tbuckley/cabot-search huggingface dataset:
A Bayesian Mixture Model for Across-Site Heterogeneities in the Amino-Acid Replacement Process
Authors: Nicolas Lartillot, Hervé Philippe
Journal: Molecular Biology and Evolution (2004)

Most current models of sequence evolution assume that all sites of a protein evolve under the same substitution process, characterized by a 20 × 20 substitution matrix. Here, we propose to relax this assumption by developing a Bayesian mixture model that allows the amino-acid replacement pattern at different sites of a protein alignment to be described by distinct substitution processes. Our model, named CAT, assumes the existence of distinct processes (or classes) differing by their equilibrium frequencies over the 20 residues. Through the use of a Dirichlet process prior, the total number of classes and their respective amino-acid profiles, as well as the affiliations of each site to a given class, are all free variables of the model. In this way, the CAT model is able to adapt to the complexity actually present in the data, and it yields an estimate of the substitutional heterogeneity through the posterior mean number of classes. We show that a significant level of heterogeneity is present in the substitution patterns of proteins, and that the standard one-matrix model fails to account for this heterogeneity. By evaluating the Bayes factor, we demonstrate that the standard model is outperformed by CAT on all of the data sets which we analyzed. Altogether, these results suggest that the complexity of the pattern of substitution of real sequences is better captured by the CAT model, offering the possibility of studying its impact on phylogenetic reconstruction and its connections with structure-function determinants.
Approach to the Pathogenesis and Treatment of Nonalcoholic Steatohepatitis
Authors: Jesús Medina, Luis I. Fernández-Salazar, Luisa García-Buey, Ricardo Moreno-Otero
Journal: Diabetes Care (2004)

Nonalcoholic steatohepatitis (NASH) represents an advanced stage of fatty liver disease developed in the absence of alcohol abuse. Its increasing prevalence in western countries, the diagnostic difficulties by noninvasive tests, and the possibility of progression to advanced fibrosis and even cirrhosis make NASH a challenge for hepatologists. NASH is frequently associated with type 2 diabetes and the metabolic syndrome, and several genetic and acquired factors are involved in its pathogenesis. Insulin resistance plays a central role in the development of a steatotic liver, which becomes vulnerable to additional injuries. Several cyclic mechanisms leading to self-enhancement of insulin resistance and hepatic accumulation of fat have been recently identified. Excess intracellular fatty acids, oxidant stress, tumor necrosis factor-α, and mitochondrial dysfunction are causes of hepatocellular injury, thereby leading to disease progression and to the establishment of NASH. Intestinal bacterial overgrowth also plays a role, by increasing production of endogenous ethanol and proinflammatory cytokines. Therapeutic strategies aimed at modulating insulin resistance, normalizing lipoprotein metabolism, and downregulating inflammatory mediators with probiotics have promising potential.
Hypoxia-Inducible Factor-1α Causes Renal Cyst Expansion through Calcium-Activated Chloride Secretion
Authors: Bjoern Buchholz, Gunnar Schley, Diana Faria, Sven Kroening, Carsten Willam, Rainer Schreiber, Bernd Klanke, Nicolai Burzlaff, Jonathan Jantsch, Karl Kunzelmann, Kai-Uwe Eckardt
Journal: Journal of the American Society of Nephrology (2013)

Polycystic kidney diseases are characterized by numerous bilateral renal cysts that continuously enlarge and, through compression of intact nephrons, lead to a decline in kidney function over time. We previously showed that cyst enlargement is accompanied by regional hypoxia, which results in the stabilization of hypoxia-inducible transcription factor-1α (HIF-1α) in the cyst epithelium. Here we demonstrate a correlation between cyst size and the expression of the HIF-1α-target gene, glucose transporter 1, and report that HIF-1α promotes renal cyst growth in two in vitro cyst models-principal-like MDCK cells (plMDCKs) within a collagen matrix and cultured embryonic mouse kidneys stimulated with forskolin. In both models, augmenting HIF-1α levels with the prolyl hydroxylase inhibitor 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate enhanced cyst growth. In addition, inhibition of HIF-1α degradation through tubule-specific knockdown of the von Hippel-Lindau tumor suppressor increased cyst size in the embryonic kidney cyst model. In contrast, inhibition of HIF-1α by chetomin and knockdown of HIF-1α both decreased cyst growth in these models. Consistent with previous reports, plMDCK cyst enlargement was driven largely by transepithelial chloride secretion, which consists, in part, of a calcium-activated chloride conductance. plMDCKs deficient for HIF-1α almost completely lacked calcium-activated chloride secretion. We conclude that regional hypoxia in renal cysts contributes to cyst growth, primarily due to HIF-1α-dependent calcium-activated chloride secretion. These findings identify the HIF system as a novel target for inhibition of cyst growth.
Living-Cell Microarrays
Authors: Martin L. Yarmush, Kevin R. King
Journal: Annual Review of Biomedical Engineering (2009)

