bluuebunny/crossref_metadata_2025 huggingface dataset:
Patients’ Preference of Topical Therapy for Ulcerative Colitis in Japan: A Web-based 3T Survey
Authors: Yanai Shunichi , Toya Yosuke , Nakamura Shotaro , Matsumoto Takayuki
Published: April 2020

Background

The therapeutic drugs available for ulcerative colitis (UC) have recently increased. However, use of topical therapy for UC in Japan has not been determined. This study aimed to investigate real-world use of topical therapy for UC in Japan using a web-based survey designed for UC patients.

Methods

A web-based questionnaire on UC management was administered to 773 patients over a 2-day period in September 2019. The responses regarding topical therapy use were analyzed.

Results

Questionnaire responses were obtained from 323 UC patients. Of these, the mean disease duration was 12.2 years, and 220 patients (68.1%) had used topical therapy, of whom 68 (21.1%) were currently using this treatment. The frequency of using the prescribed topical therapy was appropriate in 36.8% of patients, only when needed in 38.6%, and rarely in 24.5%. Among all topical therapy users, 64.4% reported that budesonide foam was easy to use, which was significantly higher than the rates for mesalazine suppositories (43.6%), mesalazine enemas (12.9%), and glucocorticoid enemas (13.9%; P < 0.05). Regarding treatment effects, 68.9% of patients were satisfied with the budesonide foam, which was a significantly higher rate of satisfaction than those for mesalazine suppositories (44.6%), mesalazine enemas (30.2%), glucocorticoid enemas (36.1%), and glucocorticoid suppositories (41.9%; P < 0.05).

Conclusions

Although topical therapy use was common in this Japanese UC population, patient adherence was not very high. Of all the topical therapy types, budesonide foam, which has recently become available, was rated highly by these patients.
Integrating transcriptome and metabolome reveals molecular networks involved in genetic and environmental variation in tobacco
Authors: Liu Pingping , Luo Jie , Zheng Qingxia , Chen Qiansi , Zhai Niu , Xu Shengchun , Xu Yalong , Jin Lifeng , Xu Guoyun , Lu Xin , Xu Guowang , Wang Gangjun , Shao Jianfeng , Xu Hai-Ming , Cao Peijian , Zhou Huina , Wang Xusheng
Published: April 2020

Tobacco (Nicotiana tabacum) is one of the most widely cultivated commercial non-food crops with significant social and economic impacts. Here we profiled transcriptome and metabolome from 54 tobacco samples (2–3 replicates; n = 151 in total) collected from three varieties (i.e. genetic factor), three locations (i.e. environmental factor), and six developmental stages (i.e. developmental process). We identified 3,405 differentially expressed (DE) genes (DEGs) and 371 DE metabolites, respectively. We used quantitative real-time PCR to validate 20 DEGs, and confirmed 18/20 (90%) DEGs between three locations and 16/20 (80%) with the same trend across developmental stages. We then constructed nine co-expression gene modules and four co-expression metabolite modules , and defined seven de novo regulatory networks, including nicotine- and carotenoid-related regulatory networks. A novel two-way Pearson correlation approach was further proposed to integrate co-expression gene and metabolite modules to identify joint gene–metabolite relations. Finally, we further integrated DE and network results to prioritize genes by its functional importance and identified a top-ranked novel gene, LOC107773232, as a potential regulator involved in the carotenoid metabolism pathway. Thus, the results and systems-biology approaches provide a new avenue to understand the molecular mechanisms underlying complex genetic and environmental perturbations in tobacco.
Multimodality imaging derived energy loss index and outcome after transcatheter aortic valve replacement
Authors: Holy Erik W , Nguyen-Kim Thi Dan Linh , Hoffelner Lisa , Stocker Daniel , Stadler Thomas , Stähli Barbara E , Kebernik Julia , Maisano Francesco , Kasel Markus A , Frauenfelder Thomas , Ruschitzka Frank , Nietlispach Fabian , Tanner Felix C
Published: April 2020

Aims 

To assess whether the combination of transthoracic echocardiography (TTE) and multidetector computed tomography (MDCT) data affects the grading of aortic stenosis (AS) severity under consideration of the energy loss index (ELI) in patients undergoing transcatheter aortic valve replacement (TAVR).

Methods and results 

Multimodality imaging was performed in 197 patients with symptomatic severe AS undergoing TAVR at the University Hospital Zurich, Switzerland. Fusion aortic valve area index (fusion AVAi) assessed by integrating MDCT derived planimetric left ventricular outflow tract area into the continuity equation was significantly larger as compared to conventional AVAi (0.41 ± 0.1 vs. 0.51 ± 0.1 cm2/m2; P < 0.01). A total of 62 patients (31.4%) were reclassified from severe to moderate AS with fusion AVAi being >0.6 cm2/m2. ELI was obtained for conventional AVAi and fusion AVAi based on sinotubular junction area determined by TTE (ELILTL 0.47 ± 0.1 cm2/m2; fusion ELILTL 0.60 ± 0.1 cm2/m2) and MDCT (ELIMDCT 0.48 ± 0.1 cm2/m2; fusion ELIMDCT 0.61 ± 0.05 cm2/m2). When ELI was calculated with fusion AVAi the effective orifice area was >0.6 cm2/m2 in 85 patients (43.1%). Survival rate 3 years after TAVR was higher in patients reclassified to moderate AS according to multimodality imaging derived ELI (78.8% vs. 67%; P = 0.01).

