bluuebunny/crossref_metadata_2025 huggingface dataset:
Local translation of yeastERG4mRNA at the endoplasmic reticulum requires the brefeldin A resistance protein Bfr1
Authors: Manchalu Srinivas , Mittal Nitish , Spang Anne , Jansen Ralf-Peter
Published: June 2019

Brefeldin A resistance factor 1 (Bfr1p) is a non-essential RNA-binding protein and multi-copy suppressor of brefeldin A sensitivity inSaccharomyces cerevisiae. Deletion ofBFR1leads to multiple defects, including altered cell shape and size, change in ploidy, induction of P-bodies and chromosomal mis-segregation. Bfr1p has been shown to associate with polysomes, binds to several hundred mRNAs, and can target some of them to P-bodies. Although this implies a role of Bfr1p in translational control of mRNAs, its molecular function remains elusive. In the present study, we show that mutations in RNA-binding residues of Bfr1p impede its RNA-dependent co-localization with ER, yet do not mimic the known cellular defects seen uponBFR1deletion. However, a Bfr1 RNA-binding mutant is impaired in binding toERG4mRNA which encodes an enzyme required for the final step of ergosterol biosynthesis. Consistently,bfr1Δ strains show a strong reduction in Erg4p protein levels. Polysome profiling ofbfr1Δ orbfr1mutant strains reveals a strong shift ofERG4mRNA to polysomes, consistent with a function of Bfr1p in elongation. Collectively, our data reveal that Bfr1 has at least two separable functions: one in RNA-binding and elongation during translation, in particular at the ER membrane, and one in ploidy control or chromosome segregation.
Pleiotropy or linkage? Their relative contributions to the genetic correlation of quantitative traits and detection by multi-trait GWA studies
Authors: Chebib Jobran , Guillaume Frédéric
Published: June 2019

Genetic correlations between traits may cause correlated responses to selection. Previous models described the conditions under which genetic correlations are expected to be maintained. Selection, mutation and migration are all proposed to affect genetic correlations, regardless of whether the underlying genetic architecture consists of pleiotropic or tightly-linked loci affecting the traits. Here, we investigate the conditions under which pleiotropy and linkage have differential effects on the genetic correlations between traits by explicitly modeling multiple genetic architectures to look at the effects of selection strength, degree of correlational selection, mutation rate, mutational variance, recombination rate, and migration rate. We show that at mutation-selection(-migration) balance, mutation rates differentially affect the equilibrium levels of genetic correlation when architectures are composed of pairs of physically linked loci compared to architectures of pleiotropic loci. Even when there is perfect linkage (no recombination within pairs of linked loci), a lower genetic correlation is maintained than with pleiotropy, with a lower mutation rate leading to a larger decrease. These results imply that the detection of causal loci in multi-trait association studies will be affected by the type of underlying architectures, whereby pleiotropic variants are more likely to be underlying multiple detected associations. We also confirm that tighter linkage between non-pleiotropic causal loci maintains higher genetic correlations at the traits and leads to a greater proportion of false positives in association analyses.
The CC′ loop of IgV domain containing immune checkpoint receptors: From a bystander to an active determinant of receptor:ligand binding
Authors: Kundapura Shankar V. , Ramagopal Udupi A.
Published: June 2019

Antibodies targeting negative regulators of immune checkpoints have shown unprecedented and durable response against variety of malignancies. While the concept of blocking the negative regulators of immune checkpoints using mAbs appears to be an outstanding approach, their limited effect and several drawbacks such as resistance, poor solid tumor penetration and so on, calls for the rational design of next generation of therapeutics. Soluble isoforms of negative regulators of immune checkpoints are expressed naturally and are shown to regulate the immune response, suggesting the soluble version of these molecules and affinity-modified versions of these self-molecules could be effective lead molecules for immunotherapy. To get a better insight on hotspot regions for modification, we have analysed structures of available immune receptor:ligand complexes containing IgV domains. Interestingly, this analysis reveals that the CC′ loop of IgV domain, a loop which is distinct from CDRs which are generally utilized by antibodies to recognize antigens, plays a pivotal role in affinity modulation. Here, we present several examples of cognate partner specific conformational variation observed in CC′ loop of several checkpoint receptor:ligand complexes. In addition,in silicoswapping of CC′ loop targeting TIGIT:Nectin-2/PVR pathway corroborated well with biophysically determined affinity values for these complexes. Thus, CC′ loop appears to be a hotspot for affinity modification without affecting the specificity to their cognate receptors, an important requirement to avoid unintended interaction of these modified molecules with undesired targets.
Why did theTc1-like elements of mollusks acquired the spliceosomal introns?
Authors: Puzakov M.V. , Puzakova L.V. , Cheresiz S.V.
Published: June 2019

