors: J Morel, C Roubille, L Planelles, C Rocha, L Fernandez, C Lukas, M Hahne, B Combe
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Objective:</h3> To determine whether serum levels of a proliferation-inducing ligand (APRIL) are altered in patients with systemic lupus erythematosus (SLE), and correlate with disease parameters. <h3>Methods:</h3> Clinical and biological parameters were analysed for 43 patients that fulfilled American College of Rheumatology (ACR) criteria for SLE classification and were positive for anti-double-stranded DNA (dsDNA) antibodies at least once in their medical records. Tests included measurement of serum levels of the tumour necrosis factor (TNF) family members APRIL and B lymphocyte stimulator (BLyS; a cytokine shown to promote SLE disease). <h3>Results:</h3> Median APRIL levels were elevated in patients with SLE compared to patients with osteoarthritis and healthy controls, but did not correlate with the SLE Disease Activity Index (SLEDAI). APRIL serum levels showed an inverse correlation with BLyS serum levels (r = −0.339; p = 0.03). For patients with SLE with positive anti-dsDNA titres (&gt;40 arbitrary units (AU)/ml) at inclusion (n = 25), circulating APRIL was inversely correlated with BLyS levels (r = −0.465; p = 0.022) and anti-dsDNA antibody titres (r = −0.411; p = 0.046). In a follow-up study at their second visit, 27 patients showed an inverse correlation of APRIL serum levels with BLyS (r = −0.398; p = 0.03) as well as with anti-dsDNA (r = −0.408; p = 0.03) titres and SLEDAI (r = −0.408; p = 0.01). <h3>Conclusion:</h3> The inverse correlation observed between APRIL and BLyS suggests that APRIL acts as a protective factor. APRIL and BLyS may thus have opposite roles in SLE, which must be considered when defining therapeutic applications of these cytokines.