bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacotherapy in paediatric heart failure: a Delphi process
Authors: Díez Cristina C. , Khalil Feras , Makowski Nina , Schwender Holger , Jovanovic Ida , Dalinghaus Michiel , Walsh Jennifer , van der Meulen Marijke , Bajcetic Milica , de Wildt Saskia N. , Läer Stephanie
Published: June 2019

Background:

Little evidence exists to support pharmacotherapeutic strategies for heart failure management in paediatrics. A recent Europe-wide survey suggests that this translates into substantial variability in clinical practice.

Objective:

To conduct a formal discussion among an expert group of paediatric cardiology physicians on controversial aspects regarding the pharmacotherapy of children heart failure, facilitate consensus, and highlight areas of agreement and disagreement.

Methods:

A two-round modified Delphi process was conducted between July and August 2015. Topics addressed were predominantly selected from the results of a previous Europe-wide survey. Fourteen statements were presented for discussion grouped under three categories; Angiotensin-converting-enzyme-inhibitors: Considerations for optimal dosage; Angiotensin-converting-enzyme-inhibitors for the management of CHDs; Neurohumoral antagonists for the management of dilated cardiomyopathy-related heart failure.

Results:

A total of 13 paediatricians dedicated to cardiology from across Europe and the United States of America completed the study; of them, 92% had a working experience in the field of more than 10 years and were working in a specific paediatric cardiology unit. Agreement on the acceptance/rejection of 11 statements was achieved. Results show agreement on the importance of a set of topics relevant to the standardisation of the therapy as well as consensus upon specific therapeutic attitudes.

Conclusions:

We have found areas of common thinking and motivation, which can provide a means of triggering scientific collaboration. Our results might also contribute to disseminate available paediatric evidence and promote reducing unjustified variability in everyday practice. Until solid evidence is available, other research methods can contribute to advancing the goal of safe and effective paediatric heart failure pharmacotherapy.
Evaluation of a non-diagnostic ‘Psychology of Emotions’ group intervention within a UK youth IAPT service: a mixed-methods approach
Authors: Howells Lawrence , Rose Alice , Gee Brioney , Clarke Tim , Carroll Ben , Harbrow Sam , Oliver Clio , Wilson Jon
Published: June 2019

Background:

A novel CBT-based intervention, tailored for young people, was developed in response to concerns about traditional diagnostically based approaches. Psychology of Emotions workshops use a normative approach to emotional difficulty instead of a diagnostic framework.

Aims:

To evaluate the acceptability and efficacy of Psychology of Emotions workshops within an IAPT service for young people aged 16–25 years.

Method:

This was a mixed-methods study, evaluating routinely collected self-report measures of depression and anxiety, and qualitative feedback forms. The main outcomes were rates of attendance, change in symptom severity, and participant views of the intervention.

Results:

From January to September 2016, 595 young people were invited to attend the Psychology of Emotions workshops, of whom 350 (58.8%) attended at least one session. Young people who attended all six sessions (8.1%) experienced significant reductions in self-reported anxiety (d = .72) and depression (d = .58) and 35.5% were classified as recovered at completion. Those who attended at least two sessions (41.3%) reported smaller but significant improvements in anxiety (d = .42) and depression (d = .45); 22.0% were classified as recovered at the last session attended. Participants provided largely positive feedback about the intervention.

Conclusion:

Psychology of Emotions is a promising treatment option, delivered outside of a diagnostic framework, for young people with mild to moderate mental health difficulties seen within IAPT services. Better understanding reasons for non-attendance might enable the intervention to be made accessible to more young people.
Latent Classes of Cognitive Functioning Among Depressed Older Adults Without Dementia
Authors: Morin Ruth T. , Insel Philip , Nelson Craig , Butters Meryl , Bickford David , Landau Susan , Saykin Andrew , Weiner Michael , Mackin R. Scott ,   the ADNI Depression Project
Published: June 2019

Objective:

Use latent class analysis (LCA) to identify patterns of cognitive functioning in a sample of older adults with clinical depression and without dementia and assess demographic, psychiatric, and neurobiological predictors of class membership.

Method:

Neuropsychological assessment data from 121 participants in the Alzheimer’s Disease Neuroimaging Initiative-Depression project (ADNI-D) were analyzed, including measures of executive functioning, verbal and visual memory, visuospatial and language functioning, and processing speed. These data were analyzed using LCA, with predictors of class membership such as depression severity, depression and treatment history, amyloid burden, and APOE e4 allele also assessed.

Results:

A two-class model of cognitive functioning best fit the data, with the Lower Cognitive Class (46.1% of the sample) performing approximately one standard deviation below the Higher Cognitive Class (53.9%) on most tests. When predictors of class membership were assessed, carrying an APOE e4 allele was significantly associated with membership in the Lower Cognitive Class. Demographic characteristics, age of depression onset, depression severity, history of psychopharmacological treatment for depression, and amyloid positivity did not predict class membership.

