bluuebunny/crossref_metadata_2025 huggingface dataset:
Home- and hospital-based exercise training programme after Fontan surgery
Authors: Sutherland Nigel , Jones Bryn , Westcamp Aguero Sofia , Melchiori Tristan , du Plessis Karin , Konstantinov Igor E. , Cheung Michael M. H. , d’Udekem Yves
Published: August 2018

Background

Exercise training has been shown to increase exercise capacity in survivors of Fontan surgery. The geographic distribution of the Fontan population has been a barrier to hospital-based exercise training programmes. The objective of this study was to establish whether a home exercise training programme could achieve similar improvements to a hospital programme.

Methods

Adolescents with a Fontan circulation aged 12–19 years were prospectively recruited in a hospital or home exercise training programme. Patients underwent cardiopulmonary exercise testing and completed the Paediatric Quality of Life Inventory at initial assessment and after completion of an 8-week programme. Both groups performed two 1-hour training sessions per week. Patients in the home training programme had their first session in the hospital, and then progressed independently with one phone consult per week and one home visit by a physiotherapist.

Results

In total, 17 patients, with a mean age of 15±3 years, completed the training programme (six hospital). Characteristics and baseline performance of patients were similar in both groups. Oxygen consumption at anaerobic threshold increased from 19.3±3.8 to 21.6±6.0 ml/kg/minute (p=0.02) and peak oxygen pulse increased from 8.8±2.5 to 9.5±2.7 ml/beat (p=0.049). Total quality of life scale improved from 68 to 74% (p=0.01) and psychosocial health improved from 67 to 74% (p=0.02). No patient experienced training-related complications.

Conclusions

Exercise training is beneficial and most likely safe after Fontan, resulting in improved exercise capacity and self-reported quality of life. Home exercise training programmes are probably as effective as hospital programmes. Home exercise training programmes should be integrated in the follow-up care of patients undergoing Fontan surgery.
2D-Speckle tracking echocardiography contributes to early identification of impaired left ventricular myocardial function in children with chronic kidney disease
Authors: Demetgul Hasan , Giray Dilek , Delibas Ali , Hallioglu Olgu
Published: August 2018

Introduction

The aim of this study is to determine early changes in cardiac function of children with chronic kidney disease by using 2D-speckle tracking echocardiography.

Method

The study included 38 children – 16 girls and 22 boys – diagnosed as having chronic kidney disease in the nephrology department with a glomerular filtration rate of <90 ml/minute/1.73 m2 for at least 3 months. A total of 37 – 15 girls and 22 boys – age- and sex-matched healthy children were included as the control group. 2D-Speckle tracking echocardiography was performed in all subjects.

Results

The mean age was 13.45±2.8 years in patients and 12.89±3.07 years in controls. Systolic and diastolic blood pressures and left ventricular mass index were significantly higher in patients (p<0.05). The values of mitral e, mitral a, mitral e/a ratio, and mitral deceleration time were not different between the groups. Tricuspid annular plane systolic excursion values were lower in patients (p<0.01). Global strain values in apical long-axis 3-chamber and 2-chamber views were significantly lower in patients (p<0.05). Longitudinal, radial, and circumferential peak systolic strain values were lower in patients, but the difference was statistically significant in all segments of longitudinal view and basal segment of circumferential view (p<0.05). Radial and circumferential systolic strain rates were significantly lower in patients in all three segments (p<0.05). Moreover, early diastolic strain rate was significantly lower in longitudinal and radial apical segments and in all segments of circumferential measurements in patients. Besides, strain rate e/a ratio was significantly lower in all longitudinal segments of patients (p=0.01).

Conclusion

The study concluded that 2D-speckle tracking echocardiography method can determine cardiac involvement earlier than conventional echocardiography in children with chronic kidney disease having preserved ejection fraction.
No difference found in safety or efficacy of balloon atrial septostomy performed at the bedside versus the catheterisation laboratory
Authors: Savorgnan Fabio , Zaban Nicholas B. , Elhoff Justin J. , Ross Michael M. , Breinholt John P.
Published: August 2018

Background

Balloon atrial septostomy is performed in infants with dextro-transposition of the great arteries to improve oxygenation before surgery. It is performed in the catheterisation laboratory with fluoroscopy or at the bedside using echocardiography. It is unclear whether procedural safety and efficacy is superior in one location versus the other, although the bedside procedure may improve resource utilisation and present an opportunity for reducing cost. This study compares safety and efficacy of atrial septostomy performed at the patient’s bedside versus the catheterisation laboratory.

Methods

Neonates with dextro-transposition of the great arteries who underwent balloon atrial septostomy from October, 2000 to January, 2014 were included. Medical and procedural records, echocardiograms, and catheterisation data were reviewed. Comparisons between the two procedural locations included patient demographics, pre- and post-procedure oxygen saturations, and outcomes. Complications reviewed included bleeding, arrhythmia, cardiac trauma, stroke, and death. Coronary artery evaluations were recorded. T-tests were used for continuous variables, and Fisher’s exact tests were used for all categorical variables. Wilcoxon rank sum and analysis of covariance modelling were used for time variables and oxygen saturation, respectively.

Results

A total of 88 infants met the inclusion criteria. Among them, 53 underwent septostomy at the bedside and 35 underwent septostomy in the catheterisation laboratory. No safety or outcome benefit was identified between the two procedural locations.

