bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factors regulating quiescent stem cells: insights from the intestine and other self‐renewing tissues
Authors: Richmond Camilla A. , Shah Manasvi S. , Carlone Diana L. , Breault David T. 
Published: December 2015

AbstractLong‐lived and self‐renewing adult stem cells (SCs) are essential for homeostasis in a wide range of tissues and can include both rapidly cycling and quiescent (q)SC populations. Rapidly cycling SCs function principally during normal tissue maintenance and are highly sensitive to stress, whereas qSCs exit from their quiescent state in response to homeostatic imbalance and regenerative pressure. The regulatory mechanisms underlying the quiescent state include factors essential for cell cycle control, stress response and survival pathways, developmental signalling pathways, and post‐transcriptional modulation. Here, we review these regulatory mechanisms citing observations from the intestine and other self‐renewing tissues.
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Weakly Deleterious Mutations and Low Rates of Recombination Limit the Impact of Natural Selection on Bacterial Genomes
Authors: Price Morgan N. , Arkin Adam P. 
Published: December 2015

ABSTRACT

Free-living bacteria are usually thought to have large effective population sizes, and so tiny selective differences can drive their evolution. However, because recombination is infrequent, “background selection” against slightly deleterious alleles should reduce the effective population size (

N
e

) by orders of magnitude. For example, for a well-mixed population with 10
12
individuals and a typical level of homologous recombination (
r
/
m
= 3, i.e., nucleotide changes due to recombination [
r
] occur at 3 times the mutation rate [
m
]), we predict that

N
e

is
<
10
7
. An argument for high

N
e

values for bacteria has been the high genetic diversity within many bacterial “species,” but this diversity may be due to population structure: diversity across subpopulations can be far higher than diversity within a subpopulation, which makes it difficult to estimate

N
e

correctly. Given an estimate of

N
e

, standard population genetics models imply that selection should be sufficient to drive evolution if

N
e

×
s
is >1, where
s
is the selection coefficient. We found that this remains approximately correct if background selection is occurring or when population structure is present. Overall, we predict that even for free-living bacteria with enormous populations, natural selection is only a significant force if
s
is above 10
−7
or so.

IMPORTANCE
Because bacteria form huge populations with trillions of individuals, the simplest theoretical prediction is that the better allele at a site would predominate even if its advantage was just 10
−9
per generation. In other words, virtually every nucleotide would be at the local optimum in most individuals. A more sophisticated theory considers that bacterial genomes have millions of sites each and selection events on these many sites could interfere with each other, so that only larger effects would be important. However, bacteria can exchange genetic material, and in principle, this exchange could eliminate the interference between the evolution of the sites. We used simulations to confirm that during multisite evolution with realistic levels of recombination, only larger effects are important. We propose that advantages of less than 10
−7
are effectively neutral.
Suppression of Drug Resistance in Dengue Virus
Authors: Mateo Roberto , Nagamine Claude M. , Kirkegaard Karla 
Published: December 2015

ABSTRACT
Dengue virus is a major human pathogen responsible for 400 million infections yearly. As with other RNA viruses, daunting challenges to antiviral design exist due to the high error rates of RNA-dependent RNA synthesis. Indeed, treatment of dengue virus infection with a nucleoside analog resulted in the expected genetic selection of resistant viruses in tissue culture and in mice. However, when the function of the oligomeric core protein was inhibited, no detectable selection of drug resistance in tissue culture or in mice was detected, despite the presence of drug-resistant variants in the population. Suppressed selection of drug-resistant virus correlated with cooligomerization of the targeted drug-susceptible and drug-resistant core proteins. The concept of “dominant drug targets,” in which inhibition of oligomeric viral assemblages leads to the formation of drug-susceptible chimeras, can therefore be used to prevent the outgrowth of drug resistance during dengue virus infection.