Conclusion:

LCA allows for identification of subgroups of cognitive functioning in a mostly cognitively intact late life depression (LLD) population. One subgroup, the Lower Cognitive Class, more likely to carry an APOE e4 allele, may be at a greater risk for subsequent cognitive decline, even though current performance on neuropsychological testing is within normal limits. These findings have implications for early identification of those at greatest risk, risk factors, and avenues for preventive intervention.
The effects of voluntary front-of-pack nutrition labels on volume shares of products: the case of the Dutch Choices
Authors: Smed Sinne , Edenbrandt Anna K , Jansen Léon
Published: June 2019

Objective:

The study examines the impact of a front-of-pack label (Dutch Choices) on household purchase patterns.

Design:

Change in households’ volume share of products eligible for the label (treatment group) is estimated as a function of changes in the market share of products displaying the label (treatment), while controlling for other relevant factors.

Setting:

Home-scan data for five food categories, subdivided into eighteen food groups, for households participating in a Dutch consumer panel. The data are from the period 2005 to 2009, which includes the date of the introduction of the Choices label.

Participants:

Between 831 and 7216 households from all over the Netherlands.

Results:

An increase in the market share of products displaying the label led to an increase in the volume share purchased of products eligible for the label for dairy products, yoghurts and for sauces. For some of the products, the partial effect is considerable (e.g. a 10 percentage point (pp) increase in the share of products displaying the label is associated with a 11·5 and 14·0 pp increase in the volume share of eligible products for chocolate milk and quark, respectively).

Conclusions:

The results suggest a positive effect from the presence of the Choices label on the volume share of eligible products purchased. Provided that eligible products are healthier than non-eligible products, the Choices label is a good guide for consumers in order to help them make healthier food choices. The positive effect is found mainly in food groups with a mix of both healthy and unhealthy food products.
Validation of the Mindful Self-Care Scale (MSCS) and development of the Brief-MSCS among hospice and healthcare professionals: a confirmatory factor analysis approach to validation
Authors: Hotchkiss Jason T. , Cook-Cottone Catherine P.
Published: June 2019

Objective

In the emotionally intense field of healthcare, the ability to peacefully inhabit one's body, maintain good boundaries, and be fully present during care is essential. This study aimed to validate the recently developed Mindful Self-Care Scale (MSCS) among hospice and healthcare professionals and develop a brief version of the 33-item MSCS.

Method

A sample of hospice and healthcare professionals from all 50 states (n = 858) was used. A confirmatory factor analysis was run using a rigorous methodology for validation and item reduction to develop a brief version of the 33-item MSCS. The brief MSCS (B-MSCS) was developed by identifying items for exclusion through examination of conceptual overlap, descriptive statistics by detecting sources of improvement model fit using confirmatory factor analysis. Model modifications were done sequentially and with regard to theoretical considerations.

Result

The existing model, 33-item MSCS with six subscales, had good fit to the data with all indicators in acceptable ranges (chi-square/df = 3.08, df (480), p < 0.01, root mean square error of approximation = 0.059, comparative fit index = 0.915, Tucker and Lewis's index of fit = 0.907). Nine items were excluded on the basis of very low loadings and conceptual and empirical overlap with other items.

Significance of results

The final 24-item, B-MSCS model was consistent with the original conceptual model and had a closer fit to the data (chi-square/df = 1.85, df (215), p < 0.01, root mean square error of approximation = 0.041, comparative fit index = 0.961, Tucker and Lewis's index of fit = 0.955). In addition, the reliability, construct, and concurrent validity of the MSCS and B-MSCS were in the acceptable and good ranges, respectively. Mean and standard deviation of the MSCS and B-MSCS scores were similar; B-MSCS mean scores well approximated the MSCS scores. Informal mindful self-care, in the process of everyday life, was practiced more regularly and associated with increased wellness and reduced burnout risk than formal mind-body practices.
Harvest weed seed control of Italian ryegrass [Lolium perenne L. ssp. multiflorum (Lam.) Husnot], common ragweed (Ambrosia artemisiifolia L.), and Palmer amaranth (Amaranthus palmeri S. Watson)
Authors: Beam Shawn C. , Mirsky Steven , Cahoon Charlie , Haak David , Flessner Michael
Published: June 2019

Herbicide resistance is a major problem in United States and global agriculture, driving farmers to consider other methods of weed control. One of these methods is harvest weed seed control (HWSC), which has been demonstrated to be effective in Australia. HWSC studies were conducted across Virginia in 2017 and 2018, targeting Italian ryegrass in continuous winter wheat as well as common ragweed and Palmer amaranth in continuous soybean. These studies assessed the impact of HWSC (via weed seed removal) on weed populations in the next year’s crop compared with conventional harvest (weed seeds returned). HWSC reduced Italian ryegrass tillers compared with the conventional harvest at two locations in April (29% and 69%), but no difference was observed at a third location. At wheat harvest, HWSC at one location reduced Italian ryegrass seed heads (41 seed heads m−2) compared with conventional harvest (125 seed heads m−2). In soybean, before preplant herbicide applications and POST herbicide applications, HWSC reduced common ragweed densities by 22% and 26%, respectively, compared with the conventional harvest plots. By soybean harvest, no differences in common ragweed density, seed retention, or crop yield were observed, because of effectiveness of POST herbicides. No treatment differences were observed at any evaluation timing for Palmer amaranth, which is attributed to farmer weed management (i.e., effective herbicides) and low weed densities making any potential treatment differences difficult to detect. Across wheat and soybean, there were no differences observed in crop yield between treatments. Overall, HWSC was demonstrated to be a viable method to reduce Italian ryegrass and common ragweed populations.
Higher oxidative balance score is associated with better glycemic control among Iranian adults with type-2 diabetes
Authors: Golmohammadi Mona , Ayremlou Pravin , Zarrin Rasoul
Published: June 2019