Conclusion 

Multimodality imaging derived ELI reclassifies AS severity in 43% undergoing TAVR and predicts mid-term outcome.
Totally thoracoscopic ablation: a unilateral right-sided approach
Authors: Fleerakkers Jelle , Hofman Frederik N , van Putte Bart P
Published: April 2020

The aim of this article is to describe a unilateral approach for totally thoracoscopic ablation and left atrial appendage closure for the treatment of atrial fibrillation to simplify the procedure, avoid a technically more demanding thoracoscopy on the left side and potentially reduce postoperative pain without compromising the lesion set.
Overweight and obesity in shift workers: associated dietary and lifestyle factors
Authors: O’Brien Victoria M , Nea Fiona M , Pourshahidi L Kirsty , Livingstone M Barbara E , Bardon Laura , Kelly Ciara , Kearney John M , Corish Clare A
Published: April 2020

Background

Approximately 17% of the European Union workforce is engaged in shift work. Shift work has been associated with a number of chronic conditions, including obesity and obesity-related metabolic diseases. The aim of this study was to explore the dietary and lifestyle behaviours of shift workers with a healthy vs. overweight/obese body mass index (BMI).

Methods

A cross-sectional study was conducted on 1080 shift workers using a 15-min, telephone-administered questionnaire developed from qualitative research on Irish shift workers and national dietary intake data. Demographic and work-related factors, as well as dietary and lifestyle behaviours were recorded. BMI was calculated using self-reported height and weight. Univariate and multivariate logistic regression methods were used to analyze data according to BMI category.

Results

Over 40% of shift workers were classified as overweight or obese. Multivariate analysis indicated that being male [P < 0.001, aOR = 2.102, 95% CI (1.62–2.73)] and middle- or older-aged were independently associated with overweight and obesity [P < 0.001, aOR = 2.44 95% CI (1.84–3.24) and P < 0.001, aOR = 2.9 95% CI (1.94–4.35), respectively]. Having a medium–high consumption of fried foods was independently associated with overweight and obesity [aOR = 1.38, 95% CI (1.06–1.8)].

Conclusions

Similar to the general population, overweight and obesity were strongly associated with male sex and middle- or older-age. Male shift workers may benefit from targeted dietary and lifestyle advice specifically focused on limiting fried foods to help protect against overweight and obesity.
Rebuilding depleted fisheries towards BMSY under uncertainty: harvest control rules outperform combined management measures
Authors: Sun Ming , Li Yunzhou , Ren Yiping , Chen Yong
Published: April 2020

Rebuilding depleted fisheries towards sustainable levels, such as BMSY, is challenging under uncertainty. Although a substantial amount of research has highlighted the importance of accounting for uncertainty in fisheries management, tactical measures remain to be identified. We consider two approaches to achieve this goal: (i) the naive maximum sustainable yield (MSY) approach, combining management measures based on effort control, catch quotas, and spatial–temporal closures, and (ii) the harvest control rules (HCRs) approach, developing HCRs based on short-term or long-term targets. A suite of strategies is developed accordingly and tested with management strategy evaluation for their performance under four sources of uncertainty that may negatively impact management effects, including reduced recruitment strength, increased natural mortality, inadequate implementation error, and varying levels of temporal effort aggregation. Combining management measures using the naive MSY approach is found to perform poorly in tackling uncertainty. Complex HCRs that account for both short-term and long-term BMSY targets can mitigate the adverse effects of uncertainty. The rebuilding target can be only achieved by compromising yield, especially when uncertainties with natural mortality and recruitment are present. Strategies based on catch quotas are prone to all sources of uncertainty, indicating latent risks in many current management practices.
Diagnosis of a primary pericardial mesothelioma by the combination of conventional echocardiography and contrast echocardiography
Authors: Wang Hongxia , Mou Yun , Zheng Zhelan
Published: April 2020

Primary malignancies arising from the pericardium are rare, even more unusual for primary pericardial mesothelioma. The diagnosis is difficult and has no standard treatment. We herein present a case of a 65-year-old woman with primary pericardial mesothelioma associated with dyspnoea and palpitations. Transthoracic conventional echocardiography revealed mild pericardial effusion and a hypo-echogenic mass in the pericardium. Contrast echocardiography showed that the mass was hyper-enhanced with a radial enhancement pattern. The patient underwent open chest exploration and was diagnosed by pathological examination. She had no further treatment and died 2 years later. In conclusion, the combination of conventional echocardiography and contrast echocardiography plays a significant role in diagnosing primary pericardial mesothelioma. Comprehensive evaluation and accurately preoperative diagnosis are important to exclude certain tumours that do not require surgery.
Cost of Hospitalization Associated With Respiratory Syncytial Virus Infection Versus Influenza Infection in Hospitalized Older Adults
Authors: Ackerson Bradley , An Jaejin , Sy Lina S , Solano Zendi , Slezak Jeff , Tseng Hung-Fu
Published: April 2020

Despite the severity of respiratory syncytial virus (RSV) disease in older adults, data on its costs are limited. We compared hospitalization costs for 2090 adults aged ≥ 60 years hospitalized with RSV or influenza by assigning direct health care costs. Hospitalization with RSV was associated with longer hospitalization and increased frequency of diagnosis-related groups for pulmonary complications, resulting in costs at least as great as those for influenza ($16 034 vs $15 163; 95% confidence interval for the difference, −$811 to $2547). Awareness of RSV disease burden in adults is needed to facilitate vaccination and treatment when they become available.
Indoor Environmental Factors and Acute Respiratory Illness in a Prospective Cohort of Community-Dwelling Older Adults
Authors: Han Lefei , Ran Jinjun , Chan Kwok-Hung , Mak Yim-Wah , Suen Lorna , Cowling Benjamin John , Yang Lin
Published: April 2020

Background

Ambient environmental factors have been associated with respiratory infections in ecological studies, but few studies have explored the impact of indoor environmental factors in detail. The current study aimed to investigate the impact of indoor environment on the risk of acute respiratory illness (ARI) in a subtropical city.

