bluuebunny/crossref_metadata_2025 huggingface dataset:
Cytosine, but not adenine, base editors induce genome-wide off-target mutations in rice
Authors: Jin Shuai , Zong Yuan , Gao Qiang , Zhu Zixu , Wang Yanpeng , Qin Peng , Liang Chengzhi , Wang Daowen , Qiu Jin-Long , Zhang Feng , Gao Caixia
Published: March 2019

Spotting off-targets from gene editing

Unintended genomic modifications limit the potential therapeutic use of gene-editing tools. Available methods to find off-targets generally do not work in vivo or detect single-nucleotide changes. Three papers in this issue report new methods for monitoring gene-editing tools in vivo (see the Perspective by Kempton and Qi). Wienert
et al.
followed the recruitment of a DNA repair protein to DNA breaks induced by CRISPR-Cas9, enabling unbiased detection of off-target editing in cellular and animal models. Zuo
et al.
identified off-targets without the interference of natural genetic heterogeneity by injecting base editors into one blastomere of a two-cell mouse embryo and leaving the other genetically identical blastomere unedited. Jin
et al.
performed whole-genome sequencing on individual, genome-edited rice plants to identify unintended mutations. Cytosine, but not adenine, base editors induced numerous single-nucleotide variants in both mouse and rice.

Science
, this issue p.
286
, p.
289
, p.
292
; see also p.
234
Linking lysosomes to stem cell differentiation
Authors: VanHook Annalisa M.
Published: February 2019

Lysosomal signaling enables stem cell differentiation by sequestering the transcription factor Tfe3 in the cytoplasm.
Generating Robust and Informative Nonclinical
In Vitro
and
In Vivo
Bacterial Infection Model Efficacy Data To Support Translation to Humans
Authors: Bulitta Jürgen B. , Hope William W. , Eakin Ann E. , Guina Tina , Tam Vincent H. , Louie Arnold , Drusano George L. , Hoover Jennifer L.
Published: March 2019

In June 2017, the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, organized a workshop entitled “Pharmacokinetics-Pharmacodynamics (PK/PD) for Development of Therapeutics against Bacterial Pathogens.” The aims were to discuss details of various PK/PD models and identify sound practices for deriving and utilizing PK/PD relationships to design optimal dosage regimens for patients. Workshop participants encompassed individuals from academia, industry, and government, including the United States Food and Drug Administration.
Methionine Limitation Impairs Pathogen Expansion and Biofilm Formation Capacity
Authors: Jochim A. , Shi T. , Belikova D. , Schwarz S. , Peschel A. , Heilbronner S.
Published: March 2019

New antibiotics that attack novel targets are needed to circumvent widespread resistance to conventional drugs. Bacterial anabolic pathways, such as the enzymes for biosynthesis of the essential amino acid methionine, have been proposed as potential targets. However, the eligibility of enzymes in these pathways as drug targets is unclear because metabolites might be acquired from the environment to overcome inhibition. We investigated the nutritional needs of methionine auxotrophs of the pathogens
Staphylococcus aureus
,
Pseudomonas aeruginosa
, and
Escherichia coli
. We found that each auxotrophic strain retained a growth disadvantage at methionine concentrations mimicking those available
in vivo
and showed that biofilm biomass was strongly influenced by endogenous methionine biosynthesis. Our experiments suggest that inhibition of the methionine biosynthesis pathway has deleterious effects even in the presence of external methionine. Therefore, additional efforts to validate the effects of methionine biosynthesis inhibitors
in vivo
are warranted.
A Noncanonical Function of Polycomb Repressive Complexes Promotes Human Cytomegalovirus Lytic DNA Replication and Serves as a Novel Cellular Target for Antiviral Intervention
Authors: Svrlanska Adriana , Reichel Anna , Schilling Eva-Maria , Scherer Myriam , Stamminger Thomas , Reuter Nina
Published: February 2019

Polycomb group (PcG) proteins are primarily known as transcriptional repressors that modify chromatin and contribute to the establishment and maintenance of cell fates. Furthermore, emerging evidence indicates that overexpression of PcG proteins in various types of cancers contributes to the dysregulation of cellular proliferation. Consequently, several inhibitors targeting PcG proteins are presently undergoing preclinical and clinical evaluation. Here, we show that infection with human cytomegalovirus also induces a strong upregulation of several PcG proteins. Our data suggest that viral DNA replication depends on a noncanonical function of polycomb repressor complexes which is independent of the so-far-described enzymatic activities of individual PcG factors. Importantly, we observe that a subclass of inhibitory drugs that affect the abundance of PcG proteins strongly interferes with viral replication. This principle may serve as a novel promising target for antiviral treatment.
Arterioportal fistula after partial gastrectomy treated with coil embolisation
Authors: Miranda Rita Nascimento , Leonardo Gordinho Andre Jose , Visconti Virginia , Oliveira Isménia
Published: February 2019