IMPORTANCE
Drug resistance is a major hurdle in the development of effective antivirals, especially those directed at RNA viruses. We have found that one can use the concept of the genetic dominance of defective subunits to “turn cousins into enemies,” i.e., to thwart the outgrowth of drug-resistant viral genomes as soon as they are generated. This requires deliberate targeting of larger assemblages, which would otherwise rarely be considered by antiviral researchers.
Protocol for an investigator-blinded, randomised, 3-month, parallel-group study to compare the efficacy of intraoperative tendon sheath irrigation only with both intraoperative and postoperative irrigation in the treatment of purulent flexor tenosynovitis
Authors: Leppänen Olli V , Jokihaara Jarkko , Kaivorinne Antti , Havulinna Jouni , Göransson Harry 
Published: December 2015

IntroductionThe management of purulent flexor tenosynovitis of the hand consists of surgical debridement followed by antibiotic treatment. Usually, the debridement is carried out by irrigating the tendon sheath in a proximal to distal direction facilitated by two small incisions. It is unclear whether intraoperative irrigation by itself is adequate for healing or if it should be combined with postoperative irrigation in the ward. The hypothesis of this prospective randomised trial is that intraoperative catheter irrigation alone is as effective as a combination of intraoperative and postoperative intermittent catheter irrigation in the treatment of purulent flexor tenosynovitis.Methods and analysisIn this investigator-blinded, prospective randomised trial, 48 patients suffering from purulent flexor tenosynovitis are randomised in two groups. Intraoperative catheter irrigation of the flexor tendon sheath and antibiotic treatment is identical in both groups, whereas only the patients in one group are subjected to intermittent postoperative catheter irrigation three times a day for 3 days. The primary outcome measure is total active range of movement of the affected finger after 3 months of surgery. The secondary outcome is the need for reoperation.Ethics and disseminationThe research ethics committee of Pirkanmaa Hospital District has approved the study protocol. The protocol has been registered with ClinicalTrials.gov registry (#NCT02320929). All participants will give written informed consent. The study results will elucidate the role of postoperative irrigation, which can be criticised as being labour consuming and unpleasant to the patient. The results of the study will be disseminated as a published article in a peer-reviewed journal.Trial registration number:NCT02320929; pre-results.
A feasibility study on the effects of Triton X-100 for the in vitro inactivation of Ebola virus on haematological assays
Authors: Mifsud Antoinette , Peelen Daphne , Brincat Patricia , Abela Sylvana , Debattista Neville , Laspina Stefan , Zammit Daniel , Camilleri David J , Gatt Alex 
Published: December 2015

AimsThe aim of this study was to check the effect of Triton X-100 on various, commonly used haematology test parameters.MethodsAnonymised blood samples were treated with 10 µL of 10% Triton X-100 per 1 mL of blood. Treated and untreated samples were tested in parallel for blood film morphology, complete blood counts (CBCs), flow cytometry, blood grouping and antibody screens. Samples were also taken in 3.2% citrate tubes for coagulation test analyses.ResultsStatistical differences were noted in all CBC parameters apart from the mean cell volume, eosinophil and basophil counts. Platelet counts were significantly different with an apparent rise after the addition of Triton X-100. Samples were noted to have a high red cell fragmentation index. Immunological platelet counting methods using flow cytometry and fluorescent methods showed no significant differences and gave reliable results. Neither flow cytometry for T-cell subsets nor blood grouping/antibody screens were affected by Triton X-100. However, coagulation samples were severely haemolysed prohibiting analysis.ConclusionsWe have demonstrated that the addition of Triton X-100 to haematology blood samples impacts mainly on platelet counts and coagulation studies due to haemolysis. The platelet count is spuriously raised probably due to the presence of red cell fragments. The latter can be circumvented by the use of immunological platelet counting technology.
Ubiquitin-Specific Protease 4-Mediated Deubiquitination and Stabilization of PRL-3 Is Required for Potentiating Colorectal Oncogenesis
Authors: Xing Cheng , Lu Xing-Xing , Guo Peng-Da , Shen Tong , Zhang Shen , He Xiao-Shun , Gan Wen-Juan , Li Xiu-Ming , Wang Jing-Ru , Zhao Yuan-Yuan , Wu Hua , Li Jian-Ming 
Published: December 2015