Method

A prospective cohort study was conducted in 285 community-dwelling older adults from December 2016 through May 2019. Individual household indoor environment data and ARI incidence were continuously collected. A time-stratified case-crossover analysis was conducted to estimate the excess risk of ARI associated with per-unit increase of daily mean indoor temperature, relative humidity, and absolute humidity (AH).

Result

In total, 168 episodes of ARI were reported with an average risk of 36.8% per year. We observed a negative association of ARI with indoor AH up to 5 lag days in cool seasons, with a 6-day cumulative excess risk estimate of −9.0% (95% confidence interval, −15.9% to −1.5%). Negative associations between household temperature or relative humidity and ARI were less consistent across warm and cool seasons.

Conclusions

Lower indoor AH in household was associated with a higher risk of ARI in the community-dwelling older adults in Hong Kong during cold seasons.
What patients “see” doctors in online fever clinics during COVID-19 in Wuhan?
Authors: Li Gang , Fan Guorui , Chen Yanyan , Deng Zhaohua
Published: April 2020

Objective

In December 2019, coronavirus disease 2019 (COVID-19) occurred in Wuhan, China. Online fever clinics were developed by hospitals, largely relieving the hospital’s burden. Online fever clinics could help people stay out of crowded hospitals and prevent the risk of cross infections. The objective of our study was to describe the patient characteristics of an online fever clinic and explore the most important concerns and question of online patients.

Materials and Methods

Our study extracted data from fever clinic records in medical information systems from January 24 to February 18, 2020 in a tertiary hospital in Wuhan. We described the characteristics of patients in fever clinic, then we extracted and classified questions of patient consultations through the online fever clinic dataset.

Results

For the 64 487 patients who attended the online fever clinic, the average age was 30.4 years, and 37 665 (58.4%) were female patients. The current state of patients from online were home without isolation (52 360 [81.2%]), home isolated (11 152 [17.29%]), and outpatient observation (975 [1.51%]). From the 594 patient questions analyzed, confirming diagnosis and seeking medical treatment account for 60.61% and 38.05%, respectively, followed by treating (25.59%), preventing (4.38%), and relieving anxiety (1.68%).

Discussion

Online fever clinics can effectively relieve patients’ mood of panic, and doctors can guide patients with suspected of COVID-19 to isolate and protect themselves through online fever clinic. Online fever clinics can also help to reduce the pressure of hospital fever clinics and prevent cross infection.

Conclusions

This study indicated the importance of online fever clinics during the COVID-19 outbreak for prevention and control.
Simultaneous Spectrophotometric Determination of Brilliant Blue and Tartrazine in Diverse Sample Matrices after Solid Phase Extraction
Authors: Bişgin Abdullah Taner
Published: April 2020

Background

Brilliant blue (BB) and tartrazine (TZ) are manufactured from petroleum and its products. These are the most popular consumed food dyes and are widely used in foodstuffs. Therefore, overuse of these dyes in foodstuffs and consumption of excessive amounts of these dyes can lead to health problems in humans.

Objective

The aim of this study was to develop a simple separation and preconcentration method for simultaneous spectrophotometric determination of BB and TZ dyes.

Methods

A column solid-phase separation extraction method combined with UV-Vis spectrophotometry was preferred and developed for single and simultaneous determination of BB and TZ dyes.

Results

The preconcentration factor was obtained as 80. Relative standard deviations were below than 4%. Detection limits of the method were determined as 0.29 and 1.21 µg/L for BB and TZ, respectively. Recovery values were obtained between 95–99% and 96–100% for BB and TZ, respectively. 10.9–235.7 µg/g and 1.7–8.0 µg/mL of BB contents of real samples were determined for solid and liquid samples, respectively. TZ concentrations of solid and liquid samples were ranged between 18.7–220.7 µg/g and 5.9–7.5 µg/mL, respectively.

Conclusions

Quantitative extraction results and satisfactory recovery values showed that method was successful and applicable for determination of BB and TZ concentrations in real pharmaceutical, industrial, and foodstuff samples.

Highlights

The method has exhibited a high preconcentration factor and effective separation against to matrix ions. The method did not need an experienced operator with high operation experience. Elution solvent can be chosen according to the availability of the chemicals in the laboratory and cheapness of the chemicals.
Report on the Emergence Time of a Species of Thitarodes Ghost Moth (Lepidoptera: Hepialidae), Host of the Caterpillar Fungus Ophiocordyceps sinensis (Ascomycota: Ophiocordycipitaceae) in Uttarakhand, India
Authors: Wang Zhengyang , Yang Darong , Janak Rawal , Pierce Naomi E
Published: April 2020