Living cells are remarkably complex. To unravel this complexity, living-cell assays have been developed that allow delivery of experimental stimuli and measurement of the resulting cellular responses. High-throughput adaptations of these assays, known as living-cell microarrays, which are based on microtiter plates, high-density spotting, microfabrication, and microfluidics technologies, are being developed for two general applications: (a) to screen large-scale chemical and genomic libraries and (b) to systematically investigate the local cellular microenvironment. These emerging experimental platforms offer exciting opportunities to rapidly identify genetic determinants of disease, to discover modulators of cellular function, and to probe the complex and dynamic relationships between cells and their local environment.
Neuropeptide depletion impairs postischemic recovery of the isolated rat heart: role of substance P
Authors: Elena E. Ustinova, Dale Bergren, Harold D. Schultz
Journal: Cardiovascular Research (1995)

Ischemia of the myocardium stimulates cardiac sensory nerve endings resulting in the local release of neuropeptides. The significance of the release of neuropeptides, such as substance P (SP), for the function of the heart during ischemia and reperfusion is not known. We examined the effects of both chronic and acute neuropeptide depletion and of SP administration on contractile function and rhythmicity of the isolated rat heart during global ischemia and subsequent reperfusion.Experiments were conducted on the isolated perfused heart from vehicle and capsaicin-pretreated rats (100 mg/kg) to deplete neuropeptides from peripheral nerve terminals. The hearts were perfused with Krebs-Henseleit solution (95%O2 + 5% CO2, 37 degrees C, at constant pressure of 90 cmH2O). Left ventricular developed and diastolic pressures (LVDevP and LVEDP), heart rate (HR) and coronary flow (CF) were measured. Hearts were subjected to 20 min global no-flow ischemia and 30 min reperfusion.Prior to interrupting coronary flow, LV pressures, HR and CF did not differ between vehicle and capsaicin-pretreated rats. However, throughout the reperfusion period, the recovery of LVDevP, HR and CF in hearts from capsaicin-pretreated rats was consistently less than in control hearts (P < 0.05), and the incidence of fibrillation during reperfusion was higher (P < 0.05). In other experiments, acute perfusion of isolated hearts with capsaicin (10(-6) M) for 5 min before ischemia had a similar limiting effect during reperfusion. Administration of SP (10(-6)-10(-9) M) to capsaicin-pretreated hearts before ischemia restored their ability to recover contractile function and CF during reperfusion. Administration of SP to untreated hearts before ischemia also improved their recovery above normal during reperfusion and decreased the incidence of fibrillation without affecting postischemic CF. The beneficial effects of SP were abolished by an NK-1 receptor antagonist, CP-96,345 (10(-6) M).These data indicate that sensory neuropeptides play a role in protection of the isolated heart against ischemic damage and suggest a role of SP in the resistance of the myocardium to ischemia and reperfusion injury.
Cancer Mortality Among Mormons in California During 1968–75&lt;xref ref-type="fn" rid="FN1"&gt;1&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: James E. Enstrom
Journal: JNCI Journal of the National Cancer Institute (1980)