Conclusion

Septostomy performed at the bedside and in the catheterisation laboratory had similar outcomes and efficacy. Further, bedside septostomy has the advantage of no radiation exposure, and obviating risks with patient transfer from the ICU to the catheterisation laboratory.
Helpful and Hindering Events in Internet-Delivered Cognitive Behavioural Treatment for Generalized Anxiety
Authors: Burke John , Richards Derek , Timulak Ladislav
Published: August 2018

Background: Anxiety disorders are a highly prevalent cause of impairment globally with generalized anxiety disorder (GAD) sharing many features with other anxiety disorders. Aims: The present study investigated the helpful and hindering events and impacts for individuals with generalized anxiety who engaged with a supported 6-week online intervention based on cognitive behavioural therapy (iCBT). Method: Participants (n = 36) completed the Helpful and Hindering Aspects of Therapy (HAT) for each session. A descriptive-interpretative framework was used to analyse the data. Results: Helpful events were identified by participants as CBT techniques including psychoeducation, monitoring, cognitive restructuring and relaxation, and found supporter interaction, mindfulness and reading personal stories helpful. The associated impacts were identified as support and validation; behavioural change/applying coping strategies; clarification, awareness, and insight; reassurance/relief; and self-efficacy/empowerment. Hindering events were identified as treatment content/form; and amount of work/technical issues, which led to impacts such as frustration/irritation; increased anxiety; and isolation. Conclusion: The implications of the results, potential future directions of research and limitations of the study are discussed.
Changes in food intake from 2005 to 2010 by a cohort of black rural and urban African men and women in the North West Province of South Africa: the PURE-NWP-SA study
Authors: Wentzel-Viljoen Edelweiss , Laubscher Ria , Vorster Hester H
Published: August 2018

Objective

We have shown that nutrient intakes of rural and urban black Africans in the North West Province (NWP) of South Africa (SA) followed the typical nutrition transition pattern upon urbanization and modernization. The current study aimed to examine and report on the changes in food intakes from 2005 to 2010 in rural and urban black South Africans participating in the PURE-NWP-SA study.

Design/Setting/Subjects

The PURE-NWP-SA study recruited 2010 volunteers aged 35–70 years in 2005, from which detailed food intakes, measured with a validated quantified FFQ, for 1858 participants were available. In 2010, food intakes of a cohort of 1154 of these participants were measured.

Results

Median energy intake increased in men and women in both rural and urban areas from 2005 to 2010. Changes in food intake were interpreted keeping these changes in energy intake and the contribution of foods and food groups to total energy intake in mind. No ‘new’ foods were eaten in 2010, but more participants consumed certain foods and products in 2010 than in 2005. Beneficial changes were increased intakes of vegetables, fruit and milk in most groups. The contribution of cooked staple porridges and bread made from fortified maize and bread flour decreased and therefore also did their contribution to micronutrient intakes.

Conclusions

By promoting and supporting observed beneficial changes such as increased intakes of milk, vegetables and fruit by appropriate policies and educational interventions, it should be possible to steer the nutrition transition in this population into a positive direction.
Therapists’ attitudes to offering eCBT in an inner-city IAPT service: a survey study
Authors: Meisel Susanne F. , Drury Helena , Perera-Delcourt Ramesh P.
Published: August 2018

Despite an emerging evidence base for the efficacy of supported computerized cognitive behavioural therapy (eCBT), uptake in services has been slow. Therapists’ beliefs about eCBT may constitute a barrier to offering eCBT to clients, but little research has investigated this topic. The aim of this study was to investigate therapist attitudes towards eCBT in one inner-city Improving Access to Psychological Therapies (IAPT) service using a survey design. Data were analysed using descriptive statistics. Thirty-three therapists took part in the study. Although 97% of participants reported that they knew ‘what eCBT involves’, and 62% reported that they were ‘confident to offer eCBT to clients’, only 10% endorsed that ‘there is a strong evidence-base to support the use of eCBT’. Two-thirds of the sample believed that eCBT ‘could be effective for mild and moderate mental health difficulties’, but most participants believed that eCBT would perform ‘worse’ or ‘much worse’ than face-to-face interventions for a range of disorders. Barriers to offering eCBT related predominantly to assumptions about client expectations of therapy, and perceived lack of a therapeutic relationship. Participants identified the provision of training on eCBT for those recommending treatment options to clients as a potential solution. Results from this study highlight therapists’ attitudes to eCBT that might contribute to low uptake rates of eCBT. Particularly, misperceptions about the evidence base for eCBT may be prevalent. Appropriate training and ongoing supervision for therapists are considered as interventions that may increase acceptance of eCBT as a valid treatment option.
Two‐Mode Ionospheric Disturbances Following the 2005 Northern California Offshore Earthquake From GPS Measurements
Authors: Jin Shuanggen
Published: August 2018

Seismo‐ionospheric anomalies have been reported, while its disturbance modes, patterns, and mechanism are very complex for different kinds of earthquakes. The earthquake with Mw = 7.2 occurred off the coast of Northern California with strike‐slip faulting on 15 June 2005, which may provide a new insight on ionospheric disturbance waves and patterns from dense Global Positioning System (GPS) observations. In this paper, the detailed seismic ionospheric disturbance modes and characteristics are investigated from dense GPS observations following the 2005 Northern California offshore earthquake. Around 10 min after the earthquake, significant ionospheric disturbances are observed by GPS total electron content (TEC). Furthermore, two‐mode ionospheric disturbances are clearly found with two speeds, 1.51 and 2.31 km/s. The slow‐propagating mode has an amplitude of 0.02–0.04 total electron content unit (TECU), while the fast‐propagating mode has an amplitude of 0.1–0.2 TECU. The frequency spectrogram of the slow mode is around 3.7 mHz, while typical frequency of the fast mode is about 5.3 mHz. The fast‐propagating mode is close to the speed of the seismic Rayleigh wave, which is the up propagating secondary acoustic wave triggered by the Rayleigh wave. The slow mode ionospheric disturbance is propagating horizontally as the acoustic wave at the ionospheric level, which is caused by the fault rupture in focal regions.
Nuclear YAP localization as a key regulator of podocyte function
Authors: Bonse Jakob , Wennmann Dirk Oliver , Kremerskothen Joachim , Weide Thomas , Michgehl Ulf , Pavenstädt Hermann , Vollenbröker Beate
Published: August 2018