Abstract. The oxidative balance score (OBS) is a measure of combined pro- and anti-oxidant exposure status, with a higher OBS representing a predominance of anti- over pro-oxidant exposures. We aimed to examine the association of OBS and glycemic control among Iranian adults with type-2 diabetes. This cross-sectional study was conducted among 476 adults with type-2 diabetes (mean age 56.2 y; 66.6% female). Fasting glycosylated hemoglobin (HbA1c) and serum glucose (FSG) levels were measured as markers of glycemic control. The OBS was calculated by combining information from a total of 18 a priori selected pro- and anti-oxidant components. These components were comprised of the following four categories: dietary anti-oxidants (i.e., dietary intakes of selenium, fiber, retinol, α-carotene, β-carotene, β-cryptoxanthin, lutein, lycopene, vitamin D, vitamin E, folate, and vitamin C); dietary pro-oxidants (i.e., dietary intakes of iron, saturated fatty acid, and poly-unsaturated fatty acid); non-dietary anti-oxidants (i.e., physical activity); and non-dietary pro-oxidants (i.e., smoking and obesity). After adjusting for several potential confounders in the analysis of covariance models, multivariable adjusted means of HbA1c and FSG of subjects in the highest tertile of OBS were significantly lower than those in the lowest tertile (for HbA1c: mean difference –0.73%; and for FSG: mean difference –10.2 mg/dL; both P < 0.050). The findings suggest that a higher OBS, indicating a predominance of anti- over pro-oxidant exposures, is associated with a better glycemic control among Iranian adults with type-2 diabetes. However, future prospective studies of adequate methodological quality are warranted to confirm these findings.
Endless Forams: >34,000 Modern Planktonic Foraminiferal Images for Taxonomic Training and Automated Species Recognition Using Convolutional Neural Networks
Authors: Hsiang Allison Y. , Brombacher Anieke , Rillo Marina C. , Mleneck‐Vautravers Maryline J. , Conn Stephen , Lordsmith Sian , Jentzen Anna , Henehan Michael J. , Metcalfe Brett , Fenton Isabel S. , Wade Bridget S. , Fox Lyndsey , Meilland Julie , Davis Catherine V. , Baranowski Ulrike , Groeneveld Jeroen , Edgar Kirsty M. , Movellan Aurore , Aze Tracy , Dowsett Harry J. , Miller C. Giles , Rios Nelson , Hull Pincelli M.
Published: June 2019

Planktonic foraminiferal species identification is central to many paleoceanographic studies, from selecting species for geochemical research to elucidating the biotic dynamics of microfossil communities relevant to physical oceanographic processes and interconnected phenomena such as climate change. However, few resources exist to train students in the difficult task of discerning amongst closely related species, resulting in diverging taxonomic schools that differ in species concepts and boundaries. This problem is exacerbated by the limited number of taxonomic experts. Here we document our initial progress toward removing these confounding and/or rate‐limiting factors by generating the first extensive image library of modern planktonic foraminifera, providing digital taxonomic training tools and resources, and automating species‐level taxonomic identification of planktonic foraminifera via machine learning using convolution neural networks. Experts identified 34,640 images of modern (extant) planktonic foraminifera to the species level. These images are served as species exemplars through the online portal Endless Forams (endlessforams.org) and a taxonomic training portal hosted on the citizen science platform Zooniverse (zooniverse.org/projects/ahsiang/endless‐forams/). A supervised machine learning classifier was then trained with ~27,000 images of these identified planktonic foraminifera. The best‐performing model provided the correct species name for an image in the validation set 87.4% of the time and included the correct name in its top three guesses 97.7% of the time. Together, these resources provide a rigorous set of training tools in modern planktonic foraminiferal taxonomy and a means of rapidly generating assemblage data via machine learning in future studies for applications such as paleotemperature reconstruction.
The Great Storm of May 1921: An Exemplar of a Dangerous Space Weather Event
Authors: Hapgood Mike
Published: June 2019

We reconstruct the timeline of the extreme space weather event of May 1921, reviewing a wealth of reports from scientific literature, databases, newspaper reports, and reports by historians and astronomers. A series of coronal mass ejections (CMEs) bombarded Earth between 13 and 16 May, as shown by a series of sudden commencements observed across the global network of magnetometers. These CMEs produced three major periods of geomagnetic activity. The first period followed the arrival of two CMEs on 13 May. These may have cleared much density from the inner heliosphere, enabling a subsequent CME to travel quickly to Earth and cause intense activity. Continuing moderate magnetic activity following the first period may also have preconditioned the magnetosphere so it responded strongly to that later CME. This arrived late on 14 May, driving a short period of very intense activity early on 15 May, including technological impacts indicative of strong geoelectric fields. Another CME arrived early on 16 May, driving intense activity similar to that on 13 May. We show how these impacts fit with scientific observations to give a timeline that can be used in worst‐case studies/benchmarks. We also show that some impacts were probably coincidental with the storm, but due to more prosaic faults. This sequence of preconditioning, intense geoelectric fields, and their impacts, plus coincidental faults, makes the 1921 event an excellent basis for building space weather scenarios. Such scenarios are vital scientific input to the development and implementation of policies for mitigation of severe space weather.
Recent mixing of Vibrio parahaemolyticus populations
Authors: Yang Chao , Pei Xiaoyan , Wu Yarong , Yan Lin , Yan Yanfeng , Song Yuqin , Coyle Nicola M , Martinez-Urtaza Jaime , Quince Christopher , Hu Qinghua , Jiang Min , Feil Edward , Yang Dajin , Song Yajun , Zhou Dongsheng , Yang Ruifu , Falush Daniel , Cui Yujun
Published: June 2019