Transposable elements are the DNA sequences capable of transpositions within the genome and, thus, exerting a considerable influence on the genome functioning and structure and providing the source of new genes. Transposable elements are classified into retrotransposons and the DNA transposons.IS630/Tc1/marinersuperfamily of DNA transposons is one of the most diverse groups broadly represented among the eukaryotes. We identified a new group ofTc1-like elements in the mollusks, which we namedTLEWI. These DNA transposons are characterized by the low copy number, the lack of terminal inverted repeats and the presence of DD36E signature and the spliceosomal introns in transposase sequence. Their prevalence among the mollusks is limited to subclass Pteriomorpha (Bivalvia). SinceTLEWIpossess the features of domesticated TE and the structure similar to the eukaryotic genes, which is not typical for the DNA transposons, we consider the hypothesis of co-optation ofTLEWIgene by the bivalves.
Pediatric High Grade Glioma Resources From the Children’s Brain Tumor Tissue Consortium (CBTTC) and Pediatric Brain Tumor Atlas (PBTA)
Authors: Ijaz Heba , Koptyra Mateusz , Gaonkar Krutika S. , Rokita Jo Lynne , Baubet Valerie P. , Tauhid Lamiya , Zhu Yankun , Brown Miguel , Lopez Gonzalo , Zhang Bo , Diskin Sharon J. , Vaksman Zalman ,   Children’s Brain Tumor Tissue Consortium, Mason Jennifer L. , Appert Elizabeth , Lilly Jena , Lulla Rishi , De Raedt Thomas , Heath Allison P. , Felmeister Alex , Raman Pichai , Nazarian Javad , Santi Maria Rita , Storm Phillip B. , Resnick Adam , Waanders Angela J. , Cole Kristina A.
Published: June 2019

Background

Pediatric high grade glioma (pHGG) remains a fatal disease. Increased access to richly annotated biospecimens and patient derived tumor models will accelerate pHGG research and support translation of research discoveries. This work describes the pediatric high grade glioma set of the Children’s Brain Tumor Tissue Consortium (CBTTC) from the first release (October 2018) of the Pediatric Brain Tumor Atlas (PBTA).

Methods

pHGG tumors with associated clinical data and imaging were prospectively collected through the CBTTC and analyzed as the Pediatric Brain Tumor Atlas (PBTA) with processed genomic data deposited into PedcBioPortal for broad access and visualization. Matched tumor was cultured to create high grade glioma cell lines analyzed by targeted and WGS and RNA-seq. A tissue microarray (TMA) of primary pHGG tumors was also created.

Results

The pHGG set included 87 collection events (73 patients, 60% at diagnosis, median age of 9 yrs, 55% female, 46% hemispheric). Analysis of somatic mutations and copy number alterations of known glioma genes were of expected distribution (36%H3.3, 47%TP53, 24%ATRXand 7%BRAFV600E variants). A pHGG TMA (n=77), includes 36 (53%) patient tumors with matched sequencing. At least one established glioma cell line was generated from 23 patients (32%). Unique reagents include those derived from aH3.3G34R glioma and from tumors with mismatch repair deficiency.

Conclusion

The CBTTC and PBTA have created an openly available integrated resource of over 2,000 tumors, including a rich set of pHGG primary tumors, corresponding cell lines and archival fixed tissue to advance translational research for pHGG.