Podocytes are crucial for the establishment of the blood-urine filtration barrier in the glomeruli of the kidney. These cells are mainly affected during glomerulopathies causing proteinuria and kidney function impairment. Ongoing podocyte injury leads to podocyte loss, finally followed by end-stage kidney disease. Podocytes display a predominant nuclear localization of YAP (Yes-associated protein), one effector protein of the Hippo pathway, which regulates the balance between proliferation, differentiation, and apoptosis in cells. Nuclear active YAP seems to be critical for podocyte survival in vivo and in vitro. We can show here that different treatments leading to sequestration of YAP into the cytoplasm in podocytes, like decreased rigidity of the substrate, incubation with dasatinib, or overexpression of Hippo pathway members result in the induction of apoptosis. A RNA sequencing analysis of large tumor suppressor kinase 2 (LATS2) overexpressing podocytes confirmed a significant upregulation of apoptotic genes. The downregulation of Hippo pathway components suggests a feedback mechanism in podocytes. Noteworthy was the regulation of genes involved in cell–cell junction, the composition of the extracellular space, and cell migration. This suggests an influence of Hippo pathway activity on podocyte integrity. As focal segmental glomerulopathy (FSGS) goes along with an activation of the Hippo pathway in podocytes, a comparison of our data with two independent studies of transcriptional regulation in human FSGS glomeruli obtained from the Nephroseq database was performed. This comparison affirmed a multitude of consistent transcriptional changes concerning the regulation of genes influencing apoptosis and the Hippo signaling pathway as well as cell junction formation and cell migration. The link between Hippo pathway activation in podocytes and the regulation of junction and migration processes in vivo might be a fundamental mechanism of glomerular sclerosis and loss of renal function.
Long noncoding RNA NEAT1, regulated by LIN28B, promotes cell proliferation and migration through sponging miR-506 in high-grade serous ovarian cancer
Authors: Yong Wu , Yu Deng , Jun Zhu , Yachen Duan , Weiwei Weng , Midie Xu , Xingzhu Ju , Xiaohua Wu
Published: August 2018

The aberrant expression of long noncoding RNAs (lncRNAs) has been reported frequently in specific cancers, including high-grade serous ovarian cancer (HGSOC). The purpose of the present study was to explore the clinical significance and underlying mechanisms of a significantly dysregulated lncRNA (NEAT1) in HGSOC. Our results showed that elevated NEAT1 expression in human HGSOC specimens correlated with a poor prognosis. Functional experiments demonstrated that knockdown of NEAT1 significantly prohibited ovarian cancer cell proliferation and invasion in vitro and restrained tumor growth in vivo. LIN28B was identified by bioinformatics analysis along with experimental evidence as a direct actor that enhanced NEAT1 stability. A rescue functional assay confirmed that the LIN28B/NEAT1 axis contributed to oncogenic functions in ovarian cancer cells. Moreover, gene expression profile data and dual luciferase reporter assay results demonstrated that NEAT1 functioned as a competing endogenous RNA (ceRNA) for miR-506 to promote cell proliferation and migration. Taken together, our results showed that NEAT1, stabilized by LIN28B, promoted HGSOC progression by sponging miR-506. Thus, NEAT1 can be regarded as a vital diagnostic biomarker for HGSOC and a therapeutic target.
JAZF1 ameliorates age and diet-associated hepatic steatosis through SREBP-1c -dependent mechanism
Authors: Wei Qin , Zhou Baoyong , Yang Gangyi , Hu Wenjing , Zhang Lili , Liu Rui , Li Minyan , Wang Kuan , Gu Harvest F. , Guan Youfei , Zhu Zhiming , Zheng Hongting , Peng Jun , Li Ling
Published: August 2018

JAZF zinc finger 1 (JAZF1) is involved in glucose and lipid metabolisms. However, its role in aging- and nutrient-related hepatic steatosis is unclear. In the current study, we demonstrated that JAZF1 expression was markedly down-regulated in obesity-associated mice and nonalcoholic fatty liver disease (NAFLD) patients. During aging, JAZF1 expression was gradually down-regulated in both C57BL/6 J and JAZF1-Tg mice. In JAZF1-Tg mice, body fat content and hepatosteatosis were protected from HFD-induced steatosis, and accompanied by decreased lipogenesis gene expression. The inhibitory effects of hepatic steatosis in JAZF1-Tg mice, however, were disappeared during aging. In hepatocytes, over-expression of JAZF1 attenuated, while knockdown of JAZF1 enhanced the expression of lipogenesis genes. The over-expressing of JAZF1 in hepatocytes displayed the increased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and decreased sterol regulatory element-binding protein 1c (SREBP-1c) expression. The roles of JAZF1 were partially attenuated by Compound C. Mechanistically, JAZF1 suppressed SREBP-1c expression through the inhibition of transcriptional activity of liver X receptor response elements (LXREs) in the SREBP-1c promoter. Data illustrate that JAZF1 may have a crucial role in the regulation of age and nutrient-associated hepatosteatosis through an AMPK/SREBP-1c-dependent mechanism.
ID1-induced p16/IL6 axis activation contributes to the resistant of hepatocellular carcinoma cells to sorafenib
Authors: Niu Lei-lei , Cheng Chuan-le , Li Ming-Yue , Yang Sheng-li , Hu Bao-guang , Chong Charing C. N. , Chan Stephen L. , Ren Jianwei , Chen George G. , Lai Paul B. S.
Published: August 2018