Ghost moths in the genus Thitarodes Viette, 1968, are hosts of the economically important caterpillar fungus, which is harvested in high mountain meadows across the Hengduan mountains and the Himalayas. In northwestern India, although caterpillar fungus has been collected in the state of Uttarakhand, no adults of Thitarodes species have been recorded. We report the sighting of a female pupa of Thitarodes sp. and its last-instar molt at Munsiyari, Uttarakhand, India, on 5 July 2019 and estimate that the adult emergence time in this habitat should be late July or early August. Although the habitats of caterpillar fungus in Uttarakhand are geographically closer to those in Nepal, they are climatically more similar to habitats of caterpillar fungus in Qinghai province in China. Among records at the same elevation, climatic variables are highly predictive of the emergence date of Thitarodes adults (adjusted-R2: 0.7925, F = 6.27, P = 0.03). Our result highlights the role of the Himalayan mountains as both a north–south climatic barrier and an east–west climatic gradient. We encourage local stakeholders and scientists in Uttarakhand to survey adult emergences of Thitarodes from July to mid-August.
Elevated Cerebrospinal Fluid and Plasma N-Cadherin in Alzheimer Disease
Authors: Choi Ji-Young , Cho Sun-Jung , Park Jung Hyun , Yun Sang-Moon , Jo Chulman , Kim Eun-Joo , Huh Gi Yeong , Park Moon Ho , Han Changsu , Koh Young Ho
Published: April 2020

N-cadherin is a synaptic adhesion molecule stabilizing synaptic cell structure and function. Cleavage of N-cadherin by γ-secretase produces a C-terminal fragment, which is increased in the brains of Alzheimer disease (AD) patients. Here, we investigated the relationship between fluid N-cadherin levels and AD pathology. We first showed that the cleaved levels of N-cadherin were increased in homogenates of postmortem brain from AD patients compared with that in non-AD patients. We found that cleaved N-cadherin levels in the cerebrospinal fluid were increased in AD dementia compared with that in healthy control. ELISA results revealed that plasma levels of N-cadherin in 76 patients with AD were higher than those in 133 healthy control subjects. The N-cadherin levels in the brains of an AD mouse model, APP Swedish/PS1delE9 Tg (APP Tg) were reduced compared with that in control. The N-terminal fragment of N-cadherin produced by cleavage at a plasma membrane was detected extravascularly, accumulated in senile plaques in the cortex of an APP Tg mouse. In addition, N-cadherin plasma levels were increased in APP Tg mice. Collectively, our study suggests that alteration of N-cadherin levels might be associated with AD pathology.
A hybrid treatment modality of a subtrochanteric femoral fracture in a patient with osteoporosis due to a renal Fanconi syndrome: a case report
Authors: Lange Stefan F , Schrooten Tim K J , de Wit Ralph J , de Groot Reinier
Published: April 2020

A 24-year-old male with an idiopathic renal Fanconi syndrome presented to our ER after a low-energetic fall. Conventional imaging revealed a right subtrochanteric femoral fracture, severely decreased bone quality and cannulated collum femoris screws on the contralateral side. Regular plate-screw osteosynthesis or cephalomedullary implantation was deemed insufficient, due to a high iatrogenic and periprosthetic fracture probability. The decision was made to perform a plate-screw osteosynthesis combined with an intramedullary polymer bone enhancement (IlluminOss), to minimize this risk. No complications occurred perioperatively. The patient was able to walk independently two months postoperatively. This case shows that use of polymer implant as an enhancement of osteosynthesis in repair of fractures in the Fanconi syndrome is a safe and possible useful treatment method.
Preventing spread of SARS-CoV-2 and preparing for the COVID-19 outbreak in the surgical department: perspectives from two Scandinavian countries
Authors: Lindeman Robbert-Jan , Sund Malin , Löfgren Jenny , Basso Trude , Søreide Kjetil
Published: April 2020

A COVID-19 pandemic was declared on March 11 by the World Health Organization (WHO). The first cases of COVID-19 were confirmed on January 31 in Sweden and on February 26 in Norway. Despite being similar countries with universal healthcare systems, the governmental approaches to mitigation of the epidemic have varied considerably. Norway initiated a societal lockdown effective from March 12, the same day as the first confirmed death. Sweden has initiated a more laxed and gradual strategy based on the appeal for a strong personal sense of responsibility to mitigate the viral spread. In both countries, the first weeks of preparation has seen a strong reduction in elective surgery, with several implemented principles to mitigate SARS-CoV-2 spread and prepare for surgical care for COVID-19 diseases as needed. This invited leading article gives a brief overview of some of the early experiences of the outbreak in two Scandinavian countries.
Solving a Paradox of Evidential Equivalence
Authors: Dorr Cian , Hawthorne John , Isaacs Yoaav
Published: April 2020

David Builes presents a paradox concerning how confident you should be that any given member of an infinite collection of fair coins landed heads, conditional on the information that they were all flipped and only finitely many of them landed heads. We argue that if you should have any conditional credence at all, it should be 1/2.
Deficiency of the onco-miRNA cluster, miR-106b∼25, causes oligozoospermia and the cooperative action of miR-106b∼25 and miR-17∼92 is required to maintain male fertility
Authors: Hurtado Alicia , Palomino Rogelio , Georg Ina , Lao Miguel , Real Francisca M , Carmona F David , Burgos Miguel , Jiménez Rafael , Barrionuevo Francisco J
Published: April 2020

