bluuebunny/crossref_metadata_2025 huggingface dataset:
Characteristics of ventricular intracardiac electrograms of ventricular tachycardias originating from the epicardia in patients with an implantable cardioverter defibrillator
Authors: Kawamura Iwanari , Fukamizu Seiji , Arai Marina , Inagaki Dai , Miyabe Tomonori , Miyazawa Satoshi , Kitamura Takeshi , Hojo Rintaro , Nishizaki Mitsuhiro , Sakurada Harumizu , Hiraoka Masayasu
Published: February 2019

Introduction

While characteristic waveforms of 12‐lead electrocardiograms have been reported to predict the epicardial origin of ventricular tachycardia (VT), it has not been fully examined whether ventricular intracardiac electrograms (VEGMs) recorded from the implantable cardioverter defibrillator (ICD) via telemetry can determine the origin of VT or not. The aim of this study was to investigate the VEGM characteristics of VT originating from the epicardia.

Method and Results

Intracardiac VEGMs of the induced VTs, with detected sites of origin during the VT study, were recorded in 15 (23 VTs) of the 46 patients. The characteristics of the 23 VTs were evaluated using far‐field and near‐field VEGMs recorded via telemetry. Five of 23 VTs were found to be focused on the epicardial site (epi group) and 18 VTs were focused on the endocardium (endo group). VTs of the epi group had longer VEGM duration in far‐field EGM than those of the endo group (epi group: 240 ± 49 ms vs endo group: 153 ± 45 ms; P = 0.002) and the duration from the onset to the peak of VEGM was also longer than that of the endo group (epi group: 153 ± 53 ms vs endo group: 63 ± 28 ms; P < 0.001). There was no difference in the V wave duration in tip‐ring EGM between both groups (epi group: 122 ± 52 ms vs endo group: 98 ± 6 ms; P = 0.377).

Conclusion

Evaluation of intracardiac VEGM before VT ablation may be helpful to predict the epicardial origin of VT in patients with an ICD.
An integrated analysis to predict micro‐RNAs targeting both stemness and metastasis in breast cancer stem cells
Authors: Rahimi Mahsa , Sharifi‐Zarchi Ali , Firouzi Javad , Azimi Mahnaz , Zarghami Nosratollah , Alizadeh Effat , Ebrahimi Marzieh
Published: February 2019

Several evidences support the idea that a small population of tumour cells representing self‐renewal potential are involved in initiation, maintenance, metastasis, and outcomes of cancer therapy. Elucidation of microRNAs/genes regulatory networks activated in cancer stem cells (CSCs) is necessary for the identification of new targets for cancer therapy. The aim of the present study was to predict the miRNAs pattern, which can target both metastasis and self‐renewal pathways using integration of literature and data mining. For this purpose, mammospheres derived from MCF‐7, MDA‐MB231, and MDA‐MB468 were used as breast CSCs model. They had higher migration, invasion, and colony formation potential, with increasing in stemness‐ and EMT‐related genes expression. Our results determined that miR‐204, ‐200c, ‐34a, and ‐10b contemporarily could target both self‐renewal and EMT pathways. This core regulatory of miRNAs could increase the survival rate of breast invasive carcinoma via up‐regulation of OCT4, SOX2, KLF4, c‐MYC, NOTCH1, SNAI1, ZEB1, and CDH2 and down‐regulation of CDH1. The majority of those target genes were involved in the regulation of pluripotency, MAPK, WNT, Hedgehog, p53, and transforming growth factor β pathways. Hence, this study provides novel insights for targeting core regulatory of miRNAs in breast CSCs to target both self‐renewal and metastasis potential and eradication of breast cancer.
Acetyltransferase p300 inhibitor reverses hypertension‐induced cardiac fibrosis
Authors: Rai Rahul , Sun Tianjiao , Ramirez Veronica , Lux Elizabeth , Eren Mesut , Vaughan Douglas E. , Ghosh Asish K.
Published: February 2019

Epigenetic dysregulation plays a crucial role in cardiovascular diseases. Previously, we reported that acetyltransferase p300 (ATp300) inhibitor L002 prevents hypertension‐induced cardiac hypertrophy and fibrosis in a murine model. In this short communication, we show that treatment of hypertensive mice with ATp300‐specific small molecule inhibitor L002 or C646 reverses hypertension‐induced left ventricular hypertrophy, cardiac fibrosis and diastolic dysfunction, without reducing elevated blood pressures. Biochemically, treatment with L002 and C646 also reverse hypertension‐induced histone acetylation and myofibroblast differentiation in murine ventricles. Our results confirm and extend the role of ATp300, a major epigenetic regulator, in the pathobiology of cardiac hypertrophy and fibrosis. Most importantly, we identify the efficacies of ATp300 inhibitors C646 and L002 in reversing hypertension‐induced cardiac hypertrophy and fibrosis, and discover new anti‐hypertrophic and anti‐fibrotic candidates.
Type 2 diabetes is associated with suppression of autophagy and lipid accumulation in β‐cells
Authors: Ji Jeff , Petropavlovskaia Maria , Khatchadourian Armen , Patapas Jason , Makhlin Julia , Rosenberg Lawrence , Maysinger Dusica
Published: February 2019