IMPORTANCE OF STUDY

High-grade gliomas (HGG) remain the leading cause of cancer death in children. Since molecularly heterogeneous, preclinical studies of pediatric HGG will be most informative if able to compare across groups. Given their relatively rarity, there are few readily available biospecimens and cellular models to inform preclinical laboratory and genomic translational research. Therefore, the aim of this CBTTC study was to highlight the panel of pediatric HGG cases whose primary tumors have undergone extensive genomic analysis, have clinical data, available imaging and additional biospecimens, including tumor, nucleic acids, cell lines and FFPE tissue on a tissue microarray (TMA).
Hybrid Refinement of Heterogeneous Conformational Ensembles using Spectroscopic Data
Authors: Hays Jennifer M. , Cafiso David S. , Kasson Peter M.
Published: June 2019

Multi-structured biomolecular systems play crucial roles in a wide variety of cellular processes but have resisted traditional methods of structure determination which often resolve only a few low-energy states. High-resolution structure determination using experimental methods that yield distributional data remains extremely difficult, especially when the underlying conformational ensembles are quite heterogeneous. We have therefore developed a method to integrate sparse, multi-multimodal spectroscopic data to obtain high-resolution estimates of conformational ensembles. We have tested our method by incorporating double electron-electron resonance data on the SNARE protein syntaxin-1a into biased molecular dynamics simulations. We find that our method substantially outperforms existing state-of-the-art methods in capturing syntaxin’s open/closed conformational equilibrium and further yields new conformational states that are both consistent with experimental data and may help in understanding syntaxin’s function. Our improved methods for refining heterogeneous conformational ensembles from spectroscopic data will greatly accelerate the structural understanding of such systems.
Gold Nanobipyramids as Second Near Infrared Optical Coherence Tomography Contrast Agents for Multiplexed In Vivo Lymphangiography
Authors: Si Peng , Shevidi Saba , Yuan Edwin , Yuan Ke , Lautman Ziv , Jeffrey Stefanie S. , Sledge George W. , de la Zerda Adam
Published: June 2019

Developing contrast-enhanced optical coherence tomography (OCT) techniques is important for specific imaging of tissue lesions, molecular imaging, cell-tracking, and highly sensitive microangiography and lymphangiography. Multiplexed OCT imaging in the second near infrared (NIR-II) window is highly desirable since it allows simultaneous imaging and tracking of multiple biological events in high resolution with deeper tissue penetration in vivo. Here we demonstrate that gold nanobipyramids can function as OCT multiplexing contrast agents, allowing the visualization of two separate lymphatic flows occurring simultaneously from different drainage basins into the same lymph node in a live mouse. Contrast-enhanced multiplexed lymphangiography of a melanoma tumor in vivo shows that the peritumoral lymphatic drainage upstream of the tumor is unidirectional, with some drainage directly into the tumor, but the lymphatic drainage from the tumor is multi-directional. We also demonstrate real-time tracking of the contrast agents draining from a melanoma tumor specifically to the sentinel lymph node of the tumor and the three-dimensional distribution of the contrast agents in the lymph node.
Assessment of the in vitro function of human stem cell-derived β cells
Authors: Srivatsava Arvind R. , Shahan Stefanie T. , Gutgesell Lisa C. , Velazco-Cruz Leonardo , Millman Jeffrey R.
Published: June 2019

Insulin-producing human embryonic stem cell-derived β (SC-β) cells are a promising cell source for diabetes cell replacement therapy. We have recently reported a differentiation strategy that produces SC-β cells in islet organoids that not only undergo glucose-stimulated insulin secretion but also have an islet-like dynamic insulin release profile, displaying both first and second phase insulin secretion. The goal of this study was to further characterize the functional profile of these SC-β cells in vitro. We utilized a Seahorse extracellular flux analyzer to measure mitochondrial respiration of SC-β cells at low and high glucose. We also used photolithography to fabricate a microfluidic device containing microwells to immobilize SC-β cells for perfusional analysis, monitoring cytoplasmic calcium using Fluo-4 AM at low and high glucose. Here we find that in addition to increased insulin secretion, SC-β cells have increased cellular respiration and cytoplasmic calcium ion concentration in response to a high glucose stimulation. Our results indicate that SC-β cells have similar function to that reported for islets, providing further performance characterization that could help with eventual development for diabetes cell therapy and drug screening.
Scanning SWATH acquisition enables high-throughput proteomics with chromatographic gradients as fast as 30 seconds
Authors: Messner Christoph B. , Demichev Vadim , Bloomfield Nic , White Matthew , Kreidl Marco , Ivosev Gordana , Wasim Fras , Zelezniak Aleksej , Lilley Kathryn S. , Tate Stephen , Ralser Markus
Published: June 2019

