bluuebunny/crossref_metadata_2025_split huggingface dataset:
Skeletal myofiber VEGF deficiency leads to mitochondrial, structural, and contractile alterations in mouse diaphragm
Authors: Cannon Daniel T. , Rodewohl Lukas , Adams Volker , Breen Ellen C. , Bowen T. Scott 
Published: September 2019

Diaphragm dysfunction accompanies cardiopulmonary disease and impaired oxygen delivery. Vascular endothelial growth factor (VEGF) regulates oxygen delivery through angiogenesis, capillary maintenance, and contraction-induced perfusion. We hypothesized that myofiber-specific VEGF deficiency contributes to diaphragm weakness and fatigability. Diaphragm protein expression, capillarity and fiber morphology, mitochondrial respiration and hydrogen peroxide (H2O2) generation, and contractile function were compared between adult mice with conditional gene ablation of skeletal myofiber VEGF (SkmVEGF−/−; n = 12) and littermate controls ( n = 13). Diaphragm VEGF protein was ~50% lower in SkmVEGF−/−than littermate controls (1.45 ± 0.65 vs. 3.04 ± 1.41 pg/total protein; P = 0.001). This was accompanied by an ~15% impairment in maximal isometric specific force ( F[1,23] = 15.01, P = 0.001) and a trend for improved fatigue resistance ( P = 0.053). Mean fiber cross-sectional area and type I fiber cross-sectional area were lower in SkmVEGF−/−by ~40% and ~25% ( P < 0.05). Capillary-to-fiber ratio was also lower in SkmVEGF−/−by ~40% ( P < 0.05), and thus capillary density was not different. Sarcomeric actin expression was ~30% lower in SkmVEGF−/−( P < 0.05), whereas myosin heavy chain and MAFbx were similar (measured via immunoblot). Mitochondrial respiration, citrate synthase activity, PGC-1α, and hypoxia-inducible factor 1α were not different in SkmVEGF−/−( P > 0.05). However, mitochondrial-derived reactive oxygen species (ROS) flux was lower in SkmVEGF−/−( P = 0.0003). In conclusion, myofiber-specific VEGF gene deletion resulted in a lower capillary-to-fiber ratio, type I fiber atrophy, actin loss, and contractile dysfunction in the diaphragm. In contrast, mitochondrial respiratory function was preserved alongside lower ROS generation, which may play a compensatory role to preserve fatigue resistance in the diaphragm.NEW & NOTEWORTHY Diaphragm weakness is a hallmark of diseases in which oxygen delivery is compromised. Vascular endothelial growth factor (VEGF) modulates muscle perfusion; however, it remains unclear whether VEGF deficiency contributes to the onset of diaphragm dysfunction. Conditional skeletal myofiber VEGF gene ablation impaired diaphragm contractile function and resulted in type I fiber atrophy, a lower number of capillaries per fiber, and contractile protein content. Mitochondrial function was similar and reactive oxygen species flux was lower. Diaphragm VEGF deficiency may contribute to the onset of respiratory muscle weakness.
Resveratrol Improves Boar Sperm Quality via 5′AMP-Activated Protein Kinase Activation during Cryopreservation
Authors: Zhu Zhendong , Li Rongnan , Fan Xiaoteng , Lv Yinghua , Zheng Yi , Hoque S. A. Masudul , Wu De , Zeng Wenxian 
Published: September 2019