Arterioportal fistulas are a rare complication of abdominal interventions. They can remain asymptomatic for a long time and manifest with symptoms of portal hypertension. We present the case of a 65-year-old man admitted to the emergency room with increasing fatigue and melena. He had a history of partial gastrectomy with Billroth II reconstruction 40 years earlier for peptic ulcer perforation. On physical examination, he was pale and presented a machinery-type murmur in the epigastric area. Blood tests revealed iron deficiency anaemia of 5.6 g/dL. During hospitalisation, he required several blood transfusions and maintained melenas. An abdominal CT angiography showed a fusiform aneurysm of the left gastric artery draining to the venous portal-splenic confluent. He was successfully treated with transarterial coil embolisation of the left gastric artery aneurysm. The correct diagnosis of arterioportal fistulas can be very challenging, whereas the standard treatment with coil embolisation offers a low morbidity resolution of symptoms.
Validation of a model for the prediction of retinopathy in persons with type 1 diabetes
Authors: Schreur Vivian , Ng Heijan , Nijpels Giels , Stefánsson Einar , Tack Cees J , Klevering B Jeroen , de Jong Eiko K , Hoyng Carel B , Keunen Jan E E , van der Heijden Amber A
Published: March 2019

Background/Aim

To validate a previously developed model for prediction of diabetic retinopathy (DR) for personalised retinopathy screening in persons with type 1 diabetes.

Methods

Retrospective medical data of persons with type 1 diabetes treated in an academic hospital setting were used for analysis. Sight-threatening retinopathy (STR) was defined as the presence of severe non-proliferative DR, proliferative DR or macular oedema. The presence and grade of retinopathy, onset of diabetes, systolic blood pressure, and levels of haemoglobin A1c were used to calculate an individual risk estimate and personalised screening interval. In persons with STR, the occurrence was compared with the calculated date of screening. The model’s predictive performance was measured using calibration and discrimination techniques.

Results

Of the 268 persons included in our study, 24 (9.0%) developed STR during a mean follow-up of 4.6 years. All incidences of STR occurred after the calculated screening date. By applying the model, the mean calculated screening interval was 30.5 months, which is a reduction in screening frequency of 61% compared with annual screening and 21% compared with biennial screening. The discriminatory ability was good (Harrell’s C-statistic=0.82, 95% CI 0.74 to 0.90), and calibration showed an overestimation of risk in persons who were assigned to a higher risk for STR.

Conclusion

This validation study suggests that a screening programme based on the previously developed prediction model is safe and efficient. The use of a personalised screening frequency could improve cost-effectiveness of diabetic eye care.
Estimating the magnitude of diabetes mellitus and diabetic retinopathy in an older age urban population in Pune, western India
Authors: Kulkarni Sucheta , Kondalkar Shridevi , Mactaggart Islay , Shamanna B R , Lodhi Azher , Mendke Rohit , Kharat Jitesh , Kapse Rajesh , Dole Kuldeep , Deshpande Madan
Published: March 2019

Objective

To estimate magnitude of diabetes mellitus (DM) and diabetic retinopathy (DR) in a high risk population in Pune, western India.

Methods

DR module in rapid assessment of avoidable blindness (RAAB) survey methodology was used. Sample size of 3527 was calculated based on estimates from previous studies in India. A certified RAAB trainer conducted a training of survey teams. Random cluster sampling with probability proportionate to size was adapted to select 60 clusters consisting of 60 individuals each. Two teams visited door to door until they finished visiting 60 persons each day. Visual acuity testing, torch light examination, red glow test were carried out to determine persons with visual impairment and its cause. Every participant then underwent a random blood sugar level testing. All diabetics (known and newly detected) underwent dilated retina evaluation with indirect ophthalmoscopy to determine their DR status. Data were entered into RAAB6 software and descriptive statistics generated.

Results

Response rate was 89.5 % (3221/3600), females (55.3%). The prevalence of DM in the sample was (706/3221) 21.9 %(95 CI 20.1 to 23.7). Prevalence of DR was 14.3 % (95% CI 11.7 to 16.9). Most diabetics (401/579, 69.3%) never had an eye examination for DR in the past. Cataract was the principal cause of blindness (50 % cases) among diabetics.

Conclusion

DM affects over fifth of persons above 50 years of age in western India. Nearly seventh of the diabetics have DR, but coverage of screening is poor in Pune.
Effect of creative writing on mood in patients with cancer
Authors: Zhu Junjia , Hussain Muhammad , Joshi Aditya , Truica Cristina I , Nesterova Darya , Collins Jolene , Saunders Erika F H , Hayes Michael , Drabick Joseph J , Joshi Monika
Published: March 2019

Objective

To determine the feasibility of conducting creative writing workshops (CWW) for patients with cancer to promote improvement in mood.

Method

We piloted a prospective study to determine the feasibility of conducting CWW over a 4-week period. Patients were randomised 2:1 to either an intervention arm (IA) or to standard of care (SOC). Patients in the IA attended four 2-hour long weekly CWW × 4 weeks, whereas those receiving SOC did not participate in the CWW. We used a validated emotion thermometer scale (ETS) to assess changes in patient’s mental health before and after intervention. Patients with metastatic or unresectable cancer were included.

Primary endpoint

(1) Feasibility and (2) mood scores before and after CWW using ETS.