Both type 2 diabetes (T2D) and obesity are characterized by excessive hyperlipidaemia and subsequent lipid droplet (LD) accumulation in adipose tissue. To investigate whether LDs also accumulate in β‐cells of T2D patients, we assessed the expression of PLIN2, a LD‐associated protein, in non‐diabetic (ND) and T2D pancreata. We observed an up‐regulation of PLIN2 mRNA and protein in β‐cells of T2D patients, along with significant changes in the expression of lipid metabolism, apoptosis and oxidative stress genes. The increased LD buildup in T2D β‐cells was accompanied by inhibition of nuclear translocation of TFEB, a master regulator of autophagy and by down‐regulation of lysosomal biomarker LAMP2. To investigate whether LD accumulation and autophagy were influenced by diabetic conditions, we used rat INS‐1 cells to model the effects of hyperglycaemia and hyperlipidaemia on autophagy and metabolic gene expression. Consistent with human tissue, both LD formation and PLIN2 expression were enhanced in INS‐1 cells under hyperglycaemia, whereas TFEB activation and autophagy gene expression were significantly reduced. Collectively, these results suggest that lipid clearance and overall homeostasis is markedly disrupted in β‐cells under hyperglycaemic conditions and interventions ameliorating lipid clearance could be beneficial in reducing functional impairments in islets caused by glucolipotoxicity.
Resveratrol promotes trophoblast invasion in pre‐eclampsia by inducing epithelial‐mesenchymal transition
Authors: Zou Yanfen , Li Shuhong , Wu Dan , Xu Yetao , Wang Sailan , Jiang Ying , Liu Fang , Jiang Ziyan , Qu Hongmei , Yu Xiang , Wang Xiaoli , Wang Yuanli , Sun Lizhou
Published: February 2019

Impairment spiral arteries remodelling was considered to be the underlying cause of pathogenesis of pre‐eclampsia (PE). Resveratrol (RE) was reported that it could modulate cellar phenotype to ameliorate diverse human diseases. However, the biological function of RE in PE remains poorly understood. In this report, we investigated the effect of RE on trophoblast phenotype both in vivo and in vitro. We conducted MTT and transwell assays to explore cell proliferation and invasion events in HTR‐8/SVneo. In mice model, the clinical characteristics of PE were established through the injection of NG‐nitro‐l‐arginine methyl ester (L‐NAME). Furthermore, related experiments were performed to detect cellar phenotype‐associated signalling pathway, including epithelial‐mesenchymal transition (EMT) and Wnt/β‐catenin. Cell assays indicated that RE could increase trophoblasts migration and invasion. In addition, hypertension and proteinuria were markedly ameliorated by RE compared with the controls in PE mice model. Moreover, treatment by RE in trophoblasts or in PE model, we found that RE activated EMT progress through the regulation of E‐cadherin, β‐catenin, N‐cadherin, vimentin expression, and further altered the WNT‐related gene expression, including WNT1, WNT3 and WNT5B. Our findings demonstrated that RE might stimulate the invasive capability of human trophoblasts by promoting EMT and mediating the Wnt/β‐catenin pathway in PE.
Comparison between two bone substitutes for alveolar ridge preservation after tooth extraction: Cone‐beam computed tomography results of a non‐inferiority randomized controlled trial
Authors: Llanos Alexandre Hugo , Sapata Vítor Marques , Jung Ronald E. , Hämmerle Christoph H. , Thoma Daniel S. , César Neto João Batista , Pannuti Claudio Mendes , Romito Giuseppe Alexandre
Published: February 2019

Aim

To test the non‐inferiority of demineralized bovine bone mineral (DBBM) compared toDBBMwith 10% collagen (DBBM‐C) for maintenance of bone volume after tooth extraction in the anterior maxilla.

Materials and Methods

Sixty‐six patients were randomly treated withDBBMorDBBM‐C, both of which were covered with a collagen matrix for ridge preservation in the anterior maxilla. Cone‐beam computed tomographic analysis was performed immediately and 4 months after treatment. The primary outcome, for which non‐inferiority ofDBBMwas tested, was change in the horizontal ridge width 1 mm below the buccal alveolar crest (HW‐1) 4 months after extraction.

Results

Four months after extraction,HW‐1 measured −1.60 mm ± 0.82 mm forDBBM‐C, while theDBBMgroup showed a mean loss of −1.37 mm ± 0.84 mm (p = 0.28, 0.23 [95%CI: −0.19; 0.64]). The horizontal ridge width at 3 mm (HW‐3) showed −0.98 mm (±0.67 mm) forDBBM‐C and −0.84 mm (±0.62 mm) forDBBM(p = 0.40, 0.12 [95%CI: −0.19; 0.45]), and the horizontal ridge width at 5 mm (HW‐5) showed −0.67 mm (±0.47 mm) forDBBM‐C and −0.56 mm (±0.48 mm) forDBBM(p = 0.36, 0.11 [95%CI: −0.13; 0.34]).

Conclusions

The present clinical trial demonstrated non‐inferiority ofDBBMcompared toDBBM‐C for maintenance of alveolar bone volume 4 months after tooth extraction in the anterior maxilla.
Leucine–glycine and carnosine dipeptides prevent diabetes induced by multiple low‐doses of streptozotocin in an experimental model of adult mice
Authors: Vahdatpour Tohid , Nokhodchi Ali , Zakeri‐Milani Parvin , Mesgari‐Abbasi Mehran , Ahmadi‐Asl Naser , Valizadeh Hadi
Published: February 2019

Aims/Introduction

Peptides are considered to be quasi‐hormones and effective molecules for regulation of the cells function and prevention of metabolic disorders. Di‐ and tripeptides gastrointestinal absorption ability have been proposed to prevent diabetes progression.