Mammalian sperm is highly susceptible to the reactive oxygen species (ROS) stress caused by biochemical and physical modifications during the cryopreservation process. 5′AMP-activated protein kinase (AMPK) is involved in regulating both cell metabolism and cellular redox status. The aim of the present study was to investigate whether the resveratrol protects boar sperm against ROS stress via activation of AMPK during cryopreservation. Boar sperm was diluted with the freezing medium supplemented with resveratrol at different concentrations (0, 25, 50, 75, 100, and 125 μM). It was observed that the addition of 50 μM resveratrol significantly improved the postthaw sperm progressive motility, membrane integrity, acrosome integrity, mitochondrial activity, glutathione (GSH) level, activities of enzymatic antioxidants (glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase), and the phosphorylation of AMPK. Meanwhile, the lipid peroxidation, ROS levels, and apoptosis of postthaw sperm were reduced in the presence of 50 μM resveratrol. Furthermore, when fresh boar sperm was incubated with the medium in the presence of 50 μM resveratrol and 30 μM Compound C (an AMPK inhibitor), the effects of the resveratrol were partly counteracted by the Compound C. These observations suggest that the resveratrol protects boar sperm via promoting AMPK phosphorylation. In conclusion, the addition of resveratrol to the freezing extenders protects boar sperm against ROS damage via promoting AMPK phosphorylation for decreasing the ROS production and improving the antioxidative defense system of postthaw sperm. These findings provide novel insights into understanding the mechanisms of resveratrol on how to protect boar sperm quality contrary to the ROS production during cryopreservation.
False-Positive Results in a Population-Based Colorectal Screening Program: Cumulative Risk from 2000 to 2017 with Biennial Screening
Authors: Ibáñez-Sanz Gemma , Garcia Montse , Milà Núria , Hubbard Rebecca A. , Vidal Carmen , Binefa Gemma , Benito Llúcia , Moreno Víctor 
Published: September 2019

Abstract

Background:
The aim of this study was to estimate the cumulative risk of a false-positive (FP) result in a fecal occult blood test (FOBT) through 7 screening rounds and to identify its associated factors in a population-based colorectal cancer screening program.

Methods:
Retrospective cohort study, which included participants ages 50 to 69 years of a colorectal cancer screening program in Catalonia, Spain. During this period, 2 FOBTs were used (guaiac and immunochemical). A discrete-time survival model was performed to identify risk factors of receiving a positive FOBT with no high-risk adenoma or colorectal cancer in the follow-up colonoscopy. We estimated the probability of having at least 1 FP over 7 screening rounds.

Results:
During the period of 2000 to 2017, the cumulative FP risk was 16.3% (IC95%: 14.6%–18.3%), adjusted by age, sex, and type of test. The median number of screens was 2. Participants who began screening at age 50 years had a 7.3% [95% confidence interval (CI), 6.35–8.51] and a 12.4% (95% CI, 11.00–13.94) probability of an FP with 4 screening rounds of guaiac-based test and immunochemical test, respectively. Age, the fecal immunochemical test, first screening, and number of personal screens were factors associated with an FP result among screenees.

Conclusions:
The cumulative risk of an FP in colorectal screening using FOBT seems acceptable as the colonoscopy, with its high accuracy, lengthens the time until additional colorectal screening is required, while complication rates remain low.

Impact:
It is useful to determine the cumulative FP risk in cancer screening for both advising individuals and for health resources planning.
Transgelin 2 Promotes Paclitaxel Resistance, Migration, and Invasion of Breast Cancer by Directly Interacting with PTEN and Activating PI3K/Akt/GSK-3β Pathway
Authors: Liu Leichao , Meng Ti , Zheng Xiaowei , Liu Yang , Hao Ruifang , Yan Yan , Chen Siying , You Haisheng , Xing Jianfeng , Dong Yalin 
Published: September 2019