Bridging genotype to phenotype, the proteome has increasingly become of major importance to generate large, longitudinal sample series for data-driven biology and personalized medicine. Major improvements in laboratory automation, chromatography and software have increased the scale and precision of proteomics. So far missing are however mass spectrometric acquisition techniques that could deal with very fast chromatographic gradients. Here we present scanning SWATH, a data-independent acquisition (DIA) method, in which the DIA-typical stepwise windowed acquisition is replaced by a continuous movement of the precursor isolation window. Scanning SWATH accelerates the duty cycles to a few hundreds of milliseconds, and enables precursor mass assignment to the MS2 fragment traces for improving true positive precursor identification in fast proteome experiments. In combination with 800 µL/min high-flow chromatography, we report the quantification of 270 precursors per second, increasing the precursor identifications by 70% or more compared to previous methods. Scanning SWATH quantified 1,410 Human protein groups in conjunction with chromatographic gradients as fast as 30 seconds, 2,250 with 60-second gradients, and 4,586 in conjunction with 5-minute gradients. At high quantitative precision, our method hence increases the proteomic throughput to hundreds of samples per day per mass spectrometer. Scanning SWATH hence enables a broad range of new proteomic applications that depend on large numbers of cheap yet quantification precise proteomes.
Model-based analysis of response and resistance factors of cetuximab treatment in gastric cancer cell lines
Authors: Raimúndez Elba , Keller Simone , Zwingenberger Gwen , Ebert Karolin , Hug Sabine , Theis Fabian J. , Maier Dieter , Luber Birgit , Hasenauer Jan
Published: June 2019

Targeted cancer therapies are powerful alternatives to chemotherapies or can be used complementary to these. Yet, the response to targeted treatments depends on a variety of factors, including mutations and expression levels, and therefore their outcome is difficult to predict. Here, we develop a mechanistic model of gastric cancer to study response and resistance factors for cetuximab treatment. The model captures the EGFR, ERK and AKT signaling pathways in two gastric cancer cell lines with different mutation patterns. We train the model using a comprehensive selection of time and dose response measurements, and provide an assessment of parameter and prediction uncertainties. We demonstrate that the proposed model facilitates the identification of causal differences between the cell lines. Furthermore, our study shows that the model provides accurate predictions for the responses to different perturbations, such as knockdown and knockout experiments. Among other results, the model predicted the effect of MET mutations on cetuximab sensitivity. These predictive capabilities render the model a powerful basis for the assessment of gastric cancer signaling and for the development and discovery of predictive biomarkers.

Author Summary

Unraveling the causal differences between drug responders and non-responders is an important challenge. The information can help to understand molecular mechanisms and to guide the selection and design of targeted therapies. Here, we approach this problem for cetuximab treatment for gastric cancer using mechanistic mathematical modeling. The proposed model describes multiple gastric cancer cell lines and can accurately predict the response in several validation experiments. Our analysis provides a differentiated view on mutations and explains, for instance, the relevance of MET mutations and the insignificance of PIK3CA mutation in the considered cell lines. The model might provide the basis for understanding the recent failure of several clinical studies.
Biting rhythm, fecundity and longevity rate ofAedes albopictus(Skuse) females from different urbanized settings in Penang Island, Malaysia under uncontrolled laboratory conditions
Authors: Muhammad Nor Atikah Farhah , Kassim Nur Faeza Abu , Ab Majid Abdul Hafiz , Dieng Hamady , Avicor Silas Wintuma
Published: June 2019

Urbanization could potentially modifyAedes albopictus’ecology by changing the dynamics of the species, and increasing the abundance of their breeding sites due to environmental changes, and thus contribute to dengue outbreaks. An efficient control of the vector requires a deeper understanding on the biological components of this vector. Thus, this study was conducted to evaluate the biting rhythm, fecundity and longevity rate ofAe. albopictusin relation to urbanization strata; urban, suburban and rural areas in Penang Island, Malaysia. The experiments were done in comparison to a laboratory strain. Twenty-four hours biting activity of all the mosquito strains showed a clear bimodal biting activity, with morning and evening twilight peaks. A two-way analysis of variance (ANOVA) found that there was statistically no significant interaction (F(69,192) = 1.337, P > 0.05) between the effects of biting time and mosquito strains. Meanwhile, fecundity rates were shown to be statistically significantly different between mosquito strains (F(3,442) = 10.559, P < 0.05) with urban areas having higher mean number of eggs (mean = 107.69, standard error = 3.98) than suburban (mean = 94.48, standard error = 5.18), and rural areas (mean = 72.52, standard error = 3.87). Longevity rates were significantly higher (F(3,441) = 31.259, P < 0.05) for mosquito strains from urban areas compared to the other strains. These findings would provide crucial and relevant fundamental information to the planning of control program in Malaysia, particularly Penang.