Materials and Methods

Small peptides with different sequences of specific amino acids were synthesized based on a solid phase peptide synthesis protocol, and carnosine (A) and glutathione were examined for the prevention of diabetes induced by multiple low‐doses of streptozotocin in mice.

Results

The peptides A, Leu‐Gly (D) and Pro‐Pro showed preventive effects on blood glucose elevation and impairment of the signaling and performance of β‐cells. The β‐cell function assessed by immunofluorescence and blood glucose level in mice exposed to diabetes treated by the peptides A and D was similar to the normal mice. The peptide D prevented bodyweight loss caused by diabetes induction. The use of D and A peptides dramatically prevented the incidence of disruption in β‐cells signaling by maintaining the natural balance of intracellular Akt‐2 and cyclic adenosine monophosphate.

Conclusions

The results proved that peptide D (Leu‐Gly), named Hannaneh, inhibits the bodyweight loss caused by diabetes induction. The Hannaneh and carnosine dipeptides, with preservation of normal β‐cell signaling and anti dipeptidyl peptidase‐4 activity, prevented blood glucose increases in mice at risk of diabetes. These dipeptides might be regarded as the pharmaceutical agents for the prevention of diabetes.
Efficacy of photodynamic therapy combined with topical interventions for the treatment of actinic keratosis: a meta‐analysis
Authors: Heppt M.V. , Steeb T. , Leiter U. , Berking C.
Published: February 2019

Background

Photodynamic therapy (PDT) is a highly effective treatment option for patients with actinic keratoses (AK). However, efficacy can be reduced by insufficient illumination or hyperkeratotic nature of lesions.

Objectives

To investigate if PDT combined with a topical intervention is superior to monotherapy in terms of efficacy and tolerability.

Methods

A systematic literature research was conducted in Medline, Embase and CENTRAL. Pertinent trial registers were hand‐searched for eligible randomized controlled trials (RCTs) until 20 August 2018. Results were pooled using a random effects model to calculate relative risks (RR) or mean differences. The risk of bias was assessed with the Cochrane Risk of Bias Tool. The quality of evidence was estimated for each outcome of interest according to GRADE.

Results

Out of 1800 references initially identified, 10 RCTs with a total sample size of n = 277 were included. Four studies investigated a combination of PDT with imiquimod cream, three with 5‐fluorouracil cream and one each with ingenol mebutate gel, tazarotene gel and calcipotriol ointment, respectively. Patients treated with a combination showed higher participant complete (RR 1.63; 95% CI 1.15‐2.33; P = 0.007) and partial clearance rates (RR 1.19; 95% CI 0.84–1.67; P = 0.33). Similarly, the lesion‐specific clearance was higher for PDT plus topical intervention compared to monotherapy (RR 1.48; 95% CI 1.04–2.11; P = 0.03). A subgroup analysis was performed for PDT combined with imiquimod, revealing an increased participant complete clearance rate compared to monotherapy (RR 1.57, 95% CI 1.09–2.25, P = 0.02). PDT‐induced pain and local skin reactions after treatment were poorly reported. The studies were estimated at high risk for performance and detection bias.

Conclusion

The combination of PDT with another topical drug intervention does improve AK clearance rates compared to either monotherapy alone. This study highlights that the sequential application of two field‐directed treatments represents an efficient approach in patients with multiple AK and field cancerization.
Challenges in creating dissectible anatomical 3D prints for surgical teaching
Authors: Ratinam Ratheesraj , Quayle Michelle , Crock John , Lazarus Michelle , Fogg Quentin , McMenamin Paul
Published: February 2019

Three‐dimensional (3D) printing, or additive manufacturing, is now a widely used tool in pre‐operative planning, surgical teaching and simulator training. However, 3D printing technology that produces models with accurate haptic feedback, biomechanics and visuals for the training surgeon is not currently available. Challenges and opportunities in creating such surgical models will be discussed in this review paper. Surgery requires proper tissue handling as well as knowledge of relevant anatomy. To prepare doctors properly, training models need to take into account the biomechanical properties of the anatomical structures that will be manipulated in any given operation. This review summarises and evaluates the current biomechanical literature as it relates to human tissues and correlates the impact of this knowledge on developing high fidelity 3D printed surgical training models. We conclude that, currently, a printer technology has not yet been developed which can replicate many of the critical qualities of human tissue. Advances in 3D printing technology will be required to allow the printing of multi‐material products to achieve the mechanical properties required.
Yield and quality of grapes cultivated under plastic coverings with different downy mildew control strategies
Authors: Holcman Ester , Sentelhas Paulo Cesar , Spósito Marcel Bellato , Conceição Marco Antônio Fonseca , Couto Hilton Thadeu Zarate
Published: February 2019