Sorafenib is the only approved drug for the treatment of advanced hepatocellular carcinoma (HCC). However, its efficacy is limited by the emergence of primary and/or acquired resistance. Senescence-associated secretory phenotype (SASP)-mediated chemo-resistance, which depends on the secreted bioactive molecules, has attracted increasing attention but never revealed in HCC. In this study, we investigated the effect of SASP-related p16/IL6 axis on sorafenib resistance in HCC. Initially, we noticed that HCC cells with a high level of p16/IL6 axis exhibited a low sensitivity to sorafenib. Further in vivo and in vitro studies demonstrated that such a primary resistance resulted from ID1-mediated activation of p16/IL6 axis. Overexpression of ID1 or IL6 blocking in sorafenib-resistant HCC cells could increase the cytotoxicity of sorafenib. Moreover, SASP-related p16/IL6 axis contributed to the formation of acquired resistance in cells received long-term exposure to sorafenib. In acquired sorafenib-resistant cells, ID1 low expression, p16/IL6 axis up-regulation, and AKT phosphorylation activation were observed. A reduced cytotoxicity of sorafenib was detected when sorafenib-sensitive cells incubated with conditioned media from the resistant cells, accompanied by the stimulation of AKT phosphorylation. The reversal of sorafenib resistance could be achieved through ID1 overexpression, IL6 blocking, and AKT pathway inhibition. Our study reveals that SASP-related p16/IL6 axis activation is responsible for sorafenib resistance, which will be a novel strategy to prevent the drug resistance.
Exosomal miR-21-5p derived from gastric cancer promotes peritoneal metastasis via mesothelial-to-mesenchymal transition
Authors: Li Qiang , Li Bowen , Li Qing , Wei Song , He Zhongyuan , Huang Xiaoxu , Wang Lu , Xia Yiwen , Xu Zhipeng , Li Zheng , Wang Weizhi , Yang Li , Zhang Diancai , Xu Zekuan
Published: August 2018

Peritoneal metastasis is a primary metastatic route for gastric cancers, and the mechanisms underlying this process are still unclear. Peritoneal mesothelial cells (PMCs) undergo mesothelial-to-mesenchymal transition (MMT) to provide a favorable environment for metastatic cancer cells. In this study, we investigated how the exosomal miR-21-5p induces MMT and promotes peritoneal metastasis. Gastric cancer (GC)-derived exosomes were identified by transmission electron microscopy and western blot analysis, then the uptake of exosomes was confirmed by PKH-67 staining. The expression of miR-21-5p and SMAD7 were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot, and the interactions between miR-21-5p and its target genes SMAD7 were confirmed by Luciferase reporter assays. The MMT of PMCs was determined by invasion assays, adhesion assays, immunofluorescent assay, and western blot. Meanwhile, mouse model of tumor peritoneal dissemination model was performed to investigate the role of exosomal miR-21-5p in peritoneal metastasis in vivo. We found that PMCs could internalize GC-derived exosomal miR-21-5p and led to increased levels of miR-21-5p in PMCs. Through various types of in vitro and in vivo assays, we confirmed that exosomal miR-21-5p was able to induce MMT of PMCs and promote tumor peritoneal metastasis. Moreover, our study revealed that this process was promoted by exosomal miR-21-5p through activating TGF-β/Smad pathway via targeting SMAD7. Altogether, our data suggest that exosomal miR-21-5p induces MMT of PMCs and promote cancer peritoneal dissemination by targeting SMAD7. The exosomal miR-21-5p may be a novel therapeutic target for GC peritoneal metastasis.
Long non-coding RNA DSCR8 acts as a molecular sponge for miR-485-5p to activate Wnt/β-catenin signal pathway in hepatocellular carcinoma
Authors: Wang Yufeng , Sun Liankang , Wang Liang , Liu Zhikui , Li Qing , Yao Bowen , Wang Cong , Chen Tianxiang , Tu Kangsheng , Liu Qingguang
Published: August 2018

Previous evidences reveal that long non-coding RNA (lncRNA) down syndrome critical region 8 (DSCR8) involves in the progression of multiple cancers. However, the exact expression, function, and mechanism of DSCR8 in hepatocellular carcinoma (HCC) remain uncovered. In this study, real-time PCR in HCC tissues and cell lines indicated that DSCR8 expression was upregulated, while miR-485-5p was downregulated. MTT assay, plate clone formation, Edu assay, flow cytometry, and in vivo experiments indicated that DSCR8 promoted HCC cell proliferation and cycle, whereas accelerated cell apoptosis. Luciferase reporter gene assay, RIP assay, and rescue experiments demonstrated that DSCR8 functioned as a competing endogenous RNA (ceRNA) by sponging miR-485-5p in HCC cells. Furthermore, gain- and loss-of-function studies showed that miR-485-5p activated Wnt/β-catenin signal pathway by targeting Frizzled-7 (FZD7). Moreover, DSCR8 activated Wnt/β-catenin signal pathway to promote HCC progression by DSCR8/miR-485-5p/FZD7 axis. Statistical analysis revealed that DSCR8 and miR-485-5p were closely related to some malignant clinicopathological features and 5-year survival rates of HCC patients. Taken together, the present study reports for the first time that DSCR8 activates Wnt/β-catenin signal pathway to promote HCC progression by DSCR8/miR-485-5p/FZD7 axis. The findings provide promising and valuable strategies for targeted therapy of HCC.
JAM-A knockdown accelerates the proliferation and migration of human keratinocytes, and improves wound healing in rats via FAK/Erk signaling
Authors: Wang Yunchuan , Zheng Jianping , Han Yue , Zhang Yijie , Su Linlin , Hu Dahai , Fu Xiaobing
Published: August 2018