The identification of new genes involved in sexual development and gonadal function as potential candidates causing male infertility is important for both diagnostic and therapeutic purposes. Deficiency of the onco-miRNA cluster miR-17∼92 has been shown to disrupt spermatogenesis, whereas mutations in its paralog cluster, miR-106b∼25, that is expressed in the same cells, were reported to have no effect on testis development and function. The aim of this work is to determine the role of these two miRNA clusters in spermatogenesis and male fertility. For this, we analyzed miR-106b∼25 and miR-17∼92 single and double mouse mutants and compared them to control mice. We found that miR-106b∼25 knock out testes show reduced size, oligozoospermia and altered spermatogenesis. Transcriptomic analysis showed that multiple molecular pathways are deregulated in these mutant testes. Nevertheless, mutant males conserved normal fertility even when early spermatogenesis and other functions were disrupted. In contrast, miR-17∼92+/−; miR-106b∼25−/− double mutants showed severely disrupted testicular histology and significantly reduced fertility. Our results indicate that miR-106b∼25 and miR-17∼92 ensure accurate gene expression levels in the adult testis, keeping them within the required thresholds. They play a crucial role in testis homeostasis and are required to maintain male fertility. Hence, we have identified new candidate genetic factors to be screened in the molecular diagnosis of human males with reproductive disorders. Finally, considering the well-known oncogenic nature of these two clusters and the fact that patients with reduced fertility are more prone to testicular cancer, our results might also help to elucidate the molecular mechanisms linking both pathologies.
Immediate Effect of Abdominal and Pelvic Floor Muscle Exercises on Interrecti Distance in Women With Diastasis Recti Abdominis Who Were Parous
Authors: Gluppe Sandra B , Engh Marie Ellström , Bø Kari
Published: April 2020

Objective

There is a lack of consensus on which abdominal or pelvic floor muscle (PFM) exercises to recommend for the treatment of diastasis recti abdominis (DRA). The objective of this study was to investigate the immediate effect of abdominal and PFM exercises on interrecti distance (IRD) in women with DRA who are parous.

Methods

In this cross-sectional study, 38 women who were parous, with a mean age of 36.2 years (SD = 5.2), diagnosed with DRA participated. IRD was assessed with 2-dimensional real-time ultrasonography during rest and during 8 randomly ordered different exercises. A paired t test was used to compare the IRD at rest with the IRD recorded during each exercise as well as the differences between exercises. Means with 95% CI are reported.

Results

Head lift and twisted curl-up exercises significantly decreased the IRD both above and below the umbilicus. Above the umbilicus, the mean IRD difference from rest during head lift was 10 mm (95% CI = 7 to 13.2), whereas during twisted curl-up it was 9.4 mm (95% CI = 6.3 to 12.5). Below the umbilicus, the corresponding values were 6.1 mm (95% CI = 3.2 to 8.9) and 3.5 mm (95% CI = 0.5 to 6.4), respectively, but PFM contraction, maximal in-drawing, and PFM contraction + maximal in-drawing increased the IRD (mean difference = −2.8 mm [95% CI = −5.2 to 0.5], −4.7 mm [95% CI = −7.2 to −2.1], and − 5.0 mm [95% CI = −7.9 to −2.1], respectively).

Conclusions

Head lift and twisted curl-up exercises decreased the IRD both above and below the umbilicus, whereas maximal in-drawing and PFM contraction exercises only increased the IRD below the umbilicus. A randomized controlled trial is needed to investigate whether head lift and twisted curl-up exercises are effective in permanently narrowing the IRD.

Impact

To date there is scant scientific knowledge of which exercises to recommend in the treatment of DRA. In-drawing and PFM contraction leads to an acute increase in IRD, while head lift and twisted curl-up leads to an acute decrease in IRD in postpartum women. There is a need for high-quality randomized controlled trials to investigate if there is a long-term reduction in IRD by doing these exercises over time. The acute IRD increase and decrease during the different exercises is also present in a sample of women with larger separations.
A framework for mission-oriented innovation policy: Alternative pathways through the problem–solution space
Authors: Wanzenböck Iris , Wesseling Joeri H , Frenken Koen , Hekkert Marko P , Weber K Matthias
Published: April 2020

We aim for a better conceptualization of mission-oriented innovation policy (MIP). Our starting point is an analytical decomposition of societal problems and innovative solutions based on three dimensions of wickedness: (1) contestation; (2) complexity; and (3) uncertainty. We argue that both problems and solutions can be divergent (contested, complex, and uncertain) or convergent (uncontested, well-defined, and informed). Based on the resulting problem–solution typology, we suggest a process-oriented view on MIP and discuss three alternative pathways along which convergence between problems and solutions can be achieved to come from wicked problems to legitimate solutions. We illustrate these pathways using examples for different societal problems related to health (smoking bans), security (CCTV), and energy (wind turbines). For policy makers, locating a societal challenge in this problem–solution space, and implementing policy strategies to achieve problem and solution convergence, is expected to accelerate both the legitimacy of a mission and the resulting solutions.
Enhanced apoptogenesis and oncogene regulatory mechanism of troxerutin in triple negative breast cancer cells
Authors: Saranya Thiruvenkataswamy , Kavithaa Krishnamoorthy , Paulpandi Manickam , Ramya Sennimalai , Preethi Sivashanmugam , Balachandar Vellingiri , Narayanasamy Arul
Published: April 2020