Abstract
Ubiquitin specific protease 4 (USP4) is a deubiquitinating enzyme with key roles in the regulation of p53 and TGFβ signaling, suggesting its importance in tumorigenesis. However, the mechanisms and regulatory roles of USP4 in cancer, including colorectal cancer, remain largely elusive. Here, we present the first evidence that USP4 regulates the growth, invasion, and metastasis of colorectal cancer. USP4 expression was significantly elevated in colorectal cancer tissues and was significantly associated with tumor size, differentiation, distant metastasis, and poor survival. Knockdown of USP4 diminished colorectal cancer cell growth, colony formation, migration, and invasion in vitro and metastasis in vivo. Importantly, we found that phosphatase of regenerating liver-3 (PRL-3) is indispensable for USP4-mediated oncogenic activity in colorectal cancer. Mechanistically, we observed that USP4 interacted with and stabilized PRL-3 via deubiquitination. This resulted in activation of Akt and reduction of E-cadherin, critical regulators of cancer cell growth and metastasis. Examination of clinical samples confirmed that USP4 expression positively correlates with PRL-3 protein expression, but not mRNA transcript levels. Taken together, our results demonstrate that aberrant expression of USP4 contributes to the development and progression of colorectal cancer and reveal a critical mechanism underlying USP4-mediated oncogenic activity. These observations suggest that the potential of harnessing proteolytic degradation processes for therapeutic manipulation may offer a much-needed new approach for improving colorectal cancer treatment strategies. Cancer Res; 76(1); 83–95. ©2015 AACR.
The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase
Authors: Erazo Tatiana , Lorente Mar , López-Plana Anna , Muñoz-Guardiola Pau , Fernández-Nogueira Patricia , García-Martínez José A. , Bragado Paloma , Fuster Gemma , Salazar María , Espadaler Jordi , Hernández-Losa Javier , Bayascas Jose Ramon , Cortal Marc , Vidal Laura , Gascón Pedro , Gómez-Ferreria Mariana , Alfón José , Velasco Guillermo , Domènech Carles , Lizcano Jose M. 
Published: December 2015

Abstract
Purpose: ABTL0812 is a novel first-in-class, small molecule which showed antiproliferative effect on tumor cells in phenotypic assays. Here we describe the mechanism of action of this antitumor drug, which is currently in clinical development.
Experimental Design: We investigated the effect of ABTL0812 on cancer cell death, proliferation, and modulation of intracellular signaling pathways, using human lung (A549) and pancreatic (MiaPaCa-2) cancer cells and tumor xenografts. To identify cellular targets, we performed in silico high-throughput screening comparing ABTL0812 chemical structure against ChEMBL15 database.
Results: ABTL0812 inhibited Akt/mTORC1 axis, resulting in impaired cancer cell proliferation and autophagy-mediated cell death. In silico screening led us to identify PPARs, PPARα and PPARγ as the cellular targets of ABTL0812. We showed that ABTL0812 activates both PPAR receptors, resulting in upregulation of Tribbles-3 pseudokinase (TRIB3) gene expression. Upregulated TRIB3 binds cellular Akt, preventing its activation by upstream kinases, resulting in Akt inhibition and suppression of the Akt/mTORC1 axis. Pharmacologic inhibition of PPARα/γ or TRIB3 silencing prevented ABTL0812-induced cell death. ABTL0812 treatment induced Akt inhibition in cancer cells, tumor xenografts, and peripheral blood mononuclear cells from patients enrolled in phase I/Ib first-in-human clinical trial.
Conclusions: ABTL0812 has a unique and novel mechanism of action, that defines a new and drugable cellular route that links PPARs to Akt/mTORC1 axis, where TRIB3 pseudokinase plays a central role. Activation of this route (PPARα/γ-TRIB3-Akt-mTORC1) leads to autophagy-mediated cancer cell death. Given the low toxicity and high tolerability of ABTL0812, our results support further development of ABTL0812 as a promising anticancer therapy. Clin Cancer Res; 22(10); 2508–19. ©2015 AACR.
N‐Terminal Pro–Brain Natriuretic Peptide (NT‐proBNP) Levels are Increased in Patients With Transient Ischemic Attack Accompanied by Nonfocal Symptoms
Authors: Plas Gerben J. J. , Jurg Susanne D. , Brusse‐Keizer Marjolein , Dippel Diederik W. J. , Koudstaal Peter J. , den Hertog Heleen M. 
Published: December 2015