Results

A total of 16 patients were enrolled: 11 in the IA vs 5 in SOC. Seven out of 11 (63%) patients enrolled in the IA attended at least 75% of classes. Patients in the IA showed a trend towards mood improvement relative to the SOC when comparing initial and final ETS scores. Within the IA group significantly lower postclass total ETS scores were observed relative to preclass ETS scores. Also, a significant decreasing trend over time was observed in the preclass total ETS scores for participants in the IA group.

Conclusions

It is feasible for patients with cancer to attend CWW. Our results also show a positive effect on mood in the CWW arm. Further prospective clinical studies are needed to evaluate the effect of this intervention in patients with cancer.
Diagnosis and management of pancreatic cystic neoplasms
Authors: Keegan Mathew James , Paranandi Bharat
Published: March 2019

This review outlines the current classification of pancreatic cystic lesions, with a particular emphasis on pancreatic cystic neoplasms (PCNs). It will describe the diagnostic approach to PCNs, with reference to clinicopathological features, cross-sectional radiology and endoscopic ultrasound. This review will conclude with an evidence-based discussion of the management of PCNs focused on recent clinical guidelines.
Lack of validity of self-reported mammography data
Authors: Levine Robert S , Kilbourne Barbara J , Sanderson Maureen , Fadden Mary K , Pisu Maria , Salemi Jason L , Mejia de Grubb Maria Carmenza , O’Hara Heather , Husaini Baqar A , Zoorob Roget J , Hennekens Charles H
Published: February 2019

This qualitative literature review aimed to describe the totality of peer-reviewed scientific evidence from 1990 to 2017 concerning validity of self-reported mammography. This review included articles about mammography containing the words accuracy, validity, specificity, sensitivity, reliability or reproducibility; titles containing self-report, recall or patient reports, and breast or ‘mammo’; and references of identified citations focusing on evaluation of 2-year self-reports. Of 45 publications meeting the eligibility criteria, 2 conducted in 1993 and 1995 at health maintenance organisations in Western USA which primarily served highly educated whites provided support for self-reports of mammography over 2 years. Methodological concerns about validity of self-reports included (1) telescoping, (2) biased overestimates particularly among black women, (3) failure to distinguish screening and diagnostic mammography, and (4) failure to address episodic versus consistent mammography use. The current totality of evidence supports the need for research to reconsider the validity of self-reported mammography data as well as the feasibility of alternative surveillance data sources to achieve the goals of the Healthy People Initiative.
Non-invasive neuromodulation for migraine and cluster headache: a systematic review of clinical trials
Authors: Reuter Uwe , McClure Candace , Liebler Eric , Pozo-Rosich Patricia
Published: March 2019

Non-invasive neuromodulation therapies for migraine and cluster headache are a practical and safe alternative to pharmacologics. Comparisons of these therapies are difficult because of the heterogeneity in study designs. In this systematic review of clinical trials, the scientific rigour and clinical relevance of the available data were assessed to inform clinical decisions about non-invasive neuromodulation. PubMed, Cochrane Library and ClinicalTrials.gov databases and the WHO’s International Clinical Trials Registry Platform were searched for relevant clinical studies of non-invasive neuromodulation devices for migraine and cluster headache (1 January 1990 to 31 January 2018), and 71 were identified. This analysis compared study designs using recommendations of the International Headache Society for pharmacological clinical trials, the only available guidelines for migraine and cluster headache. Non-invasive vagus nerve stimulation (nVNS), single-transcranial magnetic stimulation and external trigeminal nerve stimulation (all with regulatory clearance) were well studied compared with the other devices, for which studies frequently lacked proper blinding, sham controls and sufficient population sizes. nVNS studies demonstrated the most consistent adherence to available guidelines. Studies of all neuromodulation devices should strive to achieve the same high level of scientific rigour to allow for proper comparison across devices. Device-specific guidelines for migraine and cluster headache will be soon available, but adherence to current guidelines for pharmacological trials will remain a key consideration for investigators and clinicians.
Rapid onset and progression of myelopathy following an STI: a case for screening?
Authors: Caswell Rachel J , Nall Peter , Boothby Meg , Taylor Graham P
Published: March 2019

Human T lymphotropic virus type 1 (HTLV-1) is recognised as an STI with serious manifestations of the disease in approximately 10% of those infected. This case report is the first to describe the short interval from sexual acquisition of HTLV-1 to the onset of HTLV-1-associated myelopathy and rapid progression to spastic paraparesis. The number of adult infections in the UK per annum is unknown, but surveillance data indicate that around 30% of newly diagnosed infections are occurring in persons born in the UK, rather than in migrants from HTLV-1-endemic regions. Despite this, and despite the risk of chronic debilitating disease, HTLV-1 infection is not part of sexual health screening in the UK, with the consequence that patients requesting sexual health screens are not informed of their carrier status and transmission from asymptomatic carriers to the partners will continue.
Little association between birth weight and health of preweaned dairy calves
Authors: Glover Ian D , Barrett David C , Reyher Kristen K
Published: March 2019