On the basis of Church records, detailed cancer and total death rates were determined for an average of 360,000 California Mormons during 1968--75, for an average of 700,000 Utah Mormons during 1970 and 1975, and for a subgroup of active Mormon males known as High Priests and Seventies. For cancer as a whole, the standardized mortality ratio was 68% for all California Mormon males, 83% for all California females, and 50% for active Mormon males in California and Utah compared with 1970 U.S. whites. Age-specific and age-adjusted total mortality rates were substantially lower in Mormons than in 1970 U.S. whites, with the greatest differences occurring between 35 and 65 years of age, where the rates for active Mormon males were reduced by more than 60%. Methodologic issues and sources of error were discussed, and the overall quality of the data was good. Some health-related characteristics of Mormons are also summarized.
The Upstream Enhancer Is Necessary and Sufficient for the Expression of the Pre-T Cell Receptor α Gene in Immature T Lymphocytes
Authors: Boris Reizis, Philip Leder
Journal: The Journal of Experimental Medicine (2001)

The expression of the pre-T cell receptor α (pTa) gene occurs exclusively in immature T lymphocytes and is regulated by poorly defined mechanisms. We have analyzed the role of the upstream enhancer in pTa expression using conventional and bacterial artificial chromosome (BAC) reporter transgenes. The deletion of the enhancer completely abolished the expression of pTa BAC reporter in transgenic mice. Conversely, the combination of pTa enhancer and promoter targeted transgenes specifically to immature thymocytes, recapitulating the expression pattern of pTa. The core enhancer is conserved between mice and humans and contains a critical binding site for the transcription factor c-Myb. We also show that pTa promoter contains a conserved tandem E box site activated by E protein, HEB. These data establish the enhancer as a critical element regulating pTa gene expression and identify additional targets for c-Myb and E proteins in T cell development.
Ultrastructure of the intercellular space in adult murine ventricle revealed by quantitative tomographic electron microscopy
Authors: Alejandra Leo-Macías, Feng-Xia Liang, Mario Delmar
Journal: Cardiovascular Research (2015)

Progress in tissue preservation (high-pressure freezing), data acquisition (tomographic electron microscopy, TEM), and analysis (image segmentation and quantification) have greatly improved the level of information extracted from ultrastructural images. Here, we combined these methods and developed analytical tools to provide an in-depth morphometric description of the intercalated disc (ID) in adult murine ventricle. As a point of comparison, we characterized the ultrastructure of the ID in mice heterozygous-null for the desmosomal gene plakophilin-2 (PKP2; mice dubbed PKP2-Hz). Tomographic EM images of thin sections of adult mouse ventricular tissue were processed by image segmentation analysis. Novel morphometric routines allowed us to generate the first quantitative description of the ID intercellular space based on three-dimensional data. We show that complex invaginations of the cell membrane significantly increased the total ID surface area. In addition, PKP2-Hz samples showed increased average intercellular spacing, ID surface area, and membrane tortuosity, as well as reduced number and length of mechanical junctions compared with control. Finally, we observed membranous structures reminiscent of junctional sarcoplasmic reticulum at the ID, which were significantly more abundant in PKP2-Hz hearts. We have developed a systematic method to characterize the ultrastructure of the intercellular space in the adult murine ventricle and have provided a quantitative description of the structure of the intercellular membranes and of the intercellular space. We further show that PKP2 deficiency associates with ultrastructural defects. The possible importance of the intercellular space in cardiac behaviour is discussed.
Current and Projected Workforce of Nonphysician Clinicians
Authors: Richard A. Cooper
Journal: JAMA (1998)

Nonphysician clinicians (NPCs) are becoming increasingly prominent as health care providers. This study examines 10 such disciplines: nurse practitioners (NPs), physician assistants (PAs), nurse-midwives, chiropractors, acupuncturists, naturopaths, optometrists, podiatrists, nurse anesthetists, and clinical nurse specialists. The aggregate number of NPCs graduating annually in these 10 disciplines doubled between 1992 and 1997, and a further increment of 20% is projected for 2001. Assuming that enrollments remain at the levels attained in 2001, NPC supply will grow from 228000 in 1995 to 384000 in 2005, and it will continue to expand at a similar rate thereafter. The greatest growth is projected among those NPCs who provide primary care services. Moreover, the greatest concentrations of both practicing NPCs and NPC training programs are in those states that already have the greatest abundance of physicians. On a per capita basis, the projected growth in NPC supply between 1995 and 2005 will be double that of physicians. Because of the existing training pipeline, it is probable that most of the growth projected for 2005 will occur. The further expansion of both NPC and physician supply thereafter warrants careful reconsideration.
Inhibition of coronary blood flow by a vascular waterfall mechanism.
Authors: J M Downey, E S Kirk
Journal: Circulation Research (1975)