Junctional adhesion molecule-A (JAM-A) belongs to the immunoglobulin superfamily, it predominantly exists at the tight junctions of epithelial and endothelial cells. JAM-A is known to regulate leukocyte trans-endothelial migration, however, how it affects the proliferation and migration of keratinocytes, the two essential steps during wound healing, has less been explored. In this study, we showed that JAM-A was significantly expressed in normal skin epidermis. RNAi-mediated JAM-A knockdown remarkably promoted the proliferation and migration of keratinocytes. We also found that loss of JAM-A increased the protein levels of p-FAK, p-Erk1/2, and p-JNK; however, FAK inhibitor PF-562271 restrained the expression of p-FAK and p-Erk1/2 elevated by JAM-A RNAi, but not p-JNK, and also slowed down keratinocyte proliferation and migration. Finally, in a rat wound model we showed that absence of JAM-A significantly promoted the wound healing process, while the use of PF-562271 or Erk1/2 inhibitor PD98059 repressed those effects. These data collectively demonstrate that suppressing JAM-A expression could promote the proliferation and migration of keratinocytes and accelerate the healing process of rat skin wounds, potentially via FAK/Erk pathway, indicating that JAM-A might serve as a potential therapeutic target for the treatment of chronic refractory wounds.
Tolerance to sustained activation of the cAMP/Creb pathway activity in osteoblastic cells is enabled by loss of p53
Authors: Walia Mannu K. , Taylor Scott , Ho Patricia W. M. , Martin T. John , Walkley Carl R.
Published: August 2018

The loss of p53 function is a central event in the genesis of osteosarcoma (OS). How mutation of p53 enables OS development from osteoblastic lineage cells is poorly understood. We and others have reported a key role for elevated and persistent activation of the cAMP/PKA/Creb1 pathway in maintenance of OS. In view of the osteoblast lineage being the cell of origin of OS, we sought to determine how these pathways interact within the context of the normal osteoblast. Normal osteoblasts (p53 WT) rapidly underwent apoptosis in response to acute elevation of cAMP levels or activity, whereas p53-deficient osteoblasts tolerated this aberrant cAMP/Creb level and activity. Using the p53 activating small-molecule Nutlin-3a and cAMP/Creb1 activator forskolin, we addressed the question of how p53 responds to the activation of cAMP. We observed that p53 acts dominantly to protect cells from excessive cAMP accumulation. We identify a Creb1-Cbp complex that functions together with and interacts with p53. Finally, translating these results we find that a selective small-molecule inhibitor of the Creb1-Cbp interaction demonstrates selective toxicity to OS cells where this pathway is constitutively active. This highlights the cAMP/Creb axis as a potentially actionable therapeutic vulnerability in p53-deficient tumors such as OS. These results define a mechanism through which p53 protects normal osteoblasts from excessive or abnormal cAMP accumulation, which becomes fundamentally compromised in OS.
Disentangling astroglial physiology with a realistic cell model in silico
Authors: Savtchenko Leonid P. , Bard Lucie , Jensen Thomas P. , Reynolds James P. , Kraev Igor , Medvedev Nikolay , Stewart Michael G. , Henneberger Christian , Rusakov Dmitri A.
Published: August 2018

Electrically non-excitable astroglia take up neurotransmitters, buffer extracellular K+and generate Ca2+signals that release molecular regulators of neural circuitry. The underlying machinery remains enigmatic, mainly because the sponge-like astrocyte morphology has been difficult to access experimentally or explore theoretically. Here, we systematically incorporate multi-scale, tri-dimensional astroglial architecture into a realistic multi-compartmental cell model, which we constrain by empirical tests and integrate into the NEURON computational biophysical environment. This approach is implemented as a flexible astrocyte-model builder ASTRO. As a proof-of-concept, we explore an in silico astrocyte to evaluate basic cell physiology features inaccessible experimentally. Our simulations suggest that currents generated by glutamate transporters or K+channels have negligible distant effects on membrane voltage and that individual astrocytes can successfully handle extracellular K+hotspots. We show how intracellular Ca2+buffers affect Ca2+waves and why the classical Ca2+sparks-and-puffs mechanism is theoretically compatible with common readouts of astroglial Ca2+imaging.
Inducing drop to bubble transformation via resonance in ultrasound
Authors: Zang Duyang , Li Lin , Di Wenli , Zhang Zehui , Ding Changlin , Chen Zhen , Shen Wei , Binks Bernard P. , Geng Xingguo
Published: August 2018