Intrauterine growth retardation (IUGR) may result in reduced birthweight and detrimental physiological alterations in neonates. This prospective cohort study was designed to assess if there exists an association between birthweight of dairy calves and incidence of bovine respiratory disease (BRD), neonatal calf diarrhoea (NCD) or mortality during the pre‐weaning period. Calves (n=476) on 3 farms in South West England were weighed at birth. Farmers kept records of treatments for NCD and BRD and calves were assessed weekly using clinical scoring systems (Wisconsin Calf Health Scores, California Calf Health Scores and Faeces Scores). Missing data were present in several variables. Multiple imputation coupled with generalised estimating equations (MI‐GEE analysis) was employed to analyse associations between several calf factors, including birthweight, and probability of a case of BRD or NCD. Associations between calf factors and mortality were assessed using multiple logistic regression. Associations between birthweight and disease incidence were scarce. Birthweight was associated with odds of a positive Faeces Score on one farm only in the MI‐GEE analysis (O.R. 1.03, 95% C.I. 1.0005–1.05, P=0.046). Birthweight was not associated with probability of mortality. This research suggests that birthweight, and therefore IUGR, is not associated with health of pre‐weaned dairy calves.
Lack of efficacy of triclabendazole against Fasciola hepatica is present on sheep farms in three regions of England, and Wales
Authors: Kamaludeen Juriah , Graham‐Brown John , Stephens Nathalie , Miller Josephine , Howell Alison , Beesley Nicola J , Hodgkinson Jane , Learmount Jane , Williams Diana
Published: March 2019

The liver flukeFasciola hepaticais a parasitic trematode that has a major impact on livestock production and human health. Control ofF hepaticais difficult and relies on anthelmintics, particularly triclabendazole, due to its efficacy against both adult and juvenile stages of the parasite. Emergence of triclabendazole‐resistantF hepaticapopulations has been reported in a number of countries, including the UK, but the overall prevalence and distribution of triclabendazole resistance is unknown. In this study, the authors established the presence of reduced efficacy of triclabendazole in sheep flocks in England and Wales, using a validated composite faecal egg count reduction test. Seventy‐four sheep farms were sampled from Wales, southwest, northwest and northeast England between Autumn 2013 and Spring 2015.F hepaticaeggs were detected in samples from 42/74 farms. Evidence of a lack of efficacy of triclabendazole was detected on 21/26 farms on which the faecal egg count reduction test was completed, with faecal egg count reductions ranging from 89 per cent to 0per cent. Regression analysis suggested that both prevalence ofF hepaticaand lack of efficacy of triclabendazole were spatially correlated, with higher faecal egg counts and lower percentage reductions on farms located in the northwest of England, and Wales. Overall, the results show that reduced efficacy of triclabendazole is present across England and Wales, with a complete lack of therapeutic efficacy observed on 9/26 farms.
Dark energy model in higher-dimensional FRW universe with respect to generalized entropy of Sharma and Mittal of flat FRW space–time
Authors: Demirel E.C. Gunay
Published: March 2019

In this study, we report the state parameter of dark energy in higher dimensional Friedmann–Robertson–Walker (FRW) space–time according to generalized entropy of Sharma and Mittal. In this case we analyze the state parameter of dark energy according to today’s observational evidence.
The fifth force: An enigma in this Universe
Authors: Singh Koijam Manihar , Singh Kangujam Priyokumar
Published: March 2019

In an attempt to explain some of the unknown phenomena of nature, including dark energy and dark matter, we explore the possibility of the existence of a fifth fundamental force of nature as also cited by some researchers. With the inclusion of such a force in the system, some of the vague things can be explained and there is high hope of its importance in building up a “theory of everything”. With this intention, we investigate some manifestations of the fifth force which stand from theoretical calculations or from theoretical point of view, though till now there is less experimental proof. However, the theoretical results obtained indicate the existence of a fifth force which will lead to the completion in defining the laws of physics and nature. With this discovery, science may be able to explain the whole complexity of the Universe in near future.
A classical limit of Grover’s algorithm induced by dephasing: Coherence versus entanglement
Authors: Fujikawa Kazuo , Oh C. H. , Umetsu Koichiro
Published: March 2019

A new approach to the classical limit of Grover’s algorithm is discussed by assuming a very rapid dephasing of a system between consecutive Grover’s unitary operations, which drives pure quantum states to decohered mixed states. One can identify a specific element among [Formula: see text] unsorted elements by a probability of the order of unity after [Formula: see text] steps of classical amplification, which is realized by a combination of Grover’s unitary operation and rapid dephasing, in contrast to [Formula: see text] steps in quantum mechanical amplification. The initial two-state system with enormously unbalanced existence probabilities, which is realized by a chosen specific state and a superposition of all the rest of the states among [Formula: see text] unsorted states, is crucial in the present analysis of classical amplification. This analysis illustrates Grover’s algorithm in extremely noisy circumstances. A similar increase from [Formula: see text] to [Formula: see text] steps due to the loss of quantum coherence takes place in the analog model of Farhi and Gutmann where the entanglement does not play an obvious role. This supports a view that entanglement is crucial in quantum computation to describe quantum states by a set of qubits, but the actual speedup of the quantum computation is based on quantum coherence.
SmartShell: Automated Shell Scripts Synthesis from Natural Language
Authors: Li Hao , Wang Yu-Ping , Yin Jie , Tan Gang
Published: March 2019