Viticulture has been expanding in tropical regions. However, the climate in these areas is generally favourable to the incidence of plant diseases, especially downy mildew. Plastic covers and warning systems have shown very positive results in disease control, but they are tools that have never been used simultaneously in a tropical area. The Vitis vinifera cv. BRS Morena table grape was evaluated as regards yield and quality under different downy mildew control strategies as carried out on vineyards trained on an overhead trellis system, covered by a black shading screen (BSS) or a braided polypropylene film (BPF), over a 3‐year period. Different grapevine downy mildew management approaches defined the treatments: Co) Control (no spraying); Ca) Conventional control (calendar); Ba) “Rule 3–10” (Atti Istituto Botanico, 8, 1947, 45); Ma25) Low‐infection efficiency—i0>25%; and Ma75) High‐infection efficiency—i0>75% (Plant Disease, 84, 2000, 549). The occurrence of downy mildew and the amount of damage inflicted on vine yield and grape quality are directly related to the period of the crop cycle when there is rainfall. The use of the Ma75 warning system (Plant Disease, 84, 2000, 549) under braided polypropylene film resulted, for the most part, in similar vineyard productivity compared to Ca, but did not influence the number of branches and its fertility. The other warning systems decreased productivity by 31.9% compared to Ca. It was not possible to establish a relationship between the occurrence of downy mildew and its influence on grape sweetness and acidity. The use of warning systems led to a substantial reduction in fungicide sprays, approximately 66.7 to 71.3%, compared to the calendar system commonly used by the vine growers, with the Ba (Atti Istituto Botanico, 8, 1947, 45) and Ma75 controls (Plant Disease, 84, 2000, 549) leading to the highest fungicide saving.
How floral displays affect geitonogamy in an upward foraging bumblebee‐pollinated protandrous plant
Authors: Zhu Xing‐Fu , Yang Ji‐Qin , Li Qing‐Jun
Published: February 2019

Reducing geitonogamy (pollen transfer among flowers within the same plant) has been suggested as a major selective force for plants with multiple flowers. The occurrence of geitonogamy is generally different among flowers within inflorescences; however, no researchers have examined whether plants enlarge their display size without increasing the possibility of geitonogamy by presenting more flowers at positions where they are less likely to be geitonogamously pollinated. We observed that bumblebee pollinators foraged upward within the tower‐shaped inflorescences of protandrous Megacodon stylophorus (C. B. Clarke) Harry Sm. Because M. stylophorus did not strictly bloom bottom‐up, there were substantial frequencies of geitonogamous pollination resulting from upward and horizontal pollen transfer. Although there was a strong correlation between total numbers of flowers plants produced and numbers of flowers presented on single days, proportions of flowers possibly geitonogamously pollinated were weakly correlated with total numbers of flowers. This might have been because plants with more resources enlarged their display size by producing more flowers on lower floors where flowers had a low probability of being geitonogamously pollinated. This study shows that the tower‐shaped inflorescences of M. stylophorus enlarge their size without more cost of geitonogamous mating, suggesting that geitonogamy acts as an important selective agent in the evolution of inflorescence architectures.
Controlling chronic Pseudomonas aeruginosa infections by strategically interfering with the sensory function of SagS
Authors: Dingemans Jozef , Al‐Feghali Rebecca E. , Lau Gee W. , Sauer Karin
Published: February 2019

The hybrid sensor SagS plays a central role in the formation of Pseudomonas aeruginosa biofilms, by enabling the switch from the planktonic to the biofilm mode of growth and by facilitating the transition of biofilm cells to a highly tolerant state. In this study, we examined the importance of the SagS key amino acid residues associated with biofilm formation (L154) and antibiotic tolerance (D105) in P. aeruginosa virulence. Recombinant P. aeruginosa ΔsagS and ΔsagS chromosomally expressing wild‐type sagS, or its two variants D105A and L154A, were tested for their potential to form biofilms and cause virulence in plants and mouse models of acute and chronic pneumonia. Although mutation of sagS did not alter P. aeruginosa virulence during acute infections, a significant difference in pathogenicity of sagS mutants was observed during chronic infections, with the L154A variant showing reduced bacterial loads in the chronic pneumonia model, while interference with the D105 residue enhanced the susceptibility of P. aeruginosa biofilms during tobramycin treatment. Our findings suggest that interference with the biofilm or tolerance regulatory circuits of SagS affects P. aeruginosa pathogenicity in chronic but not acute infections, and reveal SagS to be a promising new target to treat P. aeruginosa biofilm infections.
Evolutionary and ecological insights from herbicide‐resistant weeds: what have we learned about plant adaptation, and what is left to uncover?
Authors: Baucom Regina S.
Published: February 2019

The evolution of herbicide resistance in crop weeds presents one of the greatest challenges to agriculture and the production of food. Herbicide resistance has been studied for more than 60 yr, in the large part by researchers seeking to design effective weed control programs. As an outcome of this work, various unique questions in plant adaptation have been addressed. Here, I collate recent research on the herbicide‐resistant problem in light of key questions and themes in evolution and ecology. I highlight discoveries made on herbicide‐resistant weeds in three broad areas – the genetic basis of adaptation, evolutionary constraints, experimental evolution – and similarly discuss questions left to be answered. I then develop how one would use herbicide‐resistance evolution as a model for studying eco‐evolutionary dynamics within a community context. My overall goals are to highlight important findings in the weed science literature that are relevant to themes in plant adaptation and to stimulate the use of herbicide‐resistant plants as models for addressing key questions within ecology and evolution.
Professionalism in pediatric anesthesiology: Affirmation of a definition based on results of a nationally administered survey of pediatric anesthesiologists
Authors: Lockman Justin L. , Yehya Nadir , Schwartz Alan Jay , Cronholm Peter F.
Published: February 2019

Background

Previously published work established the need for a specialty‐specific definition of professionalism in pediatric anesthesiology. That work established a composite definition consisting of 11 domains and their component “defining themes” for professionalism in pediatric anesthesiology. As a next step toward assessing generalizability of our single‐center findings, we sought to gain input from a national sample of pediatric anesthesiologists.

Aims

The aim of this study was to establish the construct validity of our previously published multidimensional definition of professionalism in pediatric anesthesiology using a nationally representative sample of pediatric anesthesiologists.