Humans have profoundly affected the ocean environment but little is known about anthropogenic effects on the distribution of microbes. Vibrio parahaemolyticus is found in warm coastal waters and causes gastroenteritis in humans and economically significant disease in shrimps. Based on data from 1103 genomes of environmental and clinical isolates, we show that V. parahaemolyticus is divided into four diverse populations, VppUS1, VppUS2, VppX and VppAsia. The first two are largely restricted to the US and Northern Europe, while the others are found worldwide, with VppAsia making up the great majority of isolates in the seas around Asia. Patterns of diversity within and between the populations are consistent with them having arisen by progressive divergence via genetic drift during geographical isolation. However, we find that there is substantial overlap in their current distribution. These observations can be reconciled without requiring genetic barriers to exchange between populations if long-range dispersal has increased dramatically in the recent past. We found that VppAsia isolates from the US have an average of 1.01% more shared ancestry with VppUS1 and VppUS2 isolates than VppAsia isolates from Asia itself. Based on time calibrated trees of divergence within epidemic lineages, we estimate that recombination affects about 0.017% of the genome per year, implying that the genetic mixture has taken place within the last few decades. These results suggest that human activity, such as shipping, aquatic products trade and increased human migration between continents, are responsible for the change of distribution pattern of this species.
Transient receptor potential ion-channel subfamily V member 4: a potential target for cancer treatment
Authors: Yu Suyun , Huang Shuai , Ding Yushi , Wang Wei , Wang Aiyun , Lu Yin
Published: June 2019

The transient receptor potential ion-channel superfamily consists of nonselective cation channels located mostly on the plasma membranes of numerous animal cell types, which are closely related to sensory information transmission (e.g., vision, pain, and temperature perception), as well as regulation of intracellular Ca2+ balance and physiological activities of growth and development. Transient receptor potential ion channel subfamily V (TRPV) is one of the largest and most diverse subfamilies, including TRPV1–TRPV6 involved in the regulation of a variety of cellular functions. TRPV4 can be activated by various physical and chemical stimuli, such as heat, mechanical force, and phorbol ester derivatives participating in the maintenance of normal cellular functions. In recent years, the roles of TRPV4 in cell proliferation, differentiation, apoptosis, and migration have been extensively studied. Its abnormal expression has also been closely related to the onset and progression of multiple tumors, so TRPV4 may be a target for cancer diagnosis and treatment. In this review, we focused on the latest studies concerning the role of TRPV4 in tumorigenesis and the therapeutic potential. As evidenced by the effects on cancerogenesis, TRPV4 is a potential target for anticancer therapy.
The beneficial androgenic action of steroidal aromatase inactivators in estrogen-dependent breast cancer after failure of nonsteroidal drugs
Authors: Gao Lanyang , Bao Zheng , Deng Heng , Li Xiaofang , Li Jiamin , Rong Zuyuan , Yang Youzhe , Liu Ling , Nie Dan , Wang Guilin , Teichmann Alexander T. , Wieland F. Heinrich
Published: June 2019

Direct treatment of ER (+) breast cancer with Formestane diminishes the tumor within weeks. This is unlikely due to lack of estrogens alone. We proposed that it is the negative influence of androgens on the growth of ER(+) breast cancer. We investigated the influence of Formestane and Exemestane and of their major androgenic metabolites 4-hydroxytestosterone and 17-hydroexemestane on the proliferation of MCF-7 cells and ZR-75-1 cells. Inhibitory effects could be prevented by antiandrogens and siRNA. Activation of the AR in MCF-7 and U2-OS cells was tested by reporter gene assays. In vivo androgenicity was evaluated using the Hershberger assay. Influence on the cell cycle was demonstrated by flow-cytometry. Influence of androgens on the activity of CCND1 was demonstrated by Chip-qPCR. Antitumor activity was determined by topical treatment of DMBA tumors. We found that breast cancer cells can metabolize Formestane and Exemestane to androgenic compounds which inhibit proliferation. This can be explained by hindering the accessibility of CCND1 by histone modification. Androgenic metabolites can abolish the growth of DMBA-tumors and prevent the appearance of new tumors. The lack of cross-resistance between steroidal and nonsteroidal aromatase inhibitors is due to inhibitory effects of androgenic steroidal metabolites on the production of cyclin D1. These sterols not only inhibit proliferation of cancer cells but can also stop the growth of DMBA cancers upon direct absorption into the tumor. The quick and considerable effect on ER(+) tumors may open a new avenue for neodjuvant treatment.
Preso regulates NMDA receptor-mediated excitotoxicity via modulating nitric oxide and calcium responses after traumatic brain injury
Authors: Luo Peng , Li Xin , Wu Xiuquan , Dai Shuhui , Yang Yuefan , Xu Haoxiang , Jing Da , Rao Wei , Xu Hongyu , Gao Xiangyu , Fei Zhou , Lu Hongbing
Published: June 2019