Modern shell scripts provide interfaces with rich functionality for system administration. However, it is not easy for end-users to write correct shell scripts; misusing commands may cause unpredictable results. In this paper, we present SmartShell, an automated function-based tool for shell script synthesis, which uses natural language descriptions as input. It can help the computer system to “understand” users’ intentions. SmartShell is based on two insights: (1) natural language descriptions for system objects (such as files and processes) and operations can be recognized by natural language processing tools; (2) system-administration tasks are often completed by short shell scripts that can be automatically synthesized from natural language descriptions. SmartShell synthesizes shell scripts in three steps: (1) using natural language processing tools to convert the description of a system-administration task into a syntax tree; (2) using program-synthesis techniques to construct a SmartShell intermediate-language script from the syntax tree; (3) translating the intermediate-language script into a shell script. Experimental results show that SmartShell can successfully synthesize 53.7% of tasks collected from shell-script helping forums.
Permission-based Android Malware Detection System Using Feature Selection with Genetic Algorithm
Authors: Yildiz Oktay , Doğru Ibrahim Alper
Published: March 2019

As the use of smartphones increases, Android, as a Linux-based open source mobile operating system (OS), has become the most popular mobile OS in time. Due to the widespread use of Android, malware developers mostly target Android devices and users. Malware detection systems to be developed for Android devices are important for this reason. Machine learning methods are being increasingly used for detection and analysis of Android malware. This study presents a method for detecting Android malware using feature selection with genetic algorithm (GA). Three different classifier methods with different feature subsets that were selected using GA were implemented for detecting and analyzing Android malware comparatively. A combination of Support Vector Machines and a GA yielded the best accuracy result of 98.45% with the 16 selected permissions using the dataset of 1740 samples consisting of 1119 malwares and 621 benign samples.
On the Neumann Laplacian in nonuniformly collapsing strips
Authors: de Oliveira César R. , Verri Alessandra A.
Published: March 2019

Consider the Neumann Laplacian in the region below the graph of [Formula: see text], for a positive smooth function [Formula: see text] with both [Formula: see text] and [Formula: see text] bounded. As [Formula: see text] such region collapses to [Formula: see text] and an effective operator is found, which has Robin boundary conditions at [Formula: see text]. Then, we recover (under suitable assumptions in the case of unbounded [Formula: see text]) such effective operators through uniformly collapsing regions; in such approach, we have (roughly) got norm resolvent convergence for [Formula: see text] diverging less than exponentially.
Convergence rates in the weak law of large numbers for weighted sums of i.i.d. random variables and applications in errors-in-variables models
Authors: Zhang Mingyang , Chen Pingyan , Sung Soo Hak
Published: March 2019

We prove necessary and sufficient conditions for the convergence rates in the weak law of large numbers for weighted sums of independent and identically distributed (i.i.d.) random variables. This result is applied to simple linear error-in-variables regression models.
A 3D Spark Model to Evaluate MRR in ECDM
Authors: Singh Dilpreet , Goud Mudimallana
Published: March 2019

Electrochemical discharge machining (ECDM) is an advanced machining process which uses both chemical action and spark discharge method for removal of materials. Till date, most of the applications of ECDM are in machining nonconductive materials, although some authors have also tried machining conductive materials. This paper attempts to develop a finite element simulation model based on heat generation in the spark region to evaluate material removal rate (MRR) in case of quartz and soda lime glass. The calculation of MRR is based on melting and evaporation of the material due to high temperature generated due to spark discharge. Convection heat transfer is also considered in the analysis. The results obtained from the simulation are compared with available experimental results and previous simulation results. Although this process is not used in the industry till now, it has a lot of scope for research and development.
Foster Care Deficiencies and Human Trafficking
Authors: Robinson Jessica R. , Mordeson John N. , Mathew Sunil
Published: March 2019

Human trafficking is a present danger for youth in the foster care system. However, little research concerning states in the US has been done to address this issue. A body of literature has examined aspects of the link between human trafficking and foster care. However, few studies have explored the efficacy of state policy and practice in keeping children safe from being trafficked while in foster care. In this paper, we apply techniques from mathematics of uncertainty to examine the problems of the foster care system in the US and their implications for human trafficking.
NonLinear Programming Approach for Single-Valued Neutrosophic TOPSIS Method
Authors: Biswas Pranab , Pramanik Surapati , Giri Bibhas C.
Published: March 2019

We propose an approach for multi-attribute group decision-making (MAGDM) problems under neutrosophic information, where the preference values of alternatives over the attributes and the importance of attributes are expressed in terms of single-valued neutrosophic sets. Firstly, we develop a nonlinear programming approach based on Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) method to determine relative closeness intervals of alternatives. Secondly, we aggregate closeness intervals to find out the ranking order of all alternatives by computing their optimal membership degrees based on the ranking method of interval numbers. Finally, we provide an illustrative example to show the effectiveness of the proposed approach.
Nobusawa Gamma Nearness Rings
Authors: Öztürk Mehmet Ali , Jun Young Bae
Published: March 2019