Methods

A survey was distributed via snowball sampling to the leaders of every pediatric anesthesiology fellowship program and pediatric anesthesia department or clinical division in the United States. Survey items were designed to validate individual component themes in the working definition. For affirmed items, the respondent was asked to rate the importance of the item. Respondents were also invited to suggest novel themes to be included in the definition.

Results

A total of 216 pediatric anesthesiologists representing a variety of experience levels and practice settings responded to the survey. All 40 themes were strongly supported by the respondents, with the least supported theme receiving 71.6% approval. 92.8% of respondents indicated that the 11 domains previously identified formed a comprehensive list of domains for professionalism in pediatric anesthesiology. Four additional novel themes were suggested by respondents, including wellness/self‐care/burnout prevention, political advocacy, justice within a practice organization, and respect for leadership/experienced partners. These are topics for future study. The survey responses also indicated a near‐universal agreement that didactic lectures would be ineffective for teaching professionalism.

Conclusion

This national survey of pediatric anesthesiologists serves to confirm the construct validity of our prior working definition of professionalism in pediatric anesthesiology, and has uncovered several opportunities for further study. This definition can be used for both curriculum and policy development within the specialty.
The neural sources of N170: Understanding timing of activation in face‐selective areas
Authors: Gao Chuanji , Conte Stefania , Richards John E. , Xie Wanze , Hanayik Taylor
Published: February 2019

The N170 ERP component has been widely identified as a face‐sensitive neural marker. Despite extensive investigations conducted to examine the neural sources of N170, there are two issues in prior literature: (a) few studies used individualized anatomy as head model for the cortical source analysis of the N170, and (b) the relationship between the N170 and face‐selective regions from fMRI studies is unclear. Here, we addressed these questions by presenting pictures of faces and houses to the same group of healthy adults and recording structural MRI, fMRI, and high‐density ERPs in separate sessions. Source analysis based on the participant's anatomy showed that the middle and posterior fusiform gyri were the primary neural sources for the face‐sensitive aspects of the N170. Source analysis based on regions of interest from the fMRI revealed that the fMRI‐defined fusiform face area was the major contributor to the N170. The current study suggests that the fusiform gyrus is a major neural contributor to the N170 ERP component and provides further insights about the spatiotemporal characteristics of face processing.
P300 and positive slow waves reveal the plausibility in inductive reasoning
Authors: Lei Yi , Wang Jinxia , Zhu Yuxi , Chen Qingfei , Li Hong
Published: February 2019

Category‐based induction is an advanced cognitive function that is based on our category‐level knowledge. Previous findings have recognized the distance effect in category‐based induction: Inductive strength is affected by the hierarchical distance between the premises and conclusions. However, the neural mechanisms underlying this effect require elucidation. In the present study, we investigated the neural mechanisms of the distance effect by using EEG technology and a new experimental paradigm—category‐based induction. In this paradigm, we used three hierarchical levels of categories—the subordinate category, the basic category, the superordinate category—and an irrelevant category. We further used these categories to create four types of trial that varied in the hierarchical distance between the premise and the conclusion: the subordinate‐basic, the basic‐superordinate, the subordinate‐superordinate, and the irrelevant‐superordinate trials. In each trial, participants judged the probability that the conclusion category had the same property as the premise category. Our behavioral results revealed that people responded more slowly in the irrelevant‐superordinate trials than in the basic‐superordinate and the subordinate‐basic trials. Our ERP results showed that the irrelevant‐superordinate trials elicited smaller P300 (250–500 ms) amplitudes than did the subordinate‐basic and the basic‐superordinate trials. In addition, the subordinate‐superordinate trials elicited smaller P300 and PSW (700–998 ms) amplitudes than did the subordinate‐basic and the basic‐superordinate combinations. These findings indicate that the amplitudes of P300 and PSW may reflect the distance effect in inductive reasoning: The further the premise‐conclusion hierarchical distance, the lower the inductive strength, and thus the smaller the P300 and PSW amplitudes.
Clustering Functional Data into Groups by Using Projections
Authors: Delaigle Aurore , Hall Peter , Pham Tung
Published: February 2019

We show that, in the functional data context, by appropriately exploiting the functional nature of the data, it is possible to cluster the observations asymptotically perfectly. We demonstrate that this level of performance can sometimes be achieved by the k-means algorithm as long as the data are projected on a carefully chosen finite dimensional space. In general, the notion of an ideal cluster is not clearly defined. We derive our results in the setting where the data come from two populations whose distributions differ at least in terms of means, and where an ideal cluster corresponds to one of these two populations. We propose an iterative algorithm to choose the projection functions in a way that optimizes clustering performance, where, to avoid peculiar solutions, we use a weighted least squares criterion. We apply our iterative clustering procedure on simulated and real data, where we show that it works well.
Multiple Influential Point Detection in High Dimensional Regression Spaces
Authors: Zhao Junlong , Liu Chao , Niu Lu , Leng Chenlei
Published: February 2019

Influence diagnosis is an integrated component of data analysis but has been severely underinvestigated in a high dimensional regression setting. One of the key challenges, even in a fixed dimensional setting, is how to deal with multiple influential points that give rise to masking and swamping effects. The paper proposes a novel group deletion procedure referred to as multiple influential point detection by studying two extreme statistics based on a marginal-correlation-based influence measure. Named the min- and max-statistics, they have complementary properties in that the max-statistic is effective for overcoming the masking effect whereas the min-statistic is useful for overcoming the swamping effect. Combining their strengths, we further propose an efficient algorithm that can detect influential points with a prespecified false discovery rate. The influential point detection procedure proposed is simple to implement and efficient to run and enjoys attractive theoretical properties. Its effectiveness is verified empirically via extensive simulation study and data analysis. An R package implementing the procedure is freely available.
Identification of rheumatoid arthritis causal genes using functional genomics
Authors: Ding James , Orozco Gisela
Published: February 2019