Author Summary

Aedes mosquito populations associated with human habitation in urban area do not only have the potential to cause biting nuisance, but also cause significant public health risks through the transmission of dengue virus. The socioeconomic effects of urbanization have been comprehensively studied by socio-ecologists, but the ecological effects and their impact on this vector biology was not known. The authors found that in Penang Island, the mean number of eggs laid per female ofAedes albopictusis high in the urban areas than those in suburban and rural areas. The survivorship is high for urban populations parallel to the fecundity rate and apparent biting pattern which is peak at dawn and dusk was noted for allAe. albopictusstrains. The changed environment in the urbanized area where more kinds of breeding containers and more blood sources produced by condensed human population supported by warm climate may facilitate larval development, enhance the vector survivorship and its reproductive fitness. These might be the reasons for quick adaptation and susceptibility ofAe. albopictusin urban areas. As higher fecundity rate and longer adult survival may enhance disease transmission, this species studied is indeed need high attention in terms of vector control.
Chronic Kidney Disease‐Associated Pruritus and Quality of Life in Malaysian Patients Undergoing Hemodialysis
Authors: Rehman Inayat U , Lai Pauline SM , Kun Lim S , Lee Learn H , Chan Kok G , Khan Tahir M
Published: June 2019

CKD‐associated pruritus is one of the common symptoms in patients undergoing dialysis, thus contributing to the diminished and compromised quality of life. This study aimed to explore the association between the CKD‐associated pruritus on quality of life of patients undergoing hemodialysis in Malaysia. A cross‐sectional multicenter study, carried out from February to September 2017 at tertiary care settings in Kuala Lumpur, Malaysia. Patients aged 18 years and above, undergoing hemodialysis, understanding Malay language and willing to participate were included. The CKD‐associated pruritus was assessed by using Malay 5D‐itch scale and Malay FANLTC questionaiare. To determine the factors associated with pruritus and quality of life, multivariate logistic regression analysis was used having P value < 0.05 as statistically significant. Among n = 334 recruited patients with a response rate of 100%, 59.6% were males and total of 61.3% were having CKD‐associated pruritus. The results showed a statistically significant weak negative correlation between CKD‐associated pruritus and quality of life. Multivariate linear regression revealed none of these factors were found to be associated with pruritus; however, CKD‐associated prurtius was found to be associated with quality of life score. CKD‐associated pruritus is have a negative impact on the patient's quality of life including physical, social, mental/emotional, and functional well‐being. Despite the high prevalence and negative impact of CKD‐associated pruritus on quality of life, it is disregarded by most health care professionals. It is thus pertinent to monitor the potential risk factors and consider providing timely treatment implications for CKD‐associated pruritus in hemodialysis patients, in order to improve their quality of life.
Transient introduction of human telomerase mRNA improves hallmarks of progeria cells
Authors: Li Yanhui , Zhou Gang , Bruno Ivone G. , Zhang Ning , Sho Sei , Tedone Enzo , Lai Tsung‐Po , Cooke John P. , Shay Jerry W.
Published: June 2019

Hutchinson–Gilford progeria syndrome (HGPS) is characterized by accelerated senescence due to a de novo mutation in the LMNA gene. The mutation produces an abnormal lamin A protein called progerin that lacks the splice site necessary to remove a farnesylated domain. Subsequently, progerin accumulates in the nuclear envelope, disrupting nuclear architecture, chromatin organization, and gene expression. These alterations are often associated with rapid telomere erosion and cellular aging. Here, we further characterize the cellular and molecular abnormalities in HGPS cells and report a significant reversal of some of these abnormalities by introduction of in vitro transcribed and purified human telomerase (hTERT) mRNA. There is intra‐individual heterogeneity of expression of telomere‐associated proteins DNA PKcs/Ku70/Ku80, with low‐expressing cells having shorter telomeres. In addition, the loss of the heterochromatin marker H3K9me3 in progeria is associated with accelerated telomere erosion. In HGPS cell lines characterized by short telomeres, transient transfections with hTERT mRNA increase telomere length, increase expression of telomere‐associated proteins, increase proliferative capacity and cellular lifespan, and reverse manifestations of cellular senescence as assessed by β‐galactosidase expression and secretion of inflammatory cytokines. Unexpectedly, mRNA hTERT also improves nuclear morphology. In combination with the farnesyltransferase inhibitor (FTI) lonafarnib, hTERT mRNA promotes HGPS cell proliferation. Our findings demonstrate transient expression of human telomerase in combination with FTIs could represent an improved therapeutic approach for HGPS.
Adjunctive photodynamic therapy improves the outcomes of peri‐implantitis: a randomized controlled trial
Authors: Wang H , Li W , Zhang D , Li W , Wang Z
Published: June 2019