The mechanism whereby systole inhibits coronary blood flow was examined. A branch of the left coronary artery was maximally dilated with an adenosine infusion, and the pressure-flow relationship was obtained for beating and arrested states. The pressure-flow curve for the arrested state was shifted toward higher pressures and in the range of pressures above peak ventricular pressure was linear and parallel to that for the arrested state. Below this range the curve for the beating state converged toward that for the arrested state and was convex to the pressure axis. These results were compared with a model of the coronary vasculature that consisted of numerous parallel channels, each responding to local intramyocardial pressure by forming vascular waterfalls. When intramyocardial pressure in the model was assigned values from zero at the epicardium to peak ventricular pressure at the endocardium, pressure-flow curves similar to the experimental ones resulted. Thus, we conclude that systole inhibits coronary perfusion by the formation of vascular waterfalls and that the intramyocardial pressures responsible for this inhibition do not significantly exceed peak ventricular pressure.
Non-alcoholic duct destructive chronic pancreatitis
Authors: N Ectors, B Maillet, R Aerts, K Geboes, A Donner, F Borchard, P Lankisch, M Stolte, J Lüttges, B Kremer, G Klöppel
Journal: Gut (1997)

Background —The pathology of non-alcoholic chronic pancreatitis has not yet been sufficiently studied. Aims —To identify the major changes of pancreatic tissue in patients surgically treated for non-alcoholic chronic pancreatitis. Patients —Pancreatectomy specimens from 12 patients with non-alcoholic chronic pancreatitis, including four patients with autoimmune or related diseases (Sjögren’s syndrome, primary sclerosing cholangitis, ulcerative colitis, and Crohn’s disease), were reviewed. Methods —Morphological changes were studied histologically and immunohistochemically (to type inflammatory cells) and compared with the pancreatic alterations found in 12 patients with alcoholic chronic pancreatitis. Results —In patients with non-alcoholic chronic pancreatitis, with or without associated autoimmune or related diseases, pancreatic inflammation particularly involved the ducts, commonly resulting in duct obstruction and occasionally duct destruction. None of these features was seen in alcoholic chronic pancreatitis which, however, showed pseudocysts and calcifications. Conclusion —The pancreatic changes in patients with non-alcoholic chronic pancreatitis clearly differ from those with alcoholic chronic pancreatitis. The term chronic duct destructive pancreatitis is suggested for this type of pancreatic disease.
PREVENTION OF WASTING DISEASE BY PREGNANCY ASSOCIATED WITH HYPERTROPHY OF THE FETAL THYMUS
Authors: M. J. Elders, B. A. Parham, E. R. Hughes
Journal: The Journal of Experimental Medicine (1968)

Neonatally thymectomized female mice were studied and compared to appropriate controls. Neonatal thymectomy appears to decrease fertility significantly in the female C3H/HeJ mouse. However, if a thymectomized female mouse becomes pregnant, pregnancy offers significant protection against wasting disease and death. The maternal thymus appears to play no significant role in the development of the fetus as measured by gross examination and organ weights. Offspring of thymectomized females had comparable body and organ weights when compared to offspring from sham-operated females, except for the thymus gland and gastrointestinal tract. The absence of the maternal thymus gland did stimulate a significant increase in the gland weight of her offspring compared to sham-operated control female offspring. Parity, per se, in intact females also causes a significant increase in the weights of the thymus of newborn offspring.
Carcinomatous meningitis in solid tumours
Authors: G.C. Jayson, A. Howell
Journal: Annals of Oncology (1996)