Over the past decade, genome‐wide association studies have contributed a wealth of knowledge to our understanding of polygenic disorders such as rheumatoid arthritis. As the size of sample cohorts has improved so too have the computational and experimental methods used to robustly define variants associated with disease susceptibility. The challenge now remains to translate these findings into improved understanding of disease aetiology and patient care. Whilst much of the focus of translating the findings of genome‐wide association studies has been on global analysis of all variants identified, careful functional study of individual disease susceptibility loci will be required in order to refine our understanding of how individual variants contribute to disease risk. Here, we present the argument behind such an approach and describe some of the novel tools being used to investigate risk loci. This includes the use of chromosomal conformation capture techniques and modifications of the CRISPR‐Cas9 system, with several examples of their implementation being described.
Wheat tandem kinases provide insights on disease‐resistance gene flow and host–parasite co‐evolution
Authors: Klymiuk Valentina , Fatiukha Andrii , Fahima Tzion
Published: February 2019

Stripe (yellow) rust, caused by the fungus Puccinia striiformis f. sp. tritici (Pst), is a destructive disease of wheat spread globally. Wild emmer wheat (Triticum turgidum ssp. dicoccoides; WEW) is known as a source for novel Pst resistance genes (R‐gene), but our knowledge on wheat‐Pst co‐evolution in natural populations is limited. Yr15 is a WEW (accession G25) gene, which confers a broad‐spectrum resistance to Pst, and encodes a tandem kinase‐pseudokinase protein designated as WTK1. Exon–intron comparisons of multiple WTK1 homoeologous and paralogous copies scattered in allopolyploid wheat genomes enabled us to develop functional molecular markers (FMMs), which were used for population genetic study. The functional allele (Wtk1) was absent in a worldwide collection of 513 wheat cultivars, except for 32 introgression lines with Yr15 from G25, as well as in 84% of the 382 tested WEW accessions collected across the Fertile Crescent. Yr15 was found to be distributed along a narrow axis from Mt Carmel to the Anti‐Lebanon Mountains ridge, mostly at elevations above c. 500 m, where the climatic conditions are favorable for disease development, therefore providing insights on gene flow and host–parasite co‐evolution in WEW natural habitats. Moreover, the worldwide absence of Wtk1 in cultivated wheat and in WEW natural populations from southeast Turkey, where wheat is believed to have been domesticated, proposes that Yr15 was rather left behind, than lost during domestication. Our results highlight the importance of conservation of WEW populations in their natural habitats for discovery of novel R‐genes and studies of host–parasite co‐evolution.
Electroporated GLUT4‐7myc‐GFP detects in vivo glucose transporter 4 translocation in skeletal muscle without discernible changes in GFP patterns
Authors: Knudsen Jonas Roland , Henriquez‐Olguin Carlos , Li Zhencheng , Jensen Thomas Elbenhardt
Published: February 2019

New Findings

What is the central question of this study?

Resolving the mechanism(s) leading to glucose transporter 4 (GLUT4) translocation to the muscle surface membrane has great therapeutic potential. However, the measurement of GLUT4 translocation is technically challenging. Here, we asked whether electroporation of GLUT4‐7myc‐GFP into skeletal muscle could be used as a tool to study GLUT4 translocation in vivo.

What is the main finding and its importance?

By acutely inducing GLUT4‐7myc‐GFP expression in skeletal muscle, we verified that in vivo exercise and AICAR stimulation increased the GLUT4 presence in the sarcolemma measured as myc signal. Importantly, the increased myc signal in the sarcolemma was not accompanied by major visual changes in the distribution of the GFP signal.

Insulin and exercise lead to translocation of the glucose transporter 4 (GLUT4) to the surface membrane of skeletal muscle fibres. This process is pivotal for facilitating glucose uptake into skeletal muscle. To study this, a robust assay is needed to measure the translocation of GLUT4 in adult skeletal muscle directly. Here, we aimed to validate a simple GLUT4 translocation assay using a genetically encoded biosensor in mouse skeletal muscle. We transfected GLUT4‐7myc‐GFP into mouse muscle to study live GLUT4 movement and to evaluate GLUT4 insertion in the muscle surface membrane after in vivo running exercise and pharmacological activation of AMP‐activated protein kinase (AMPK). Transfection led to expression of GLUT4‐7myc‐GFP that was dynamic in live flexor digitorum brevis fibres and which, upon insulin stimulation, exposed the myc epitope extracellularly. Running exercise, in addition to AMPK activation by 5‐aminoimidazole‐4‐carboxamide ribonucleotide, induced ∼125 and ∼100% increase, respectively, in extracellularly exposure of GLUT4 in the surface membrane of tibialis anterior muscle. Interestingly, the clear increase in surface‐exposed GLUT4 content induced by insulin, exercise or AMPK activation was not accompanied by any discernible reorganization of the GLUT4‐GFP signal. In conclusion, we provide a detailed description of an easy‐to‐use translocation assay to study GLUT4 accumulation at the surface membrane induced by exercise and exercise‐mimicking stimuli. Notably, our analyses revealed that increased GLUT4 surface membrane accumulation was not accompanied by a discernible change in the GLUT4 localization pattern.
Improvement of Stiffness and Energy Absorption by Harnessing Hierarchical Interlocking in Brittle Polymer Blocks
Authors: Imam Muhammed , Meaud Julien , Ghosh Susanta , Sain Trisha
Published: February 2019