Bubble formation plays an important role in industries concerned with mineral flotation, food, cosmetics, and materials, which requires additional energy to produce the liquid–gas interfaces. A naturally observed fact is, owing to the effect of surface tension, a bubble film tends to retract to reduce its surface area. Here we show a “reverse” phenomenon whereby a drop is transformed into a bubble using acoustic levitation via acoustic resonance. Once the volume of the cavity encapsulated by the buckled film reaches a critical value V*, resonance occurs and an abrupt inflation is triggered, leading to the formation of a closed bubble. Experiments and simulations both reveal that V* decreases with increasing acoustic frequency, which agrees well with acoustic resonance theory. The results afford enlightening insights into acoustic resonance and highlight its role in manipulating buckled fluid–fluid interfaces, providing a reference for fabricating unique core–shell-like materials.
Single reach plans in dorsal premotor cortex during a two-target task
Authors: Dekleva Brian M. , Kording Konrad P. , Miller Lee E.
Published: August 2018

In many situations, we are faced with multiple potential actions, but must wait for more information before knowing which to perform. Movement scientists have long asked whether in these delayed-response situations the brain plans both potential movements simultaneously, or if it simply chooses one and then switches later if necessary. To answer this question, we used simultaneously recorded activity from populations of neurons in macaque dorsal premotor cortex to track moment-by-moment deliberation between two potential reach targets. We found that the neural activity only ever indicated a single-reach plan (with some targets favored more than others), and that initial plans often predicted the monkeys’ behavior on both Free-Choice trials and incorrect Cued trials. Our results suggest that premotor cortex plans only one option at a time, and that decisions are strongly influenced by the initial response to the available set of movement options.
Dynamic earthquake rupture preserved in a creeping serpentinite shear zone
Authors: Tarling Matthew S. , Smith Steven A. F. , Viti Cecilia , Scott James M.
Published: August 2018

Laboratory experiments on serpentinite suggest that extreme dynamic weakening at earthquake slip rates is accompanied by amorphisation, dehydration and possible melting. However, hypotheses arising from experiments remain untested in nature, because earthquake ruptures have not previously been recognised in serpentinite shear zones. Here we document the progressive formation of high-temperature reaction products that formed by coseismic amorphisation and dehydration in a plate boundary-scale serpentinite shear zone. The highest-temperature products are aggregates of nanocrystalline olivine and enstatite, indicating minimum peak coseismic temperatures of ca. 925 ± 60 °C. Modelling suggests that frictional heating during earthquakes of magnitude 2.7–4 can satisfy the petrological constraints on the coseismic temperature profile, assuming that coseismic fluid storage capacity and permeability are increased by the development of reaction-enhanced porosity. Our results indicate that earthquake ruptures can propagate through serpentinite shear zones, and that the signatures of transient frictional heating can be preserved in the fault rock record.
Ap4 is rate limiting for intestinal tumor formation by controlling the homeostasis of intestinal stem cells
Authors: Jaeckel Stephanie , Kaller Markus , Jackstadt Rene , Götz Ursula , Müller Susanna , Boos Sophie , Horst David , Jung Peter , Hermeking Heiko
Published: August 2018

The gene encoding the transcription factor TFAP4/AP4 represents a direct target of the c-MYC oncoprotein. Here, we deleted Ap4 in ApcMin mice, a preclinical model of inherited colorectal cancer. Ap4 deficiency extends their average survival by 110 days and decreases the formation of intestinal adenomas and tumor-derived organoids. The effects of Ap4 deletion are presumably due to the reduced number of functional intestinal stem cells (ISCs) amenable to adenoma-initiating mutational events. Deletion of Ap4 also decreases the number of colonic stem cells and increases the number of Paneth cells. Expression profiling revealed that ISC signatures, as well as the Wnt/β-catenin and Notch signaling pathways are downregulated in Ap4-deficient adenomas and intestinal organoids. AP4-associated signatures are conserved between murine adenomas and human colorectal cancer samples. Our results establish Ap4 as rate-limiting mediator of adenoma initiation, as well as regulator of intestinal and colonic stem cell and Paneth cell homeostasis.
The mitotic spindle is chiral due to torques within microtubule bundles
Authors: Novak Maja , Polak Bruno , Simunić Juraj , Boban Zvonimir , Kuzmić Barbara , Thomae Andreas W. , Tolić Iva M. , Pavin Nenad
Published: August 2018

Mitosis relies on forces generated in the spindle, a micro-machine composed of microtubules and associated proteins. Forces are required for the congression of chromosomes to the metaphase plate and their separation in anaphase. However, besides forces, torques may exist in the spindle, yet they have not been investigated. Here we show that the spindle is chiral. Chirality is evident from the finding that microtubule bundles in human spindles follow a left-handed helical path, which cannot be explained by forces but rather by torques. Kinesin-5 (Kif11/Eg5) inactivation abolishes spindle chirality. Our theoretical model predicts that bending and twisting moments may generate curved shapes of bundles. We found that bundles turn by about −2 deg µm−1 around the spindle axis, which we explain by a twisting moment of roughly −10 pNµm. We conclude that torques, in addition to forces, exist in the spindle and determine its chiral architecture.
A hexagon in Saturn’s northern stratosphere surrounding the emerging summertime polar vortex
Authors: Fletcher L. N. , Orton G. S. , Sinclair J. A. , Guerlet S. , Read P. L. , Antuñano A. , Achterberg R. K. , Flasar F. M. , Irwin P. G. J. , Bjoraker G. L. , Hurley J. , Hesman B. E. , Segura M. , Gorius N. , Mamoutkine A. , Calcutt S. B.
Published: August 2018