Traumatic brain injury (TBI) has become a major health concern worldwide, and the poor outcome of TBI increases the need for therapeutic improvement. Secondary injuries following TBI, including excitotoxicity, lead to synaptic dysfunction and provide potential targets for intervention. Postsynaptic scaffold proteins, which are involved in the regulation of excitotoxicity after neuronal injury, play a crucial role in modulating synaptic function. Therefore, exploring the role of postsynaptic scaffold proteins in TBI might uncover new treatments. In this study, we demonstrated that downregulated expression of the postsynaptic scaffold protein Preso protects against neuronal injury after TBI in vitro and in vivo, and these effects are related to the inhibition of N-methyl-D-aspartate receptor (NMDAR) function. Further study showed that Preso facilitates signaling from NMDAR to nitric oxide (NO) and calcium (Ca2+) responses. First, the complex constituting NMDAR, postsynaptic density-95 (PSD-95), and neuronal nitric oxide synthase (nNOS) was shown to be involved in the Preso regulation of the NO response. Uncoupling the linkage between Preso and PSD-95 attenuated the stability of this complex and suppressed the regulatory effect of Preso on the NO response. In addition, phosphorylation of NMDAR by cyclin-dependent kinase 5 (CDK5) was shown to be responsible for the Preso-mediated Ca2+ response, which was dependent on the interaction between Preso and CDK5. These results suggested that the association of Preso with NMDAR signaling can serve as a target for neuroprotection against TBI.
Long noncoding RNA ANCR inhibits the differentiation of mesenchymal stem cells toward definitive endoderm by facilitating the association of PTBP1 with ID2
Authors: Li Jing , Yang Yanlei , Fan Junfen , Xu Haoying , Fan Linyuan , Li Hongling , Zhao Robert Chunhua
Published: June 2019

The generation of definitive endoderm (DE) cells in sufficient numbers is a prerequisite for cell-replacement therapy for liver and pancreatic diseases. Previously, we reported that human adipose-derived mesenchymal stem cells (hAMSCs) can be induced to DE lineages and subsequent functional cells. Clarifying the regulatory mechanisms underlying the fate conversion from hAMSCs to DE is helpful for developing new strategies to improve the differentiation efficiency from hAMSCs to DE organs. Long noncoding RNAs (lncRNAs) have been shown to play pivotal roles in developmental processes, including cell fate determination and differentiation. In this study, we profiled the expression changes of lncRNAs and found that antidifferentiation noncoding RNA (ANCR) was downregulated during the differentiation of both hAMSCs and embryonic stem cells (ESCs) to DE cells. ANCR knockdown resulted in the elevated expression of DE markers in hAMSCs, but not in ESCs. ANCR overexpression reduced the efficiency of hAMSCs to differentiate into DE cells. Inhibitor of DNA binding 2 (ID2) was notably downregulated after ANCR knockdown. ID2 knockdown enhanced DE differentiation, whereas overexpression of ID2 impaired this process in hAMSCs. ANCR interacts with RNA-binding polypyrimidine tract-binding protein 1 (PTBP1) to facilitate its association with ID2 mRNA, leading to increased ID2 mRNA stability. Thus, the ANCR/PTBP1/ID2 network restricts the differentiation of hAMSCs toward DE. Our work highlights the inherent discrepancies between hAMSCs and ESCs. Defining hAMSC-specific signaling pathways might be important for designing optimal differentiation protocols for directing hAMSCs toward DE.
Phosphatidic acid homeostasis regulated by a type-2 phosphatidic acid phosphatase represents a novel druggable target in malaria intervention
Authors: Kumar Sah Raj , Garg Swati , Dangi Poonam , Ponnusamy Kalaiarasan , Singh Shailja
Published: June 2019

Type-2 phosphatidic acid phosphatase (PAP2) a member of PAP2 superfamily mediates the conversion of phosphatidic acid (PA) to diacylglycerol (DAG) and thus plays a pivotal role in numerous cellular signaling processes in diverse organisms. An elevated level of intracellular PA is detrimental for the cell and induces cell death. In this study we identified and characterized a PAP2 homologue in Plasmodium falciparum, PfPAP2 and further elucidated its significance in regulation of PA homeostasis in parasite life cycle. PfPAP2 is expressed in the blood stage and harbors the canonical acid phosphatase domain (APD) with signature motifs. PfPAP2 catalyzes the dephosphorylation of PA to produce DAG and inorganic phosphate (Pi). Propranolol, a generic inhibitor of PAP2, inhibited the phosphatase activity of PfPAP2 by binding to the active site of APD domain as evident by in silico docking and confirmed by surface plasmon resonance (SPR) analysis. Inhibition of native PfPAP2 by propranolol led to rise in intracellular PA mediating disruption of intracellular PA homeostasis in parasites. The propranolol mediated inhibition of PfPAP2 directed early secretion of a micronemal Perforin like Protein, PfPLP1 leading to untimely permeabilization and host cell egress. The merozoites following premature egress were non-invasive and were attenuated to invade erythrocytes and cannot continue next cycle growth. This study demonstrates that disruption of PA homeostasis can cause growth retardation in malaria parasites, and thus its master regulator, PfPAP2, can serve as a very good molecular target for antimalarial chemotherapeutic interventions.
Trends in erectile dysfunction research from 2008 to 2018: a bibliometric analysis
Authors: Hui Jialiang , He Shuhua , Liu Ruiyu , Zeng Qinyu , Zhang Haibo , Wei Anyang
Published: June 2019