The objective of the present work is to investigate the possibility of improving both stiffness and energy absorption in interlocking, architectured, brittle polymer blocks through hierarchical design. The interlocking mechanism allows load transfer between two different material blocks by means of contact at the mating surfaces. The contacting surfaces further act as weak interfaces that allow the polymer blocks to fail gradually under different loading conditions. Such controlled failure enhances the energy absorption of the polymer blocks but with a penalty in stiffness. Incorporating hierarchy in the form of another degree of interlocking at the weak interfaces improves stress transfer between contacting material blocks; thereby, improvement in terms of stiffness and energy absorption can be achieved. In the present work, the effects of hierarchy on the mechanical responses of a single interlocking geometry have been investigated systematically using finite element analysis (FEA) and results are validated with experiments. From finite element (FE) predictions and experiments, presence of two competing failure mechanisms have been observed in the interlock: the pullout of the interlock and brittle fracture of the polymer blocks. It is observed that the hierarchical interface improves the stiffness by restricting sliding between the contacting surfaces. However, such restriction can lead to premature fracture of the polymer blocks that eventually reduces energy absorption of the interlocking mechanism during pullout deformation. It is concluded that the combination of stiffness and energy absorption is optimal when fracture of the polymer blocks is delayed by allowing sufficient sliding at the interfaces.
Transient exciton-polariton dynamics in WSe
2
by ultrafast near-field imaging
Authors: Mrejen M. , Yadgarov L. , Levanon A. , Suchowski H.
Published: February 2019

We image the ultraslow exciton-polariton propagation in a WSe
2
nanoslab with extreme spatiotemporal resolution (50 nm, <45 fs).
X-ray Fourier ptychography
Authors: Wakonig Klaus , Diaz Ana , Bonnin Anne , Stampanoni Marco , Bergamaschi Anna , Ihli Johannes , Guizar-Sicairos Manuel , Menzel Andreas
Published: February 2019

A new image acquisition scheme increases resolution and sensitivity of x-ray microscopes.
High-speed imaging of ice nucleation in water proves the existence of active sites
Authors: Holden Mark A. , Whale Thomas F. , Tarn Mark D. , O’Sullivan Daniel , Walshaw Richard D. , Murray Benjamin J. , Meldrum Fiona C. , Christenson Hugo K.
Published: February 2019

High-speed video of freezing water proves ice formation starts at specific and very rare sites where there are surface defects.
A perfect storm: Genetics and anticommensal antibodies shore up type 1 diabetes
Authors: Luber Jacob M. , Kostic Aleksandar D.
Published: February 2019

HLA haplotypes in conjunction with serum anticommensal antibody responses are predictive of type 1 diabetes progression. See related Research Article by

Paun
et al
.
A ten-acious cytokine for a tenacious infection
Authors: Chen Jennifer S. , Eisenbarth Stephanie C.
Published: February 2019

T follicular helper cells produce interleukin-10 during chronic viral infections to support the humoral response.
Belly-born B cells bathe the brain
Authors: Stathopoulos Panos A. , O’Connor Kevin C.
Published: February 2019

IgA-expressing antibody secreting cells that are formed in the gut travel to the brain to diminish inflammation during multiple sclerosis exacerbations.
Refractory follicular conjunctival lesions: overlook as just inflammation or not?
Authors: Jung Su-Kyung , Paik Ji-Sun , Park Gyeong-Sin , Cho Seok-Goo , Yang Suk-Woo
Published: February 2019

Purpose

To report the clinical manifestations of 199 patients with suspected conjunctival lymphoma, the associations between these features and the pathological diagnoses, and the prognosis of conjunctival lesions during long-term follow-up.

Methods

We conducted a retrospective chart review of 199 patients who underwent conjunctival biopsy on suspicion of conjunctival lymphoproliferative disease between January 2008 and June 2015. We focused on slit-lamp findings in the conjunctiva and the pathological diagnoses.

Results

In total, 261 specimens of 199 patients were included in this study. The median age of patients was 42 years (range, 16–87 years), and those over 60 years of age constituted 17.1% of all patients. The proportion finally diagnosed with mucosa-associated lymphoid tissue (MALT) lymphomas was 58.2%. In these patients, the most common slit-lamp findings were the ‘salmon patch’ appearance (73.7%), followed by a follicular appearance (14.5%) and a nodular or subconjunctival mass (6.6%). Bilateral ocular manifestations were more common in patients with disease with the follicular appearance, as compared with patients with the salmon-patch appearance.

Conclusion

Conjunctival MALT lymphoma presents in various ways, not only with the salmon-patch appearance. Therefore, biopsy should be considered if suspicion is raised, even though the conjunctival lesion does not exhibit the typical appearance of MALT lymphoma. In cases of follicular lesions responding poorly to topical steroids, a conjunctival MALT lymphoma may be suspected, given that chronic inflammation may precede neoplasia in patients with extranodal marginal zone lymphoma.
Six-year incidence and progression of diabetic retinopathy in Indian adults: the Singapore Indian Eye study
Authors: Kumari Neelam , Bhargava Mayuri , Nguyen Duc Quang , Gan Alfred Tau Liang , Tan Gavin , Cheung Ning , Tan Nicholas , Wong Charlene , Wang Jie Jin , Mitchell Paul , Lamoureux Ecosse L , Cheng Ching Yu , Wong Tien Yin , Sabanayagam Charumathi
Published: February 2019

Aims

Diabetes is a major public health problem in migrants and ethnic minorities worldwide. We determined the incidence and risk factors of diabetic retinopathy (DR) in migrant Indians living in Singapore.