In this paper, we consider the problem of how to define [Formula: see text]-nearness ring in the sense of Nobusawa theory which extends the notion of a nearness ring and [Formula: see text]-rings [N. Nobusawa, Osaka J. Math. 1 (1964) 81–89; M. A. Öztürk and E. İnan, Annals of Fuzzy Mathematics and Informatics 17(2) (2019) 115–131]. Also, we introduce some properties of approximations and these algebraic structures.
Comparative and Functional Algal Genomics
Authors: Blaby-Haas Crysten E. , Merchant Sabeeha S.
Published: March 2019

Over 100 whole-genome sequences from algae are published or soon to be published. The rapidly increasing availability of these fundamental resources is changing how we understand one of the most diverse, complex, and understudied groups of photosynthetic eukaryotes. Genome sequences provide a window into the functional potential of individual algae, with phylogenomics and functional genomics as tools for contextualizing and transferring knowledge from reference organisms into less well-characterized systems. Remarkably, over half of the proteins encoded by algal genomes are of unknown function, highlighting the volume of functional capabilities yet to be discovered. In this review, we provide an overview of publicly available algal genomes, their associated protein inventories, and their quality, with a summary of the statuses of protein function understanding and predictions.
Molecular and Environmental Regulation of Root Development
Authors: Motte Hans , Vanneste Steffen , Beeckman Tom
Published: March 2019

In order to optimally establish their root systems, plants are endowed with several mechanisms to use at distinct steps during their development. In this review, we zoom in on the major processes involved in root development and detail important new insights that have been generated in recent studies, mainly using the Arabidopsis root as a model. First, we discuss new insights in primary root development with the characterization of tissue-specific transcription factor complexes and the identification of non-cell-autonomous control mechanisms in the root apical meristem. Next, root branching is discussed by focusing on the earliest steps in the development of a new lateral root and control of its postemergence growth. Finally, we discuss the impact of phosphate, nitrogen, and water availability on root development and summarize current knowledge about the major molecular mechanisms involved.
Rapid flow-induced activation of Gαq/11 is independent of Piezo1 activation
Authors: dela Paz Nathaniel G. , Frangos John A.
Published: February 2019

Endothelial cell (EC) mechanochemical transduction is the process by which mechanical stimuli are sensed by ECs and transduced into biochemical signals and ultimately into physiological responses. Identifying the mechanosensor/mechanochemical transducer(s) and describing the mechanism(s) by which they receive and transmit the signals has remained a central focus within the field. The heterotrimeric G protein, Gαq/11, is proposed to be part of a macromolecular complex together with PECAM-1 at EC junctions and may constitute the mechanochemical transducer as it is rapidly activated within seconds of flow onset. The mechanically activated cation channel Piezo1 has recently been implicated due to its involvement in mediating early responses, such as calcium and ATP release. Here, we investigate the role of Piezo1 in rapid shear stress-induced Gαq/11 activation. We show that flow-induced dissociation of Gαq/11 from PECAM-1 in ECs at 15 s is abrogated by BIM-46187, a selective inhibitor of Gαq/11 activation, suggesting that Gαq/11 activation is required for PECAM-1/Gαq/11 dissociation. Although siRNA knockdown of Piezo1 caused a dramatic decrease in PECAM-1/Gαq/11 association in the basal condition, it had no effect on flow-induced dissociation. Interestingly, siRNA knockdown of Piezo1 caused a marked decrease in PECAM-1 expression. Additionally, selective blockade of Piezo1 with ion channel inhibitors had no effect on flow-induced PECAM-1/Gαq/11 dissociations. Lastly, flow onset caused increased association of Gβ1 with Piezo1 as well as with the p101 subunit of phosphoinositide 3-kinase, which were both blocked by the Gβγ inhibitor gallein. Together, our results indicate that flow-induced activation of Piezo1 is not upstream of G protein activation.
Short-duration hyperoxia causes genotoxicity in mouse lungs: protection by volatile anesthetic isoflurane
Authors: Kundumani-Sridharan Venkatesh , Subramani Jaganathan , Raghavan Somasundaram , Maiti Guru P. , Owens Cade , Walker Trevor , Wasnick John , Idell Steven , Das Kumuda C.
Published: February 2019

High concentrations of oxygen (hyperoxia) are routinely used during anesthesia, and supplemental oxygen is also administered in connection with several other clinical conditions. Although prolonged hyperoxia is known to cause acute lung injury (ALI), whether short-duration hyperoxia causes lung toxicity remains unknown. We exposed mice to room air (RA or 21% O2) or 60% oxygen alone or in combination with 2% isoflurane for 2 h and determined the expression of oxidative stress marker genes, DNA damage and DNA repair genes, and expression of cell cycle regulatory proteins using quantitative PCR and Western analyses. Furthermore, we determined cellular apoptosis using TUNEL assay and assessed the DNA damage product 8-hydroxy-2′-deoxyguanosine (8-Oxo-dG) in the urine of 60% hyperoxia-exposed mice. Our study demonstrates that short-duration hyperoxia causes mitochondrial and nuclear DNA damage and that isoflurane abrogates this DNA damage and decreases apoptosis when used in conjunction with hyperoxia. In contrast, isoflurane mixed with RA caused significant 8-Oxo-dG accumulations in the mitochondria and nucleus. We further show that whereas NADPH oxidase is a major source of superoxide anion generated by isoflurane in normoxia, isoflurane inhibits superoxide generation in hyperoxia. Additionally, isoflurane also protected the mouse lungs against ALI (95% O2for 36-h exposure). Our study established that short-duration hyperoxia causes genotoxicity in the lungs, which is abrogated when hyperoxia is used in conjunction with isoflurane, but isoflurane alone causes genotoxicity in the lung when delivered with ambient air.
Effects of lactate ions on the cardiorespiratory system in rainbow trout (Oncorhynchus mykiss)
Authors: Thomsen Mikkel T. , Lefevre Sjannie , Nilsson Göran E. , Wang Tobias , Bayley Mark
Published: February 2019