Abstract
MDR and tumor migration and invasion are still the main obstacles to effective breast cancer chemotherapies. Transgelin 2 has recently been shown to induce drug resistance, tumor migration, and invasion. The aim of this study was to determine the biological functions of Transgelin 2 and the mechanism underlying how Transgelin 2 induces paclitaxel (PTX) resistance and the migration and invasion of breast cancer. We detected that the protein level of Transgelin 2 was significantly upregulated in breast cancer tissues compared with adjacent nontumor tissues. A bioinformatics analysis indicated that Transgelin 2 was significantly related to clinicopathologic parameters and patient prognosis. Overexpression of Transgelin 2 enhanced the migration and invasion of human breast cancer cells and decreased the sensitivity of breast cancer cells to paclitaxel. Meanwhile, the tumorigenesis and metastasis of breast cancer cells were also enhanced by Transgelin 2 overexpression in vivo. Moreover, Transgelin 2 overexpression activated the PI3K/Akt/GSK-3β pathway by increasing the phosphorylation levels of Akt and GSK-3β and decreasing the expression of PTEN. We also found that Transgelin 2 could directly interact with PTEN and was located upstream of PTEN. Furthermore, the PI3K/Akt pathway inhibitor MK-2206 reversed the resistance to paclitaxel and inhibited the migration and invasion of breast cancer cells. These findings indicate that Transgelin 2 promotes paclitaxel resistance and the migration and invasion of breast cancer by directly interacting with PTEN and activating the PI3K/Akt/GSK-3β pathway. Transgelin 2 may therefore be useful as a novel biomarker and therapeutic target for breast cancer.
Functional Outcomes and Quality of Life in Elderly Patients after Restorative Proctocolectomy for Ulcerative Colitis
Authors: Minagawa Tomohiro , Ikeuchi Hiroki , Kuwahara Ryuichi , Horio Yuki , Sasaki Hirofumi , Chohno Teruhiro , Bando Toshihiro , Uchino Motoi 
Published: September 2019

Background/Aim: Ileal pouch anal anastomosis (IPAA) has become the surgical procedure of choice for patients with ulcerative colitis (UC). However, to date few studies have examined functional outcomes or quality of life (QOL) in elderly patients after pouch construction. Methods: In December 2017, we sent questionnaires to 224 patients aged 65 years and older at the time who underwent an IPAA at our hospital between June 1987 and May 2015 regarding issues related to QOL and functional outcomes. Responders aged 65–69 years old were defined as the elderly group (EG), while those 70 years old and over comprised the super-EG (SEG). Results: The response rate was 60.7% (136/224); 70 patients were classified as EG, and 66 were classified as SEG. The SEG were older at the time of the IPAA and during the follow-up period (p < 0.01). The stool frequency per day was 8 times in both groups (p = 0.21). There was no significant difference between the EG and SEG with regard to daytime (53 vs. 56%, p = 0.73) or nighttime (65.7 vs. 53%, p = 0.16) soiling. There was also no difference in the exacerbation of daytime or nighttime soiling compared to the first year after the operation (daytime 5.7 vs. 12.1%, p = 0.23; nighttime 7.1 vs. 9.1%, p = 0.76). QOL was evaluated using the modified fecal incontinence QOL (mFIQL) scale, with no significant difference between the EG and SEG (27 vs. 31 points). Since both groups had mFIQL scores <50, QOL was considered to be maintained. Conclusion: In our analysis of elderly patients in the long-term period following surgery for UC, some noted fecal soiling, though QOL was largely maintained, and there were no serious effects on daily life.
Evaluation of Lower Extremities’ Vascular Characteristics in Myelomeningocele Patients: A Case-Control Study
Authors: Salari Farhad , Golpayegani Mehdi , Habibi Zohreh , Yaghoubi Shahin , Anbarlouei Mousarreza , Mehdizadeh Mehrzad , Nejat Farideh 
Published: September 2019