Methods

We included data from 759 Indian adults with diabetes, who participated in the baseline (aged 40–80 years, 2007–2009) and 6-year follow-up 2012–2015 of the Singapore Indian Eye Study. Retinal photographs were graded for the presence and severity of DR using modified Airlie House Classification. Incidence was assessed in participants who were free of DR at baseline visit (n=501), while progression in those with DR but free of proliferative DR at baseline visit (n=189). Risk factors included demographic, lifestyle, socioeconomic, family history, genes, duration of diabetes, glycaemic control, insulin use, ocular and clinical factors.

Results

The 6-year age-standardised DR incidence and progression were 21.89% and 33.45%, respectively. HbA1c (risk ratio (RR) 1.41, 95% CI 1.28 to 1.55 per unit increase), current smoking (RR 1.63, 95% CI 1.02 to 2.62) and insulin use (RR 2.63, 95% CI 1.44 to 4.82) were associated with higher incidence, whereas estimated cerebrospinal fluid pressure (RR 0.90, 95% CI 0.82 to 0.98) and body mass index (BMI) (RR 0.74, 95% CI 0.60 to 0.93) were associated with lower incidence of DR. Higher HbA1c (RR 1.26, 95% CI 1.13 to 1.42), BMI (RR 1.26, 95% CI 1.02 to 1.56) and estimated cerebrospinal fluid pressure (RR 1.11, 95% CI 1.02 to 1.21) were associated with DR progression. The population attributable risk of HbA1c >8% was 41.29% and 49.63% for DR incidence and progression.

Conclusion

DR incidence and progression in migrant Indians living in Singapore was more than double that reported in Indians living in urban India. Consistent with past studies, poor glycaemic control was an important predictor for incidence and progression of DR.
Microperimetry in age-related macular degeneration: association with macular morphology assessed by optical coherence tomography
Authors: Roh Miin , Laíns Inês , Shin Hyun Joon , Park Dong Ho , Mach Steven , Vavvas Demetrios G , Kim Ivana K , Miller Joan W , Husain Deeba , Miller John B
Published: February 2019

Background/aims

Microperimetry is a technique that is increasingly used to assess visual function in age-related macular degeneration (AMD). In this study, we aimed to evaluate the relationship between retinal sensitivity measured with macular integrity assessment (MAIA) microperimetry and optical coherence tomography (OCT)-based macular morphology in AMD.

Methods

Prospective, cross-sectional study. All participants were imaged with colour fundus photographs used for AMD staging (Age-Related Eye Disease Study scale), spectral-domain OCT (Spectralis, Heidelberg, Germany) and swept-source OCT (Topcon, Japan). Threshold retinal sensitivity of the central 10° diameter circle was assessed with the full-threshold, 37-point protocol of the MAIA microperimetry device (Centervue, Italy). Univariable and multivariable multilevel mixed-effect linear regression models were used for analysis.

Results

We included 102 eyes with AMD and 46 control eyes. Multivariable analysis revealed that older age (p<0.0001), advanced AMD stage (p<0.0001) and reduced retinal thickness (p<0.0001) were associated with decreased mean retinal sensitivity. No associations were found between choroidal thickness and retinal sensitivity within the macula. Within the 10° diameter circle of the macula, the presence of ellipsoid disruption, subretinal fluid, atrophy and fibrosis, and outer retinal tubulation on OCT images was also associated with decreased retinal sensitivity (all p<0.05).

Conclusions

There is an association between TRS as determined by MAIA microperimetry and several OCT structural parameters across various stages of AMD. This study highlights the relevance of microperimetry as a functional outcome measure for AMD.
Aurora borealis and string of pearls in vitreoretinal lymphoma: patterns of vitreous haze
Authors: Marchese Alessandro , Miserocchi Elisabetta , Giuffrè Chiara , Cicinelli Maria Vittoria , Querques Giuseppe , Bandello Francesco , Modorati Giulio
Published: February 2019

Aims

Peculiar retinal signs of vitreoretinal lymphoma (VRL) have been identified. However, limited information on the vitreous features of VRL is available. This study aims to characterise the vitreous involvement in VRL with the help of multimodal imaging.

Methods

In this retrospective, observational study, we reviewed charts and imaging of all patients with biopsy-proven VRL seen from January 2016 to April 2018 at a single referral centre. These included ultrawide-field imaging, ophthalmic ultrasonography and slit-lamp photography. The main outcome measures were patterns of vitreous haze of VRL, as observed by combining clinical and multimodal imaging information.

Results

Twenty-six eyes of 13 patients were included. At presentation, vitreous haze was present in 24 eyes (92%) and was the only sign of VRL in 4 eyes (15%). Three patterns of vitreous haze were identified in VRL. An aurora borealis pattern was present in 12 eyes and showed linear opacities with a myriad of cells aligned along the vitreous fibrils. A string of pearls pattern was present in two eyes at baseline and developed in other four eyes after vitrectomy, showing fine fibrils connecting bunches of inflammatory material. A non-specific pattern was observed in 10 eyes. Ophthalmic ultrasound showed corpuscular material correlating with the grading of vitreous haze.

Conclusion

VRL shows different patterns of vitreous haze. Multimodal imaging, including ultrawide-field imaging and slit-lamp photography, helps in recognising these patterns, raising suspicion for VRL.