Insufficient penile erection to facilitate vaginal penetration is a medical condition referred to as erectile dysfunction (ED). By the year 2025, the number of ED cases across the world is expected to reach 322 million. There are numerous publications and studies in the field of ED over the past decades. Our aim is to comprehensively analyze the global scientific outputs of ED research and show the trends and hotspots in ED research. Data of publications were downloaded from the Web of Science Core Collection. We used CiteSpace IV and Excel 2016 to analyze literature information, including journals, countries/regions, institutes, authors, citation reports, and research frontiers. Until October 26, 2018, a total of 8880 papers in ED research were identified as published between 2008 and 2018. Journal of Sexual Medicine published the most articles. The United States contributed the most publications and occupied leading positions in H-index value and the number of ESI top papers. Maggi M owned the highest co-citations. The keyword “Oxidative stress” ranked first in the research front-line. The amount of articles published in ED research has been stable from 2008 to 2018. The United States showed enormous progress in ED research, and is still the dominant country. Oxidative stress, vardenafil, and late-onset hypogonadism were the latest research frontiers and should be paid more attention.
Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure
Authors: Cordero Pablo , Parikh Victoria N. , Chin Elizabeth T. , Erbilgin Ayca , Gloudemans Michael J. , Shang Ching , Huang Yong , Chang Alex C. , Smith Kevin S. , Dewey Frederick , Zaleta Kathia , Morley Michael , Brandimarto Jeff , Glazer Nicole , Waggott Daryl , Pavlovic Aleksandra , Zhao Mingming , Moravec Christine S. , Tang W. H. Wilson , Skreen Jamie , Malloy Christine , Hannenhalli Sridhar , Li Hongzhe , Ritter Scott , Li Mingyao , Bernstein Daniel , Connolly Andrew , Hakonarson Hakon , Lusis Aldons J. , Margulies Kenneth B. , Depaoli-Roach Anna A. , Montgomery Stephen B. , Wheeler Matthew T. , Cappola Thomas , Ashley Euan A.
Published: June 2019

Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure.
Urinary tract colonization is enhanced by a plasmid that regulates uropathogenic Acinetobacter baumannii chromosomal genes
Authors: Di Venanzio Gisela , Flores-Mireles Ana L. , Calix Juan J. , Haurat M. Florencia , Scott Nichollas E. , Palmer Lauren D. , Potter Robert F. , Hibbing Michael E. , Friedman Laura , Wang Bin , Dantas Gautam , Skaar Eric P. , Hultgren Scott J. , Feldman Mario F.
Published: June 2019

Multidrug resistant (MDR) Acinetobacter baumannii poses a growing threat to global health. Research on Acinetobacter pathogenesis has primarily focused on pneumonia and bloodstream infections, even though one in five A. baumannii strains are isolated from urinary sites. In this study, we highlight the role of A. baumannii as a uropathogen. We develop the first A. baumannii catheter-associated urinary tract infection (CAUTI) murine model using UPAB1, a recent MDR urinary isolate. UPAB1 carries the plasmid pAB5, a member of the family of large conjugative plasmids that represses the type VI secretion system (T6SS) in multiple Acinetobacter strains. pAB5 confers niche specificity, as its carriage improves UPAB1 survival in a CAUTI model and decreases virulence in a pneumonia model. Comparative proteomic and transcriptomic analyses show that pAB5 regulates the expression of multiple chromosomally-encoded virulence factors besides T6SS. Our results demonstrate that plasmids can impact bacterial infections by controlling the expression of chromosomal genes.
Skeletal muscle PGC-1α1 reroutes kynurenine metabolism to increase energy efficiency and fatigue-resistance
Authors: Agudelo Leandro Z. , Ferreira Duarte M. S. , Dadvar Shamim , Cervenka Igor , Ketscher Lars , Izadi Manizheh , Zhengye Liu , Furrer Regula , Handschin Christoph , Venckunas Tomas , Brazaitis Marius , Kamandulis Sigitas , Lanner Johanna T. , Ruas Jorge L.
Published: June 2019