Triple negative breast carcinoma (TNBC) is an aggressive form of cancer, with high rates of morbidity, mortality, poor prognosis and limited therapeutic options. The objective of the present study was to elaborate the anticancer activity of Troxerutin (TXN) in TNBC/MDA-MB-231 cells. Herein, we demonstrated the inhibitory effects of TXN on the breast cancer cell growth via induction of apoptosis. Mitochondrial membrane potential (∆Ψm), DNA damage and apoptotic nuclear changes were analyzed by flowcytometry, AO/EtBr and Hoechst staining, respectively. Furthermore, apoptotic protein and gene expressions were analyzed by western blot and reverse transcription polymerase chain reaction (RT-PCR), respectively. Our results indicated that TXN induces apoptosis as evidenced by inhibit the cell proliferation, enhanced apoptotic activation, altered mitochondrial membrane potential and elevated level of DNA damage in TNBC cells. Furthermore, the TXN inhibit anti-apoptotic protein expression with the subsequent upregulation of Cytochrome c, Caspase-9 and Caspase-3. Thus, TXN induces apoptosis in TNBC cells through inducing nuclear damage and altered apoptotic marker expressions. Therefore, TXN might be used as a potential therapeutic agent for the treatment of triple negative breast cancer.
Detection and Identification of Phytoplasmas in the 16SrIV-A, -B, and -D Subgroups in Palms in Tabasco, Mexico
Authors: Ramos Hernández Eder , Lesher Gordillo Julia M. , Oropeza Salín Carlos , Ortiz García Carlos F. , Magaña Alejandro Miguel A. , Sánchez Soto Saúl , García Estrada Yesenia
Published: April 2020

The 16SrIV-A phytoplasmas are associated with the devastating disease lethal yellowing (LY) of palms. In Tabasco (Mexico), the death of Cocos nucifera, Adonidia merrillii, and Attalea butyracea palms have been suspected to be associated with LY based on symptomatology. Samples from the trunk of both symptomatic and nonsymptomatic palms were collected in three different environments: two species of palms within a rural zone and the other within an urban zone. DNA was extracted to perform a nested PCR with phytoplasma primers P1/P7-LY16SF/R16R2. A 1,345-bp fragment was amplified from the DNA extracted from each of the 29 LY-symptomatic palms sampled. Phytoplasma identification was achieved by amplicon sequencing and virtual restriction fragment length polymorphism analyses. Three 16SrIV phytoplasma subgroups were detected: 16SrIV-A in C. nucifera, 16SrIV-B in A. merrillii, and 16SrIV-D in C. nucifera, A. merrillii, and A. butyracea. Phylogenetic analysis showed also that the three phytoplasma strains found in the palm species clustered with phytoplasmas reported in the literature in the three subgroups identified. This is the first report of phytoplasmas associated with these palm species in Tabasco.
Zebrafish as a Model System for the Interrogation of Hematopoietic Stem Cell Engraftment
Authors: Feliz Maria A , Fraint Ellen , Bowman Teresa V
Published: April 2020

Hematopoietic stem cell (HSC) transplant is a treatment used to infuse healthy blood stem cells to patients that suffer from a range of blood disorders, such as leukemia. Although transplantations are successful nearly 85% of the time, the associated morbidity and mortality rates are still too high. To improve HSC transplantation outcomes, it is crucial to better understand all facets of HSC engraftment, which includes the seeding, expansion, and differentiation of donor HSC into the recipient. Zebrafish is an ideal animal model to study engraftment due to their small size, high fecundity, and malleable genetics. We have established a novel transplantation model using the zebrafish runx1 W84X bloodless mutant strain. These animals lack endogenous HSC and thus possess empty HSC niche available for donor cell engraftment without the need for pre‐conditioning regimens. Transplantation of donor marrow cells that ubiquitously express green fluorescent protein (ubi:GFP) into runx1 W84X homozygous mutants at two days‐post fertilization (dpf) results in robust GFP+ donor cell engraftment that sustains the blood system of the mutants into adulthood. Sham‐injected and un‐injected embryos served as negative controls. Using this model, we will image transplanted embryos daily to visualize all stages of engraftment. From 4–7 dpf, we observed seeding of GFP+ cells into all hematopoietic tissues including the thymus, caudal hematopoietic tissue, and kidney marrow (equivalent to mammalian bone marrow). We will use confocal microscopy to gain a more in‐depth view of the cell‐to‐cell interactions occurring within these niches to understand engraftment. Additionally, we will use this assay for longitudinal studies to determine what facets predict which animals will sustain high versus low donor cell chimerism. Studying this animal model could advance our understanding of human HSC transplantation outcomes.

Support or Funding Information

NIH (Grant # R25‐GM104547); Cancer Research Center (Grant # P30CA013330)
Non‐Perfused Coronary Arteries Are Able to Maintain Structural Integrity in Developing Scar Tissue Following a Transmural Myocardial Infarction
Authors: Dedkov Eduard I
Published: April 2020

Introduction

Whereas considerable effort has been devoted to identify a suitable source of contractile cells to be used for replacement of a post‐myocardial infarction (MI) scar with the newly‐formed cardiac muscle tissue, an exploration for the viable routes of arterial blood supply to the sites of regenerating myocardium remained mostly neglected. However, the presence of a sustainable blood delivery system seems imperative for survival of newly‐grown myocardium.

Hypothesis

We hypothesize that if the vessels of the original arterial bed, remaining in post‐MI region, will be able to maintain their structural integrity for the duration of post‐MI scar formation they can potentially be suitable for use as a natural blood delivery system to support the regenerating myocardium.

Methods

A large transmural MI was induced in middle‐aged, male Sprague‐Dawley rats by permanent ligation of the left coronary artery. Post‐MI rats were euthanized 3, 7 and 14 days after occlusion and their hearts were processed to paraffin for morphological evaluation. Sham‐operated rats were used as age‐matched controls. Serial sections from each heart were stained with various histological techniques or with an anti‐smooth muscle alpha‐actin antibody. Images were captured using a Leica DM 4000B microscope and analyzed by Image‐Pro Analyzer v.7.0 software. Statistical analysis was performed using Prism 6 software package.