Lactate ions are involved in several physiological processes, including a direct stimulation of the carotid body, causing increased ventilation in mammals. A similar mechanism eliciting ventilatory stimulation in other vertebrate classes has been demonstrated, but it remains to be thoroughly investigated. Here, we investigated the effects of lactate ions on the cardiorespiratory system in swimming rainbow trout by manipulating the blood lactate concentration. Lactate elicited a vigorous, dose-dependent elevation of ventilation and bradycardia at physiologically relevant concentrations at constant pH. After this initial confirmation, we examined the chiral specificity of the response and found that only l-lactate induced these effects. By removal of the afferent inputs from the first gill arch, the response was greatly attenuated, and a comparison of the responses to injections up- and downstream of the gills collectively demonstrated that the lactate response was initiated by branchial cells. Injection of specific receptor antagonists revealed that a blockade of serotonergic receptors, which are involved in the hypoxic ventilatory response, significantly reduced the lactate response. Finally, we identified two putative lactate receptors based on sequence homology and found that both were expressed at substantially higher levels in the gills. We propose that lactate ions modulate ventilation by stimulating branchial oxygen-sensing cells, thus eliciting a cardiorespiratory response through receptors likely to have originated early in vertebrate evolution.
Vestibular modulation of muscle sympathetic nerve activity assessed over a 100-fold frequency range of sinusoidal galvanic vestibular stimulation
Authors: Singh Natasha , Hammam Elie , Macefield Vaughan G.
Published: February 2019

We have previously shown that sinusoidal galvanic vestibular stimulation (sGVS), delivered at 0.2–2.0 Hz, evokes a partial entrainment of muscle sympathetic nerve activity (MSNA). Moreover, at lower frequencies of stimulation (0.08–0.18 Hz) sGVS produces two peaks of modulation: one (primary) peak associated with the positive peak of the sinusoidal stimulus and a smaller (secondary) peak associated with the trough. Here we assessed whether sGVS delivered at 0.05 Hz causes a more marked modulation of MSNA than at higher frequencies and tested the hypothesis that the primary and secondary peaks are of identical amplitude because of the longer cycle length. MSNA was recorded via tungsten microelectrodes inserted into the left peroneal nerve in 11 seated subjects. Bipolar binaural sGVS (±2 mA, 100 cycles) was applied to the mastoid processes at 0.05, 0.5, and 5.0 Hz (500 cycles). Cross-correlation analysis revealed two bursts of modulation of MSNA for each cycle at 0.05 and 0.5 Hz but only one at 5 Hz. There was a significant inverse linear relationship between vestibular modulation (primary peak) and frequency ( P < 0.0001), with the amplitudes of the peaks being highest at 0.05 Hz. Moreover, the secondary peak at this frequency was not significantly different from the primary peak. These results indicate that vestibular modulation of MSNA operates over a large range of frequencies but is greater at lower frequencies of sGVS. We conclude that the vestibular apparatus, through its influence on muscle sympathetic outflow, preferentially contributes to the control of blood pressure at low frequencies.

NEW & NOTEWORTHY Vestibulosympathetic reflexes have been documented in experimental animals and humans. Here we show that sinusoidal galvanic vestibular stimulation, a means of selectively exciting vestibular afferents in humans, induces greater modulation of muscle sympathetic nerve activity when delivered at a very low frequency (0.05 Hz) than at 0.5 or 5.0 Hz.
Chronic hypoxia changes gene expression profile of primary rat carotid body cells: consequences on the expression of NOS isoforms and ET-1 receptors
Authors: Mosqueira Matías , Iturriaga Rodrigo
Published: March 2019