The coactivator PGC-1α1 is activated by exercise training in skeletal muscle and promotes fatigue-resistance. In exercised muscle, PGC-1α1 enhances the expression of kynurenine aminotransferases (Kats), which convert kynurenine into kynurenic acid. This reduces kynurenine-associated neurotoxicity and generates glutamate as a byproduct. Here, we show that PGC-1α1 elevates aspartate and glutamate levels and increases the expression of glycolysis and malate-aspartate shuttle (MAS) genes. These interconnected processes improve energy utilization and transfer fuel-derived electrons to mitochondrial respiration. This PGC-1α1-dependent mechanism allows trained muscle to use kynurenine metabolism to increase the bioenergetic efficiency of glucose oxidation. Kat inhibition with carbidopa impairs aspartate biosynthesis, mitochondrial respiration, and reduces exercise performance and muscle force in mice. Our findings show that PGC-1α1 activates the MAS in skeletal muscle, supported by kynurenine catabolism, as part of the adaptations to endurance exercise. This crosstalk between kynurenine metabolism and the MAS may have important physiological and clinical implications.
Rearrangement of the transmembrane domain interfaces associated with the activation of a GPCR hetero-oligomer
Authors: Xue Li , Sun Qian , Zhao Han , Rovira Xavier , Gai Siyu , He Qianwen , Pin Jean-Philippe , Liu Jianfeng , Rondard Philippe
Published: June 2019

G protein-coupled receptors (GPCRs) can integrate extracellular signals via allosteric interactions within dimers and higher-order oligomers. However, the structural bases of these interactions remain unclear. Here, we use the GABAB receptor heterodimer as a model as it forms large complexes in the brain. It is subjected to genetic mutations mainly affecting transmembrane 6 (TM6) and involved in human diseases. By cross-linking, we identify the transmembrane interfaces involved in GABAB1-GABAB2, as well as GABAB1-GABAB1 interactions. Our data are consistent with an oligomer made of a row of GABAB1. We bring evidence that agonist activation induces a concerted rearrangement of the various interfaces. While the GB1-GB2 interface is proposed to involve TM5 in the inactive state, cross-linking of TM6s lead to constitutive activity. These data bring insight for our understanding of the allosteric interaction between GPCRs within oligomers.
Vertical saccades and antisaccades: complementary markers for motor and cognitive impairment in Parkinson’s disease
Authors: Waldthaler Josefine , Tsitsi Panagiota , Svenningsson Per
Published: June 2019

Previous studies provide partly contradictory results about the characteristics of saccades in PD and the possible effects of levodopa, which may be attributed to different study design regarding disease stages, medication state or cognitive functioning. We studied horizontal and vertical visually guided saccades (VGS) and antisaccades (AS) in 40 patients with PD with and without postural instability in On and Off medication state as well as in 20 healthy controls (HC). Motor and cognitive performance were assessed using UPDRS, Montreal Cognitive Assessment (MoCA) and Frontal Assessment Battery (FAB). The PD group showed decreased VGS amplitudes and increased vertical VGS and AS latencies. Only relatively few studies had assessed vertical saccades in PD so far. However, our results indicate that vertical saccadic amplitude may be a supportive marker in diagnosing PD since upwards gain demonstrated an AUC of 0.85 for the discrimination of PD and HC. Only more advanced patients in Hoehn & Yahr stage 3 executed higher numbers of AS errors than HC. Since the AS error rate correlated with FAB and MoCA scores, AS performance seems to reflect cognitive ability in PD. Furthermore, the correlation of AS latency with the UPDRS axial subscore promotes the recently highlighted connection between postural control and executive function in PD. Levodopa did not alter saccade amplitudes and had opposing effects on the initiation of VGS and AS: Levodopa intake prolonged VGS latency, but decreased AS latency. Possible mechanisms by which levodopa may be capable of partially reversing the impaired balance between voluntary and reflexive cortical saccade initiation of PD are discussed.
Optimization of Bone Scaffold Porosity Distributions
Authors: Poh Patrina S. P. , Valainis Dvina , Bhattacharya Kaushik , van Griensven Martijn , Dondl Patrick
Published: June 2019

Additive manufacturing (AM) is a rapidly emerging technology that has the potential to produce personalized scaffolds for tissue engineering applications with unprecedented control of structural and functional design. Particularly for bone defect regeneration, the complex coupling of biological mechanisms to the scaffolds’ properties has led to a predominantly trial-and-error approach. To mitigate this, shape or topology optimization can be a useful tool to design a scaffold architecture that matches the desired design targets, albeit at high computational cost. Here, we consider an efficient macroscopic optimization routine based on a simple one-dimensional time-dependent model for bone regeneration in the presence of a bioresorbable polymer scaffold. The result of the optimization procedure is a scaffold porosity distribution which maximizes the stiffness of the scaffold and regenerated bone system over the entire regeneration time, so that the propensity for mechanical failure is minimized.
Electric field tuning of spin splitting in topological insulator quantum dots doped with a single magnetic ion
Authors: Li Xiaojing , Yang Wen , Lin Liangzhong , Wu Zhenhua
Published: June 2019

We investigate theoretically the electron spin states in a disk-shaped topological insulator quantum dot (TIQD) containing a single magnetic Mn2+ ion. We demonstrate that the energy spectra and the density distributions of the symmetry-protected edge states in a HgTe TIQD can be modulated effectively by a single magnetic impurity Mn2+. Additionally, when an in-plane external electric field is applied., it not only tunes the spin splittings of edge states via the s(p)-d exchange interaction between the electron (hole) and the magnetic Mn2+ ion respectively, but also gives rise to the bright-to-dark transitions in the optical transition spectrum. Such spin properties of TIQDs with single Mn2+ ion as illustrated in this work could offer a new platform for topological electro-optical devices.
Ctt1 catalase activity potentiates antifungal azoles in the emerging opportunistic pathogen Saccharomyces cerevisiae
Authors: Martins Dorival , Nguyen Dao , English Ann M.
Published: June 2019