Results

We found that whereas most arterioles and small arteries within an infarcted region have undergone necrosis during 3 days after MI, the medium‐sized and larger arteries appeared to preserve their structural integrity up to 14 days post‐MI. Quantitative assessment showed that surviving residual arteries continued to maintain their structural parameters, such as external diameter, lumen diameter, wall thickness and wall‐to‐lumen ratio, during 7 post‐MI days. However, in 14‐day‐old scars, some non‐perfused arteries began to demonstrate the evidence of noticeable neointimal thickening, composed of activated smooth muscle cells, that narrowed the vessel lumen and led to a significant increase in wall‐to‐lumen ratio (0.35±0.02 in post‐MI rats vs. 0.11±0.01 in sham‐operated rats, P<0.0001). Moreover, the majority of remaining vessels showed a various degree of degenerative changes, including perivascular and intravascular collagen accumulation, disintegration of internal elastic lamina and patchy disappearance of smooth muscle cells from the vessel media.

Conclusion

Our findings reveal that a number of large and medium‐sized coronary arteries, residing in post‐infarcted region, were capable of maintaining their structural integrity during two post‐MI weeks. This observation supports a concept that these vessels can be used as a potential route for reestablished arterial blood supply that would be necessary to facilitate the replacement of scar tissue by newly‐formed cardiac muscle.

Support or Funding Information

New Jersey Health Foundation
The PAQosome, a novel molecular chaperoning machine for assembly of human protein complexes and networks
Authors: Coulombe Benoit , Cloutier Philippe , Pinard Maxime , Forget Diane , Poitras Christian , Gauthier Marie-Soleil
Published: April 2020

The human proteome comprises the products of more than 20,000 genes, most being arranged in complexes and networks that underlie essential cell functions. The Particle for Arrangement of Quaternary structure (PAQosome), formerly known as the R2TP/Prefoldin‐like complex, is to our knowledge the only molecular chaperoning machine designed by the evolution to assemble large protein complexes and regulatory networks in humans. The human PAQosome is a 12‐subunit complex made of two multisubunit modules, namely R2TP (RUVBL1, RUVBL2, RPAP3 and PIH1D1) and Prefoldin‐like (URI1, UXT, PDRG1, PFDN2, PFDN6 and the newly discovered ASDURF), as well as two other accessory proteins (POLR2E and WDR92). Several PAQosome clients/substrates have previously been identified, including all three nuclear RNA polymerases, various small nucleolar ribonucleoproteins (snoRNPs) and small nuclear RNPs (snRNPs), all six members of the phosphatidylinositol 3‐kinase‐related kinase (PIKK) family and others. Client specificity appears to be regulated by a number of different mechanisms, including the use of alternative core PAQosome subunits that recognize different clients directly, and the action of specificity adaptors that connect the PAQosome core to specific clients. Here, we present data identifying additional PAQosome clients, some being recruited through novel mechanisms that will be discussed. For example, and similar to what has been reported for axonemal dynein complexes involved in cilium motility, we now identify cytoplasmic dynein complexes that are responsible for cargo transport along microtubules as new clients of the PAQosome. Our recent data also indicate that specific phosphorylation of PAQosome subunits is at play for recognition of an important newly‐identified client, the pre‐ribosome, which is recruited to the PAQosome along with multiple ribosome biogenesis factors. Detailed mechanisms of assembly of some client complexes as well as the effect of mutations causing genetic diseases on complex/network integrity and PAQosome function will be presented. Characterization of the PAQosome is important not only to elucidate a newly‐recognized basal mechanism of gene regulation in eukaryotes but also to explore new research avenues that can lead to development of novel therapeutic and diagnostic tools.
Myosin: Structure, Function, Regulation and Disease
Authors: Peckham Michelle , Parker Francine , Carrington Glenn , Giralt-Pujol Marta , Casas-Mao David , Scarff Charlotte
Published: April 2020

The human myosin superfamily is made up of 12 different classes of myosin. Class 2 is the largest, and is made up of 13 genes. Of these, 9 are expressed in striated muscle and the remaining 4 in non‐muscle cells and smooth muscle. All of these myosins form filaments. In striated muscle, the filaments contain precisely 294 molecules. In contrast, non‐muscle myosins form much shorter filaments (about 30 molecules). The activity of all of these myosins is regulated by an interaction of the heads (comprising the motor domain and lever) with the first part of the coiled coil (subfragment 2, S2) to form the so‐called ‘interacting heads’ motif. Non‐muscle and smooth muscle myosin heads are additionally regulated by an interaction of the head with the tail forming region (light meromyosin, LMM).

We use a combination of cell biology, and structural approaches, including electron microscopy to understand the effects of disease‐causing mutations in S2 and in LMM. Mutations in striated myosins (MyHCβ, MyHC2a) cause cardiac and skeletal muscle diseases respectively, although mutations in the distal LMM region of MyHCβ are predominantly associated with skeletal muscle disease. Mutations in non‐muscle myosin (NM2A) cause a range of bleeding disorders. We determine how specific mutations affect the myosin’s ability to form filaments, and how they affect formation of the regulated state of the myosin. For example, we use circular dichroism to determine if specific mutations affect the secondary structure of LMM. We use negative stain electron microscopy to evaluate filament formation by the LMM (fused to GST, to prevent paracrystal formation), and we use GFP‐tagged MHC to evaluate the ability of each mutant to incorporate into filaments in cultured cells, myotubes and adult rat cardiomyocytes (Parker et al. (2018) J. Mol. Biol). Together with additional structural studies, we are starting to understand how specific mutations affect myosin function, to gain a better understanding of the disease process.