Background

Transient nonfocal neurological symptoms may serve as markers of cardiac dysfunction. We assessed whether serum N‐terminal pro–brain natriuretic peptide (
NT
‐pro
BNP)
levels, a biomarker of cardiac disease, are increased in patients with transient ischemic attack
(TIA)
accompanied by nonfocal symptoms and in patients with attacks of nonfocal symptoms (transient neurological attack [
TNA]
).

Methods and Results

We included 15 patients with
TNA
, 69 with
TIA
accompanied by nonfocal symptoms, 58 with large‐vessel
TIA
, 32 with cardioembolic
TIA
, and 46 age‐ and sex‐matched healthy control participants. Serum
NT
‐pro
BNP
levels were determined within 1 week after the attack. We compared log‐transformed
NT
‐pro
BNP
levels of patients with cardioembolic
TIA
s and mixed or nonfocal
TNA
s, with those of patients with noncardioembolic
TIA
s as a reference group. Adjustments for age, sex, atrial fibrillation, and a history of nonischemic heart disease were made with a multiple linear regression model. Compared with large‐vessel
TIA
(mean 14.2 pmol/L), mean
NT
‐pro
BNP
levels were significantly higher in patients with
TIA
accompanied by nonfocal symptoms (40.5 pmol/L,
P
=0.049) and with cardioembolic
TIA
(123.5 pmol/L;
P
=0.004) after adjustments for age, sex, atrial fibrillation, and a history of nonischemic heart disease. Patients with
TNA
also had higher mean
NT
‐pro
BNP
levels (20.8 pmol/L,
P
=0.38) than those with large‐vessel
TIA
, but this difference was not statistically significant.

Conclusion

NT
‐pro
BNP
levels are increased in patients with
TIA
accompanied by nonfocal symptoms.
Disparities in Temporal and Geographic Patterns of Declining Heart Disease Mortality by Race and Sex in the United States, 1973–2010
Authors: Vaughan Adam S. , Quick Harrison , Pathak Elizabeth B. , Kramer Michael R. , Casper Michele 
Published: December 2015

Background
Examining small‐area differences in the strength of declining heart disease mortality by race and sex provides important context for current racial and geographic disparities and identifies localities that could benefit from targeted interventions. We identified and described temporal trends in declining county‐level heart disease mortality by race, sex, and geography between 1973 and 2010.

Methods and Results
Using a Bayesian hierarchical model, we estimated age‐adjusted mortality with diseases of the heart listed as the underlying cause for 3099 counties. County‐level percentage declines were calculated by race and sex for 3 time periods (1973–1985, 1986–1997, 1998–2010). Strong declines were statistically faster or no different than the total national decline in that time period. We observed county‐level race–sex disparities in heart disease mortality trends. Continual (from 1973 to 2010) strong declines occurred in 73.2%, 44.6%, 15.5%, and 17.3% of counties for white men, white women, black men, and black women, respectively. Delayed (1998–2010) strong declines occurred in 15.4%, 42.0%, 75.5%, and 76.6% of counties for white men, white women, black men, and black women, respectively. Counties with the weakest patterns of decline were concentrated in the South.

Conclusions
Since 1973, heart disease mortality has declined substantially for these race–sex groups. Patterns of decline differed by race and geography, reflecting potential disparities in national and local drivers of these declines. Better understanding of racial and geographic disparities in the diffusion of heart disease prevention and treatment may allow us to find clues to progress toward racial and geographic equity in heart disease mortality.
Satellite and In Situ Salinity: Understanding Near-Surface Stratification and Subfootprint Variability
Authors: Boutin J. , Chao Y. , Asher W. E. , Delcroix T. , Drucker R. , Drushka K. , Kolodziejczyk N. , Lee T. , Reul N. , Reverdin G. , Schanze J. , Soloviev A. , Yu L. , Anderson J. , Brucker L. , Dinnat E. , Santos-Garcia A. , Jones W. L. , Maes C. , Meissner T. , Tang W. , Vinogradova N. , Ward B. 
Published: December 2015