<b><i>Objective:</i></b> Myelomeningocele (MMC) is the most common neural tube defect. Patients with MMC have multiple risk factors for venous thrombosis, but this complication rarely occurs. This lower rate of venous thrombosis in MMC children could be related to some characteristics of the vessels in the lower extremities. This study aimed at finding explanations for this dilemma. <b><i>Methods:</i></b> A case-control study was designed in the Children’s Hospital Medical Center, Tehran considering paraplegic patients with MMC as the case group and nonparaplegic MMC patients as a control group. Doppler ultrasound was performed to evaluate femoral and popliteal arterial and venous properties. <b><i>Results:</i></b> Patients aged from 8 months to 12 years were evaluated. The mean diameter of the femoral arteries was 3.73 ± 0.23 and 4.72 ± 0.39 mm among paraplegic and nonparaplegic MMC patients, respectively (<i>p</i> = 0.02). The femoral artery flow was 0.52 ± 0.08 and 0.75 ± 0.06 L/min, respectively in the case and control groups (<i>p</i> = 0.015). The diameters of the femoral veins were 4.85 ± 0.34 and 5.13 ± 0.32 mm in the case and control groups, respectively (<i>p</i> &#x3e; 0.05). Besides, the blood flows of the case and control groups’ femoral veins were 0.27 ± 0.08 and 0.14 ± 0.01 L/min, respectively (<i>p</i> = 0.6). It turned out that lower extremities’ arteries in the case group had significantly lower blood flow and diameter compared to those of the control group. However, the same venous properties did not show any significant differences. <b><i>Conclusion:</i></b> The decreased arterial flow along with the unchanged venous properties leads to less stasis and better drainage of the blood, which in turn might result in a lower incidence of deep vein thrombosis.
Automated and Interpretable Patient ECG Profiles for Disease Detection, Tracking, and Discovery
Authors: Tison Geoffrey H. , Zhang Jeffrey , Delling Francesca N. , Deo Rahul C. 
Published: September 2019

Background:
The ECG remains the most widely used diagnostic test for characterization of cardiac structure and electrical activity. We hypothesized that parallel advances in computing power, machine learning algorithms, and availability of large-scale data could substantially expand the clinical inferences derived from the ECG while at the same time preserving interpretability for medical decision-making.

Methods and Results:
We identified 36 186 ECGs from the University of California, San Francisco database that would enable training of models for estimation of cardiac structure or function or detection of disease. We segmented the ECG into standard component waveforms and intervals using a novel combination of convolutional neural networks and hidden Markov models and evaluated this segmentation by comparing resulting electrical intervals against 141 864 measurements produced during the clinical workflow. We then built a patient-level ECG profile, a 725-element feature vector and used this profile to train and interpret machine learning models for examples of cardiac structure (left ventricular mass, left atrial volume, and mitral annulus e-prime) and disease (pulmonary arterial hypertension, hypertrophic cardiomyopathy, cardiac amyloid, and mitral valve prolapse). ECG measurements derived from the convolutional neural network-hidden Markov model segmentation agreed with clinical estimates, with median absolute deviations as a fraction of observed value of 0.6% for heart rate and 4% for QT interval. Models trained using patient-level ECG profiles enabled surprising quantitative estimates of left ventricular mass and mitral annulus e′ velocity (median absolute deviation of 16% and 19%, respectively) with good discrimination for left ventricular hypertrophy and diastolic dysfunction as binary traits. Model performance using our approach for disease detection demonstrated areas under the receiver operating characteristic curve of 0.94 for pulmonary arterial hypertension, 0.91 for hypertrophic cardiomyopathy, 0.86 for cardiac amyloid, and 0.77 for mitral valve prolapse.

Conclusions:
Modern machine learning methods can extend the 12-lead ECG to quantitative applications well beyond its current uses while preserving the transparency that is so fundamental to clinical care.
Severe Cardiac Dysfunction and Death Caused by Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 Are Improved by Inhibition of Glycogen Synthase Kinase-3β
Authors: Padrón-Barthe Laura , Villalba-Orero María , Gómez-Salinero Jesús M. , Domínguez Fernando , Román Marta , Larrasa-Alonso Javier , Ortiz-Sánchez Paula , Martínez Fernando , López-Olañeta Marina , Bonzón-Kulichenko Elena , Vázquez Jesús , Martí-Gómez Carlos , Santiago Demetrio J. , Prados Belén , Giovinazzo Giovanna , Gómez-Gaviro María Victoria , Priori Silvia , Garcia-Pavia Pablo , Lara-Pezzi Enrique 
Published: September 2019

Background:
Arrhythmogenic cardiomyopathy/arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease characterized by fibrofatty replacement of the myocardium, resulting in heart failure and sudden cardiac death. The most aggressive arrhythmogenic cardiomyopathy/ARVC subtype is ARVC type 5 (ARVC5), caused by a p.S358L mutation in TMEM43 (transmembrane protein 43). The function and localization of TMEM43 are unknown, as is the mechanism by which the p.S358L mutation causes the disease. Here, we report the characterization of the first transgenic mouse model of ARVC5.