Support or Funding Information

This research is supported by the Medical Research Council, MR/R009406/1 and MR/S023593/1 to MP.
A conserved role of CBP/p300 in mitochondrial stress response and longevity
Authors: Auwerx Johan , Li Terytty Yang
Published: April 2020

Caenorhabditis elegans respond to mitochondrial stress by activating multiple stress defense pathways including the mitochondrial unfolded protein response (UPRmt). Here we show that the inhibition of CBP‐1, the C. elegans ortholog of mammalian acetyltransferases CBP/p300, either through RNA interference or by pharmacological inhibitors, robustly attenuates mitochondrial perturbation‐ induced UPRmt activation and lifespan extension. Mechanistically, CBP‐1‐mediated histone acetylation acts in conjunction with histone demethylation to transcriptionally induce a broad spectrum of UPRmt genes. In mouse and human, transcript levels of CBP/p300 systematically correlate with the expression of UPRmt genes and mitochondrial modules, as well as with longevity. Furthermore, loss‐of‐function of CBP/p300 or their pharmacological inhibition disrupts the activation of the UPRmt, the mitochondrial network and energy homeostasis in mammalian cells. These results highlight an evolutionary conserved epigenetic mechanism that protects mitochondrial function and regulates longevity through the histone acetyltransferases CBP/p300.

Support or Funding Information

This work was supported by grants from the Ecole Polytechnique Fédérale de Lausanne and the European Research Council (ERC‐AdG‐787702). T.Y.L. was supported by the “Human Frontier Science Program” (LT000731/2018‐L).
Microbiome Catabolites as Novel Modulators of Cellular Glucose and Energy Metabolism
Authors: Williamson Gary , Houghton Michael , Kerimi Asimina
Published: April 2020

The gut microbiome supplies bioactive metabolites such as butyrate from dietary fiber to enhance the function of skeletal muscle mitochondria, and influences metabolism during exercise. Trained athletes have a distinctly different microbiome compared to sedentary individuals, since the composition and activity of the microbiota is in turn affected by muscle fitness.

The gut microbiota regulate mitochondrial biogenesis through modulation of PGC‐1α, SIRT1 and AMPK, and the mitochondria regulate the gut microbiota by modulating mucosal immune responses and intestinal barrier function. Skeletal muscle is the main site of postprandial glucose disposal; the glucose transporter GLUT4 is activated by insulin by translocation to the plasma membrane from internal vesicles. In diabetic and pre‐diabetic insulin‐resistant tissues, this GLUT4 translocation is compromised. Therapeutic strategies against insulin resistance, including exercise and diet‐related interventions, aim to lower postprandial glycemia at least partly by restoring skeletal muscle glucose uptake and enhancing metabolism.

Dietary phenolics can be considered as prebiotic‐type molecules, including precursors present in the unbound form as well as covalently‐attached to dietary fiber such as in cereal brans. After microbial action, many potentially bioactive phenolics are released and absorbed in the colon. These microbial products, once absorbed, interact with other tissues, including muscle and adipose cells, and stimulate the uptake of glucose by several mechanisms. For example, the microbial metabolite isovanillic acid sulfate (IVAS) stimulated a dose‐dependent increase in glucose transport in human LHCN‐M2 muscle cells through a GLUT4‐ and PI3K‐dependent mechanism. IVAS also upregulated GLUT1, GLUT4 and PI3K p85α protein, and increased phosphorylation of Akt.

The stimulation of glucose uptake and metabolism provides a novel link between the diet, gut microbiota and skeletal muscle energy utilization.
Acetylation of Cytidine in Messenger RNA Regulates Translation
Authors: Oberdoerffer Shalini , Arango Daniel , Hosogane Masaki , Sturgill David , Yankova Ellie , Kouzarides Tony , Tzelepis Kostas
Published: April 2020

Modifications within RNA nucleobases have the potential to impact all aspects of post‐transcriptional mRNA metabolism. We recently identified N4‐acetylcytidine (ac4C) as a novel modification in mRNA that is catalyzed by the enzyme NAT10. The majority of ac4C sites were found to occur within coding sequences with a general 5′ localization bias. Comparative profiling of ac4C substrate mRNAs in the presence or absence of NAT10 demonstrated a direct role for acetylation in promoting mRNA stability through enhanced translation efficiency. However, transcriptome‐wide mapping of ac4C also revealed an increased occurrence within 5′ untranslated regions (UTRs), wherein a clear relationship to gene expression was not observed (Arango et al., Cell, 2018). Here, we directly examine the function of 5′UTR acetylation in mRNA expression and uncover a putative role in the regulation of translation initiation. Ribosomal footprinting analysis performed in the presence of the initiation inhibitor harringtonine demonstrated an increased prevalence of 80S ribosomes at annotated 5′UTRs marked by overlapping acetylation. Detailed analysis in cancer relevant cellular models supports a role for ac4C in alternative initiation at well‐established non‐AUG translation start sites of known oncogenes. Altogether, our results identify a location specific role for ac4C in mRNA translation wherein coding sequence acetylation promotes translation elongation, while 5′UTR acetylation regulates translation initiation to support pro‐proliferative protein isoforms. These findings illustrate the powerful and diverse impact of the epitranscriptome on mRNA regulation.

Support or Funding Information

This work is supported by the Intramural Research Program of the NIH, the National Cancer Institute and The Center for Cancer Research.