Abstract
Remote sensing of salinity using satellite-mounted microwave radiometers provides new perspectives for studying ocean dynamics and the global hydrological cycle. Calibration and validation of these measurements is challenging because satellite and in situ methods measure salinity differently. Microwave radiometers measure the salinity in the top few centimeters of the ocean, whereas most in situ observations are reported below a depth of a few meters. Additionally, satellites measure salinity as a spatial average over an area of about 100 × 100 km2. In contrast, in situ sensors provide pointwise measurements at the location of the sensor. Thus, the presence of vertical gradients in, and horizontal variability of, sea surface salinity complicates comparison of satellite and in situ measurements. This paper synthesizes present knowledge of the magnitude and the processes that contribute to the formation and evolution of vertical and horizontal variability in near-surface salinity. Rainfall, freshwater plumes, and evaporation can generate vertical gradients of salinity, and in some cases these gradients can be large enough to affect validation of satellite measurements. Similarly, mesoscale to submesoscale processes can lead to horizontal variability that can also affect comparisons of satellite data to in situ data. Comparisons between satellite and in situ salinity measurements must take into account both vertical stratification and horizontal variability.
Assessment and Implications of NCEP Stage IV Quantitative Precipitation Estimates for Product Intercomparisons
Authors: Nelson Brian R. , Prat Olivier P. , Seo D.-J. , Habib Emad 
Published: December 2015

Abstract
The National Centers for Environmental Prediction (NCEP) stage IV quantitative precipitation estimates (QPEs) are used in many studies for intercomparisons including those for satellite QPEs. An overview of the National Weather Service precipitation processing system is provided here so as to set the stage IV product in context and to provide users with some knowledge as to how it is developed. Then, an assessment of the stage IV product over the period 2002–12 is provided. The assessment shows that the stage IV product can be useful for conditional comparisons of moderate-to-heavy rainfall for select seasons and locations. When evaluating the product at the daily scale, there are many discontinuities due to the operational processing at the radar site as well as discontinuities due to the merging of data from different River Forecast Centers (RFCs) that use much different processing algorithms for generating their precipitation estimates. An assessment of the daily precipitation estimates is provided based on the cumulative distribution function for all of the daily estimates for each RFC by season. In addition it is found that the hourly estimates at certain RFCs suffer from lack of manual quality control and caution should be used.
Detection and management of the first human anthrax outbreak in Togo
Authors: Patassi Akouda Akessiwe , Saka Bayaki , Landoh Dadja Essoya , Agbenoko Kodjo , Tamekloe Tsidi , Salmon-Ceron Dominique 
Published: December 2015

Objective The aim of this study was to describe and define an outbreak of human anthrax in two villages in the northern savannah region of Togo. Patients and Method In December 2009, localised groups of deaths occurred among villagers and their livestock, confirmed to be due to anthrax at the district hospital of Dapaong in Northern Togo. The National Disease Control department undertook an investigation to describe the epidemiological, clinical and bacteriological characteristics of this outbreak. Results Thirty-four individuals presented with clinical manifestations of anthrax. All patients were known to have consumed meat from cattle who had died of unknown causes or had been killed as a result of unknown illness. All patients presented with muco-cutaneous lesions; some had gastro-intestinal, neurological or meningeal symptoms, or septicaemia. One patient was co-infected with Plasmodium falciparum. Six deaths (17.6%) were reported at the beginning of the epidemic; 28 patients were successfully treated with a 10-day course of intravenous Penicillin or oral Amoxicillin. The two factors that contributed to the ultimate resolution of the anthrax outbreak were the increase of community awareness toward health promotion and vaccination of all farm animals. Conclusion Although six deaths occurred among families’ members who were infected, new human anthrax cases were prevented by rapid treatment of victims as well as aggressive public health interventions. However the risk of re-emergence of infection and exposure still exists as there are no existing epidemiological mapping and no identification of infected zones; and furthermore, no functional anthrax surveillance system exists in the affected region.