Saturn’s polar stratosphere exhibits the seasonal growth and dissipation of broad, warm vortices poleward of ~75° latitude, which are strongest in the summer and absent in winter. The longevity of the exploration of the Saturn system by Cassini allows the use of infrared spectroscopy to trace the formation of the North Polar Stratospheric Vortex (NPSV), a region of enhanced temperatures and elevated hydrocarbon abundances at millibar pressures. We constrain the timescales of stratospheric vortex formation and dissipation in both hemispheres. Although the NPSV formed during late northern spring, by the end of Cassini’s reconnaissance (shortly after northern summer solstice), it still did not display the contrasts in temperature and composition that were evident at the south pole during southern summer. The newly formed NPSV was bounded by a strengthening stratospheric thermal gradient near 78°N. The emergent boundary was hexagonal, suggesting that the Rossby wave responsible for Saturn’s long-lived polar hexagon—which was previously expected to be trapped in the troposphere—can influence the stratospheric temperatures some 300 km above Saturn’s clouds.
Understanding 6th-century barbarian social organization and migration through paleogenomics
Authors: Amorim Carlos Eduardo G. , Vai Stefania , Posth Cosimo , Modi Alessandra , Koncz István , Hakenbeck Susanne , La Rocca Maria Cristina , Mende Balazs , Bobo Dean , Pohl Walter , Baricco Luisella Pejrani , Bedini Elena , Francalacci Paolo , Giostra Caterina , Vida Tivadar , Winger Daniel , von Freeden Uta , Ghirotto Silvia , Lari Martina , Barbujani Guido , Krause Johannes , Caramelli David , Geary Patrick J. , Veeramah Krishna R.
Published: August 2018

Despite centuries of research, much about the barbarian migrations that took place between the fourth and sixth centuries in Europe remains hotly debated. To better understand this key era that marks the dawn of modern European societies, we obtained ancient genomic DNA from 63 samples from two cemeteries (from Hungary and Northern Italy) that have been previously associated with the Longobards, a barbarian people that ruled large parts of Italy for over 200 years after invading from Pannonia in 568 CE. Our dense cemetery-based sampling revealed that each cemetery was primarily organized around one large pedigree, suggesting that biological relationships played an important role in these early medieval societies. Moreover, we identified genetic structure in each cemetery involving at least two groups with different ancestry that were very distinct in terms of their funerary customs. Finally, our data are consistent with the proposed long-distance migration from Pannonia to Northern Italy.
Comparing frontal eye field and superior colliculus contributions to covert spatial attention
Authors: Bollimunta Anil , Bogadhi Amarender R. , Krauzlis Richard J.
Published: August 2018

The causal roles of the frontal eye fields (FEF) and superior colliculus (SC) in spatial selective attention have not been directly compared. Reversible inactivation is an established method for testing causality but comparing results between FEF and SC is complicated by differences in size and morphology of the two brain regions. Here we exploited the fact that inactivation of FEF and SC also changes the metrics of saccadic eye movements, providing an independent benchmark for the strength of the causal manipulation. Using monkeys trained to covertly perform a visual motion-change detection task, we found that inactivation of either FEF or SC could cause deficits in attention task performance. However, SC-induced attention deficits were found with saccade changes half the size needed to get FEF-induced attention deficits. Thus, performance in visual attention tasks is vulnerable to loss of signals from either structure, but suppression of SC activity has a more devastating effect.
Image analysis with deep learning to predict breast cancer grade, ER status, histologic subtype, and intrinsic subtype
Authors: Couture Heather D. , Williams Lindsay A. , Geradts Joseph , Nyante Sarah J. , Butler Ebonee N. , Marron J. S. , Perou Charles M. , Troester Melissa A. , Niethammer Marc
Published: August 2018

RNA-based, multi-gene molecular assays are available and widely used for patients with ER-positive/HER2-negative breast cancers. However, RNA-based genomic tests can be costly and are not available in many countries. Methods for inferring molecular subtype from histologic images may identify patients most likely to benefit from further genomic testing. To identify patients who could benefit from molecular testing based on H&E stained histologic images, we developed an image analysis approach using deep learning. A training set of 571 breast tumors was used to create image-based classifiers for tumor grade, ER status, PAM50 intrinsic subtype, histologic subtype, and risk of recurrence score (ROR-PT). The resulting classifiers were applied to an independent test set (n = 288), and accuracy, sensitivity, and specificity of each was assessed on the test set. Histologic image analysis with deep learning distinguished low-intermediate vs. high tumor grade (82% accuracy), ER status (84% accuracy), Basal-like vs. non-Basal-like (77% accuracy), Ductal vs. Lobular (94% accuracy), and high vs. low-medium ROR-PT score (75% accuracy). Sampling considerations in the training set minimized bias in the test set. Incorrect classification of ER status was significantly more common for Luminal B tumors. These data provide proof of principle that molecular marker status, including a critical clinical biomarker (i.e., ER status), can be predicted with accuracy >75% based on H&E features. Image-based methods could be promising for identifying patients with a greater need for further genomic testing, or in place of classically scored variables typically accomplished using human-based scoring.
Promoter Usage and Dynamics in Vascular Smooth Muscle Cells Exposed to Fibroblast Growth Factor-2 or Interleukin-1β
Authors: Alhendi Ahmad M. N. , Patrikakis Margaret , Daub Carsten O. , Kawaji Hideya , Itoh Masayoshi , de Hoon Michiel , Carninci Piero , Hayashizaki Yoshihide , Arner Erik , Khachigian Levon M.
Published: August 2018