Carcinomatous meningitis (CM) is an uncommon but devastating complication of malignancy. The management is controversial and clear recommendations cannot be made because: 1) Most series include patients with CM that has arisen from different primary malignancies which are associated with different median survival intervals. 2) There have been no prospective randomised investigations of treatment modalities in patients with CM from a particular tumour type. 3) The definition of response varies from one report to another so that some response rates refer to cytological changes in the CSF while others take clinical, cytological and biochemical parameters into account. 4) Reports include patients with and without parenchymal metastases and the natural history of carcinomatous meningitis in the two situations may differ. The median survival of solid tumour carcinomatous meningitis (excluding leukaemia and lymphoma) is approximately 2-3 months and patients with breast cancer have the longest survival (median 3 months). Currently patients are treated with radiotherapy to part or all of the neuraxis with either intrathecal or intravenous chemotherapy but the relative contribution of these modalities to survival or quality of life remains unknown. Approximately 50% of patients with carcinomatous meningitis die from other causes, including systemic disease. The two most important endpoints for the patient, neurological improvement and overall survival, are seldom used in isolation in the literature. Many reports have focused on surrogate markers of response, namely biochemical and cytological data points but the correlation between clinical status and these parameters is poor because of differences between lumbar and ventricular CSF and disturbances of CSF flow in CM. The current literature does not provide clear guidelines for the treatment of this condition. Multicentre, prospective, randomised trials should be conducted that address questions of most relevance to the patient, namely neurological status and overall survival.
Nutrition and physical activity guidelines for cancer survivors
Authors: Cheryl L. Rock, Colleen Doyle, Wendy Demark‐Wahnefried, Jeffrey Meyerhardt, Kerry S. Courneya, Anna L. Schwartz, Elisa V. Bandera, Kathryn K. Hamilton, Barbara Grant, Marji McCullough, Tim Byers, Ted Gansler
Journal: CA A Cancer Journal for Clinicians (2012)

Abstract Answer questions and earn CME/CNE Cancer survivors are often highly motivated to seek information about food choices, physical activity, and dietary supplements to improve their treatment outcomes, quality of life, and overall survival. To address these concerns, the American Cancer Society (ACS) convened a group of experts in nutrition, physical activity, and cancer survivorship to evaluate the scientific evidence and best clinical practices related to optimal nutrition and physical activity after the diagnosis of cancer. This report summarizes their findings and is intended to present health care providers with the best possible information with which to help cancer survivors and their families make informed choices related to nutrition and physical activity. The report discusses nutrition and physical activity guidelines during the continuum of cancer care, briefly highlighting important issues during cancer treatment and for patients with advanced cancer, but focusing largely on the needs of the population of individuals who are disease free or who have stable disease following their recovery from treatment. It also discusses select nutrition and physical activity issues such as body weight, food choices, food safety, and dietary supplements; issues related to selected cancer sites; and common questions about diet, physical activity, and cancer survivorship. CA Cancer J Clin 2012. © 2012 American Cancer Society.
Altered Expression of RET Proto-oncogene Product in Prostatic Intraepithelial Neoplasia and Prostate Cancer
Authors: D. M. Dawson, E. G. Lawrence, T. P. Pretlow, G. T. MacLennan, T. G. Pretlow, S. B. Amini, M. I. Resnick, E. D. Kursh, H.-J. Kung, D. Robinson
Journal: JNCI Journal of the National Cancer Institute (1998)

Background: The RET proto-oncogene encodes a protein that belongs to the tyrosine kinase growth factor receptor family. Germline point mutations in RET are found in individuals with multiple endocrine neoplasia (MEN) syndromes, and gene rearrangements have been reported in papillary thyroid cancers. We recently identified transcripts of the RET proto-oncogene in human prostate cancer xenografts and prostate cancer cell lines by means of reverse transcription-polymerase chain reaction analyses. The purpose of this study was to investigate Ret protein expression in human prostate tissue. Methods: Ret protein expression was evaluated immunohistochemically in formalin-fixed, paraffin-embedded whole-prostate sections. The prostate specimens were obtained from 30 patients with prostate cancer after radical prostatectomies. Ret protein expression was compared in tumor foci and benign prostatic tissue. Medullary thyroid carcinoma tissue associated with an MEN syndrome and papillary thyroid cancer tissue served as positive controls. Results: Ret appeared to be overexpressed in high-grade (histopathologically advanced) prostatic intraepithelial neoplasia (PIN) and prostate cancer when compared with its expression level in benign prostatic secretory epithelium. In addition, there was an apparent increase in Ret protein expression with decreased cellular differentiation, i.e., increasing Gleason pattern. Conclusion: Expression of the RET protooncogene in benign prostatic epithelium, high-grade PIN, and histopathologically advanced prostate cancer suggests that RET may play a role in the growth of both benign and neoplastic prostate epithelial cells.