Fungi respond to antifungal drugs by increasing their antioxidant stress response. How this impacts antifungal efficacy remains controversial and not well understood. Here we examine the role of catalase activity in the resistance of Saccharomyces cerevisiae to the common antifungals, fluconazole and miconazole, for which we report minimum inhibitory concentrations (MICs) of 104 and 19 μM, respectively. At sub-MIC concentrations, fluconazole and miconazole stimulate catalase activity 2-3-fold but, unexpectedly, deletion of cytosolic catalase (ctt1) makes cells more resistant to these azoles and to clotrimazole, itraconazole and posaconazole. On the other hand, upregulating Ctt1 activity by preconditioning with 0.2 mM H2O2 potentiates miconazole 32-fold and fluconazole 4-fold. Since H2O2 preconditioning does not alter the resistance of ctt1Δ cells, which possess negligible catalase activity, we link azole potentiation with Ctt1 upregulation. In contrast, sod2Δ cells deleted for mitochondrial superoxide dismutase are 4–8-fold more azole sensitive than wild-type cells, revealing that Sod2 activity protects cells against azole toxicity. In fact, the ctt1Δ mutant has double the Sod2 activity of wild-type cells so ctt1 deletion increases azole resistance in part by Sod2 upregulation. Notably, deletion of peroxisomal/mitochondrial cta1 or cytosolic sod1 does not alter fluconazole or miconazole potency.
Iron-mediated aggregation and toxicity in a novel neuronal cell culture model with inducible alpha-synuclein expression
Authors: Bartels Martin , Weckbecker Daniel , Kuhn Peer-Hendrik , Ryazanov Sergey , Leonov Andrei , Griesinger Christian , Lichtenthaler Stefan F. , Bötzel Kai , Giese Armin
Published: June 2019

Parkinson’s disease (PD) represents an increasing problem in society. The oligomerization of alpha-synuclein (αSyn) is a suggested key event in its pathogenesis, yet the pathological modes of action remain to be fully elucidated. To identify potential disease-modifying therapeutics and to study αSyn-mediated toxic mechanisms, we established cell lines with inducible overexpression of different αSyn constructs: αSyn, αSyn coupled to the fluorescence protein Venus (αSyn-Venus), and αSyn coupled to the N-terminal or C-terminal part of Venus (V1S and SV2, respectively) for a bimolecular fluorescence complementation assay (BiFC). Inducibility was achieved by applying modified GAL4-UAS or Cre-loxP systems and addition of tebufenozide or 4-OH-tamoxifen, respectively. Expression constructs were stably integrated into the host genome of H4 neuroglioma cells by lentiviral transduction. We here demonstrate a detailed investigation of the expression characteristics of inducible H4 cells showing low background expression and high inducibility. We observed increased protein load and aggregation of αSyn upon incubation with DMSO and FeCl3along with an increase in cytotoxicity. In summary, we present a system for the creation of inducibly αSyn-overexpressing cell lines holding high potential for the screening for modulators of αSyn aggregation and αSyn-mediated toxicity.
Superintense Laser-driven Ion Beam Analysis
Authors: Passoni M. , Fedeli L. , Mirani F.
Published: June 2019

Ion beam analysis techniques are among the most powerful tools for advanced materials characterization. Despite their growing relevance in a widening number of fields, most ion beam analysis facilities still rely on the oldest accelerator technologies, with severe limitations in terms of portability and flexibility. In this work we thoroughly address the potential of superintense laser-driven proton sources for this application. We develop a complete analytical and numerical framework suitable to describe laser-driven ion beam analysis, exemplifying the approach for Proton Induced X-ray/Gamma-ray emission, a technique of widespread interest. This allows us to propose a realistic design for a compact, versatile ion beam analysis facility based on this novel concept. These results can pave the way for ground-breaking developments in the field of hadron-based advanced materials characterization.
Tear film lipid layer increase after diquafosol instillation in dry eye patients with meibomian gland dysfunction: a randomized clinical study
Authors: Fukuoka Shima , Arita Reiko
Published: June 2019

Diquafosol promotes secretion of tear fluid and mucin at the ocular surface and is administered for treatment of dry eye (DE). Tear film lipid layer is secreted from meibomian glands and stabilizes the tear film. We recently showed that diquafosol administration increased lipid layer thickness (LLT) for up to 60 min in normal human eyes. We here evaluated tear film lipid layer in DE patients (n = 47) with meibomian gland dysfunction (MGD) before as well as 30, 60, and 90 min after diquafosol administration. One drop of artificial tears or one drop of diquafosol was applied randomly to the eyes of each patient. Diquafosol significantly increased LLT at 30 (P < 0.001) and 60 (P = 0.042) min and noninvasive tear film breakup time for at least 90 min (P < 0.001 at each assessment point). Artificial tears had no such effect. Diquafosol significantly improved the tear interferometric pattern compared with artificial tears (P < 0.001 at each assessment point). A single topical administration of diquafosol thus improved LLT and tear film stability in DE patients with MGD, suggesting that diquafosol is a potential treatment not only for aqueous-deficient DE but also for evaporative DE associated with MGD.