Methods:
We generated transgenic mice overexpressing TMEM43 in either its wild-type or p.S358L mutant (TMEM43-S358L) form in postnatal cardiomyocytes under the control of the α-myosin heavy chain promoter.

Results:
We found that mice expressing TMEM43-S358L recapitulate the human disease and die at a young age. Mutant TMEM43 causes cardiomyocyte death and severe fibrofatty replacement. We also demonstrate that TMEM43 localizes at the nuclear membrane and interacts with emerin and β-actin. TMEM43-S358L shows partial delocalization to the cytoplasm, reduced interaction with emerin and β-actin, and activation of glycogen synthase kinase-3β (GSK3β). Furthermore, we show that targeting cardiac fibrosis has no beneficial effect, whereas overexpression of the calcineurin splice variant calcineurin Aβ1 results in GSK3β inhibition and improved cardiac function and survival. Similarly, treatment of TMEM43 mutant mice with a GSK3β inhibitor improves cardiac function. Finally, human induced pluripotent stem cells bearing the p.S358L mutation also showed contractile dysfunction that was partially restored after GSK3β inhibition.

Conclusions:
Our data provide evidence that TMEM43-S358L leads to sustained cardiomyocyte death and fibrofatty replacement. Overexpression of calcineurin Aβ1 in TMEM43 mutant mice or chemical GSK3β inhibition improves cardiac function and increases mice life span. Our results pave the way toward new therapeutic approaches for ARVC5.
Turmeric, Pepper, Cinnamon, and Saffron Consumption and Mortality
Authors: Hashemian Maryam , Poustchi Hossein , Murphy Gwen , Etemadi Arash , Kamangar Farin , Pourshams Akram , Khoshnia Masoud , Gharavi Abdolsamad , Brennan Paul J. , Boffetta Paolo , Dawsey Sanford M. , Abnet Christian C. , Malekzadeh Reza 
Published: September 2019

Background
Previous studies have reported the beneficial effects of spice consumption on lipid profiles, fasting glucose, and blood pressure, which suggests that spice consumption could affect the risk of cardiovascular disease, diabetes mellitus, and consequently mortality. The objective of this study was to evaluate the relationship between consumption of turmeric, black or chili pepper, cinnamon, and saffron with overall and cause‐specific mortality in an adult population in Iran.

Methods and Results

We used data from the Golestan Cohort Study, which has followed 50 045 participants aged 40 to 75 years from baseline (2004–2008). After establishing the exclusion criteria, 44 398 participants were included in the analyses. Spice consumption data were extracted from the baseline Food Frequency Questionnaire. Cox models were used to estimate hazard ratios (
HR
) and 95%
CI
for overall and cause‐specific mortality, comparing the ever consumers to the never consumers as a reference group for each type of spice (adjusted for known and suspected confounders). During 11 years of follow‐up, 5121 people died. Turmeric consumption was associated with significantly reduced risk of overall mortality (
HR
=0.90, 95%
CI
=0.85–0.96) and cardiovascular mortality (
HR
=0.91, 95%
CI
=0.82–0.99). Black or chili pepper consumption was associated with significantly reduced risk of overall mortality (
HR
=0.91, 95%
CI
=0.86–0.98). Saffron consumption was associated with significantly reduced risk of overall (
HR
=0.85, 95%
CI
=0.77–0.94) and cardiovascular mortality (
HR
=0.79, 95%
CI
=0.68–0.92). We found no associations with cinnamon consumption or between any of these spices and cancer mortality.