Smooth muscle cells (SMC) in blood vessels are normally growth quiescent and transcriptionally inactive. Our objective was to understand promoter usage and dynamics in SMC acutely exposed to a prototypic growth factor or pro-inflammatory cytokine. Using cap analysis gene expression (FANTOM5 project) we report differences in promoter dynamics for immediate-early genes (IEG) and other genes when SMC are exposed to fibroblast growth factor-2 or interleukin-1β. Of the 1871 promoters responding to FGF2 or IL-1β considerably more responded to FGF2 (68.4%) than IL-1β (18.5%) and 13.2% responded to both. Expression clustering reveals sets of genes induced, repressed or unchanged. Among IEG responding rapidly to FGF2 or IL-1β were FOS, FOSB and EGR-1, which mediates human SMC migration. Motif activity response analysis (MARA) indicates most transcription factor binding motifs in response to FGF2 were associated with a sharp induction at 1 h, whereas in response to IL-1β, most motifs were associated with a biphasic change peaking generally later. MARA revealed motifs for FOS_FOS{B,L1}_JUN{B,D} and EGR-1..3 in the cluster peaking 1 h after FGF2 exposure whereas these motifs were in clusters peaking 1 h or later in response to IL-1β. Our findings interrogating CAGE data demonstrate important differences in promoter usage and dynamics in SMC exposed to FGF2 or IL-1β.
Author Correction: Genomic diversity and macroecology of the crop wild relatives of domesticated pea
Authors: Smýkal Petr , Hradilová Iveta , Trněný Oldřich , Brus Jan , Rathore Abhishek , Bariotakis Michael , Das Roma Rani , Bhattacharyya Debjyoti , Richards Christopher , Coyne Clarice J. , Pirintsos Stergios
Published: August 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Epigenetic modulator UVI5008 inhibits MRSA by interfering with bacterial gyrase
Authors: Franci Gianluigi , Folliero Veronica , Cammarota Marcella , Zannella Carla , Sarno Federica , Schiraldi Chiara , de Lera Angel R. , Altucci Lucia , Galdiero Massimiliano
Published: August 2018

The impact of multi-drug resistant bacterial strains on human health is reaching worrisome levels. Over 2 million people are infected by resistant bacteria, and more than 700,000 people die each year because of the continuous spread of resistant strains. The development of new antibiotics and the prudent use of existing ones to prolong their lifespan require a constant effort by drug industries and healthcare workers. The re-purposing of existing drugs for use as antimicrobial agents would streamline the development of new antibacterial strategies. As part of this effort, we screened a panel of drugs previously characterized to be epigenetic modulators/pro-apoptotic/differentiative drugs. We selected a few compounds that alter Gram-positive growth. Among these, UVI5008, a derivative of the natural compound psammaplin A (Psa_A), was identified. The interaction of Psa_A with the DNA gyrase enzyme has been shown, and here, we hypothesized and confirmed the gyrase-specific activity by biochemical assays. UVI5008 exhibited growth inhibition activity against Staphylococcus aureus via structural modification of the cell wall, which was observed by SEM electron microscopy. Based on our findings, we propose UVI5008 as an alternative antibacterial compound against methicillin-resistant (Met.R) S. aureus strains.
Regulating exopolysaccharide gene wcaF allows control of Escherichia coli biofilm formation
Authors: Zhang Jingyun , Poh Chueh Loo
Published: August 2018

While biofilms are known to cause problems in many areas of human health and the industry, biofilms are important in a number of engineering applications including wastewater management, bioremediation, and bioproduction of valuable chemicals. However, excessive biofilm growth remains a key challenge in the use of biofilms in these applications. As certain amount of biofilm growth is required for efficient use of biofilms, the ability to control and maintain biofilms at desired thickness is vital. To this end, we developed synthetic gene circuits to control E. coli MG1655 biofilm formation by using CRISPRi/dCas9 to regulate a gene (wcaF) involved in the synthesis of colanic acid (CA), a key polysaccharide in E. coli biofilm extracellular polymeric substance (EPS). We showed that the biofilm formation was inhibited when wcaF was repressed and the biofilms could be maintained at a different thickness over a period of time. We also demonstrated that it is also possible to control the biofilm thickness spatially by inhibiting wcaF gene using a genetic light switch. The results demonstrate that the approach has great potential as a new means to control and maintain biofilm thickness in biofilm related applications.
Different associations of sufficient and vigorous physical activity with BMI in Northwest China
Authors: Liu Feng , Wang Weihua , Ma Jingang , Sa Rina , Zhuang Guihua
Published: August 2018

Physical activity (PA) plays an important role in maintaining a healthy weight. To develop targeted strategies that encourage physical activity, knowledge of associations between intensity of physical activity (PA) levels and body mass index (BMI) is essential. We aimed to examine the relationship between sufficient and vigorous PA and BMI distribution among adults in northwest China using quantile regression. We conducted a cross-sectional study in Shaanxi Province in 2013, using proportional probability sampling. BMI was calculated using measured height and weight. The Global Physical Activity Questionnaire was used to define and measure sufficient and vigorous PA. Associations of sufficient/vigorous PA and BMI were modelled using quantile regression. Mean BMI was 24.18 ± 3.51 and BMI distribution with age showed an inverse U shape. A total 9045 (88.97%) participants demonstrated sufficient PA and 3119 (30.68%) reported vigorous PA. After adjusting for relevant sociodemographic, dietary, and lifestyle parameters in quantile regression modelling, sufficient PA was positively associated with BMI score distribution from the 1st to 30th quantile, with β from 0.32 (95% confidence interval (CI): 0.07 to 0.63) to 0.85 (95% CI: 0.40 to 1.19). Vigorous PA was negatively associated with BMI score distribution from the 30th to 93th quantiles, with β from −0.18 (95% CI: −0.31 to −0.02) to −0.81 (95% CI: −1.10 to −0.45). Sufficient PA was positively associated with underweight and normal weight whereas vigorous PA was negatively associated with overweight and obesity.