Sustained chronic hypoxia (CH) produces morphological and functional changes in the carotid body (CB). Nitric oxide (NO) and endothelin-1 (ET-1) play a major role as modulators of the CB oxygen chemosensory process. To characterize the effects of CH related to normoxia (Nx) on gene expression, particularly on ET-1 and NO pathways, primary cultures of rat CB cells were exposed to 7 days of CH. Total RNA was extracted, and cDNA-32P was synthesized and hybridized with 1,185 genes printed on a nylon membrane Atlas cDNA Expression Array. Out of 324 differentially expressed genes, 184 genes were upregulated, while 140 genes were downregulated. The cluster annotation and protein network analyses showed that both NO and ET-1 signaling pathways were significantly enriched and key elements of each pathway were differentially expressed. Thus, we assessed the effect of CH at the protein level of nitric oxide synthase (NOS) isoforms and ET-1 receptors. CH induced an increase in the expression of endothelial NOS, inducible NOS, and ETB. During CH, the administration of SNAP, a NO donor, upregulated ETB. Treatment with Tezosentan (ET-1 receptor blocker) during CH upregulated all three NOS isoforms, while the NOS blocker L-NAME induced upregulation of iNOS and ETBand downregulated the protein levels of ETA. These results show that CH for 7 days changed the cultured cell CB gene expression profile, the NO and ET-1 signaling pathways were highly enriched, and these two signaling pathways interfered with the protein expression of each other.
Diurnal Variations in Summer Precipitation over the Yellow River Basin
Authors: Zhao Yang , Wang Minzhong , Li Jiao , Yang Xiaojun , Zhang Nan , Chen Hong
Published: February 2019

The diurnal variations in summer precipitation over the Yellow River Basin (YRB) are investigated based on the National Centers for Environmental Prediction reanalysis dataset and hourly precipitation data from 481 gauge stations over the YRB during the time period 1981–2013. Three stair steps are identified to represent the upper, middle, and lower reaches of the YRB due to complex topography elevations over the different subregions of the YRB. The summer diurnal precipitation over the YRB shows significant spatial and temporal variations. The diurnal peaks in precipitation over the upper and middle reaches of the YRB occur in the evening and late afternoon, respectively. By contrast, double peaks in diurnal precipitation occur in the early morning and late afternoon over the lower reaches of the YRB. The diurnal peaks in summer precipitation along the YRB have an eastward transition, suggested to be associated with the westerlies transporting water vapor. Differing from the increasing tendency of summer hourly precipitation from west to east across the YRB with topography elevations decreased, a distinct reduction in hourly precipitation is observed over the transition region between the first and second stair steps in the YRB. Further analysis attributes this phenomenon to the regional descending airflow induced by the steep terrain along the slope of the Tibetan Plateau (TP).
An Event‐Triggered Robust Control and Bandwidth Scheduling Codesign Approach for Networked Control Systems with Uncertain Time Delays
Authors: Niu Yun , Liang Yalin
Published: February 2019

For networked control systems, the bandwidth resource is always limited; thus besides control performance, the efficient resource utilization is also crucial. In this paper, a novel event‐triggered control and resource scheduling codesign approach is proposed to stabilize the uncertain dynamic systems which are subject to time‐varying network introduced delays. A discrete switched system with uncertain parameters is employed to model the event‐triggered control system with time‐varying network‐induced delays. Based on the model, a control law, scheduling strategy, and event‐triggered condition codesign approach is investigated. A set of linear matrix inequalities are used to tackle the codesign problem. As the solution to the problem, a control law is obtained to guarantee stability or certain performance properties; an event‐triggered condition and a scheduling strategy are also obtained to efficiently utilize the limited resources. That is, the event‐triggered condition makes the network accession be triggered when it is necessary. The scheduling strategy guarantees the control loop suffering the worst control performance can get the authority to access the network. The proposed approach is evaluated through simulated experiments, with respect to the networked control of inverted pendulums. The results show that the proposed event‐triggered control and scheduling approach can achieve better control performances with lower average resource consumption in comparison with the time‐based control strategy.
A Study of Pre-Analytical Variables and Optimization of Extraction Method for Circulating Tumor DNA Measurements by Digital Droplet PCR
Authors: Cavallone Luca , Aldamry Mohammed , Lafleur Josiane , Lan Cathy , Gonzalez Ginestet Pablo , Alirezaie Najmeh , Ferrario Cristiano , Aguilar-Mahecha Adriana , Basik Mark
Published: March 2019

Background:

Circulating free DNA (cfDNA) is an exciting novel method to diagnose, monitor, and predict resistance and response to cancer therapies, with the potential to radically alter the management of cancer patients. To fulfill its potential, greater knowledge about preanalytical variables is required to optimize and standardize the collection process, and maximize the yield and utility of the small quantities of cfDNA extracted.

Methods:

To this end, we have compared the cfDNA extraction efficiency of three different protocols, including a protocol developed in house (Jewish General Hospital). We evaluated the impact on cfDNA levels of preanalytical variables including speed and timing of the second centrifugation and the use of k-EDTA and CTAD blood collection tubes. Finally, we analyzed the impact on fractional abundance of targeted pre-amplification and whole genome amplification on tumor and circulating tumor DNA (ctDNA) from patients with breast cancer.

Results:

Making use of a novel protocol for cfDNA extraction we increased cfDNA quantities, up to double that of commercial kits. We found that a second centrifugation at 3,000 g on frozen plasma is as efficient as a high-speed (16,000 g) centrifugation on fresh plasma and does not affect cfDNA levels.

Conclusions:

These results allow for the implementation of protocols more suitable to the clinical setting. Finally, we found that, unlike targeted gene amplification, whole genome amplification resulted in altered fractional abundance of selected ctDNA variants.

Impact:

Our study of the preanalytical variables affecting cfDNA recovery and testing will significantly enhance the quality and application of ctDNA testing in clinical oncology.