Conclusions
Consuming turmeric or saffron was associated with decreased risk of overall and cardiovascular mortality. The hypothesis of a protective effect of spice consumption on mortality should be tested in other prospective studies.
Association of Intracranial Aneurysms With Aortic Aneurysms in 125 Patients With Fusiform and 4253 Patients With Saccular Intracranial Aneurysms and Their Family Members and Population Controls
Authors: Kurtelius Arttu , Väntti Nelli , Rezai Jahromi Behnam , Tähtinen Olli , Manninen Hannu , Koskenvuo Juha , Tulamo Riikka , Kotikoski Satu , Nurmonen Heidi , Kämäräinen Olli‐Pekka , Huttunen Terhi , Huttunen Jukka , von und zu Fraunberg Mikael , Koivisto Timo , Jääskeläinen Juha E. , Lindgren Antti E. 
Published: September 2019

Background

Varying degrees of co‐occurrence of intracranial aneurysms (
IA
) and aortic aneurysms (
AA
) have been reported. We sought to compare the risk for
AA
in fusiform intracranial aneurysms (
fIA
) and saccular intracranial aneurysms (
sIA
) disease and evaluate possible genetic connection between the
fIA
disease and
AA
s. Additionally, the characteristics and aneurysms of the
fIA
and
sIA
patients were compared.

Methods and Results

The Kuopio Intracranial Aneurysm Database includes all 4253
sIA
and 125
fIA
patients from its Eastern Finnish catchment population, and 13 009 matched population controls and 18 455 first‐degree relatives to the
IA
patients were identified, and the Finnish national registers were used to identify the individuals with
AA
. A total of 33
fIA
patients were studied using an exomic gene panel of 37 genes associated with
AA
s. Seventeen (14.4%)
fIA
patients and 48 (1.2%)
sIA
patients had a diagnosis of
AA
. Both
fIA
and
sIA
patients had
AA
s significantly more often than their controls (1.2% and 0.5%) or relatives (0.9% and 0.3%). In a competing risks Cox regression model, the presence of
fIA
was the strongest risk factor for
AA
(subdistribution hazard ratio 7.6, 95% CI 3.9–14.9,
P
<0.0005). One likely pathogenic variant in

COL
5A2

and 3 variants of unknown significance were identified in

MYH
11

,

COL
11A1

, and

FBN
1

in 4
fIA
patients.

Conclusions

The prevalence of
AA
s is increased slightly in
sIA
patients and significantly in
fIA
patients.
fIA
patients are older and have more comorbid diseases than
sIA
patients but this alone does not explain their clinically significant
AA
risk.
Structural Changes in the African Easterly Jet and Its Role in Mediating the Effects of Saharan Dust on the Linear Dynamics of African Easterly Waves
Authors: Grogan Dustin F. P. , Nathan Terrence R. , Chen Shu-Hua 
Published: September 2019

Abstract
Analytical and numerical analyses are used to examine how structural changes to the African easterly jet (AEJ) mediate the effects of Saharan mineral dust aerosols on the linear dynamics of African easterly waves (AEWs). An analytical expression for the generation of eddy available potential energy (APE) is derived that exposes how the AEJ and dust combine to affect the energetics of the AEWs. The expression is also used to interpret the numerical results, which are obtained by radiatively coupling a simplified version of the Weather Research and Forecasting Model to a conservation equation for dust. The WRF-Dust model is used to conduct linear simulations based on five observationally consistent zonal-mean AEJs: a reference AEJ and four other AEJs that are obtained by perturbing the maximum meridional and vertical shear. For a dust distribution consistent with summertime observations over North Africa, the numerical simulations show the following: (i) Irrespective of the AEJ structure or the zonal scale of the AEWs, the dust increases the growth rates of the AEWs. (ii) The growth rates of the AEWs are optimized when the ratio of baroclinic to barotropic energy conversions is largest. (iii) When the energy conversions are sufficiently large, the zonal scale of the fastest-growing AEW shortens. The numerical results confirm the analytical analysis, which shows that the dust effects, which are modulated by the Doppler-shifted frequency, are strongest north of the AEJ axis, a region where the dust augments the preexisting meridional temperature gradient.