Background

Photodynamic therapy (PDT) can be used for the management of peri‐implantitis. This study aimed to explore the efficacy and safety of PDT for peri‐implantitis in Chinese Han patients.

Methods

This was a single‐centre, open‐label, randomized controlled trial of participants with peri‐implantitis treated at the Beijing Chao‐Yang Hospital, randomized 1:1 to PDT or no PDT. PDT was performed using toluidine blue (10 mg/mL; 3 min) and a 635‐nm laser (750 mW; 10 s/implant side; minimum of 60 mW/cm2). The primary outcome was the decline in periodontal probing depth (PD) at 6 months. The secondary outcomes were peri‐implant plaque index (PLI), sulcular bleeding index (SBI), and clinical attachment loss (CAL).

Results

PD after treatment was smaller in the PDT group (n = 66) than in controls (n = 65) (all P < 0.001 vs. baseline). At 1 month, compared with controls, the PD in the PDT group was larger, while at 3‐ and 6‐month, the PDs were smaller (all P < 0.001). CAL, PLI and SBI in the PDT group was better (P < 0.05 vs. controls).

Conclusion

PDT combined with mechanical debridement significantly improves PD, PLI and SBI in participants with peri‐implantitis. Importantly, PDT achieved a better CAL than mechanical debridement and cleaning.
The relationship between myocardial fibrosis detected by cardiac magnetic resonance and Tp‐e interval, 5‐year sudden cardiac death risk score in hypertrophic cardiomyopathy patients
Authors: Riza Demir Ali , Celik Ömer , Sevinç Samet , Uygur Begüm , Kahraman Serkan , Yilmaz Emre , Cemek Mete , Onal Yilmaz , Erturk Mehmet
Published: June 2019

Background

The aim of this study was to investigate the relationship between QT (QTc) interval, Tp‐e interval, Tp‐e/QTc ratio, 5‐year sudden cardiac death (SCD) risk score, and late gadolinium enhancement (LGE) detected by CMR in hypertrophic cardiomyopathy (HCM) patients.

Method

A total of 74 consecutive patients who underwent CMR with HCM diagnosis were included in the study. These patients were divided into two groups according to the presence of LGE on CMR. All patients underwent detailed echocardiography and QTc interval, Tp‐e interval, and Tp‐e/QTc ratios and 5‐year SCD risk scores were calculated. These parameters were compared for two groups.

Results

CMR revealed LGE in 32 (43.2%) of 74 HCM patients. In the group with LGE, significantly higher QTc interval (p = 0.002), Tp‐e interval (p < 0.001), Tp‐e/QTc ratio (p = 0.004), and 5‐year SCD risk score were detected. In addition, QTc interval, Tp‐e interval, Tp‐e/QTc ratio, maximum wall thickness, left ventricular mass index, 5‐year SCD risk score, and cardiac fibrosis index were found to be correlated with various degrees in correlation analysis. Also, Tp‐e interval is found to be an independent predictor of LGE detected by CMR in HCM patients (p = 0.017, OR [%95 CI] = 1.017 [1.001–1.034]). In addition, the Tp‐e interval can detect the LGE with a sensitivity of 64.3% and a specificity of 84.2% at 99.4 ms. (p < 0.001, AUC [95% CI] = 0.790 [0.676–0.905]).

Conclusion

The Tp‐e interval can be used to optimize SCD risk stratification in HCM patients and determine which patients will benefit from implantable cardioverter‐defibrillator (ICD) treatment.
MicroRNA‐133 suppresses ZFHX3‐dependent atrial remodelling and arrhythmia
Authors: Cheng Wan‐Li , Kao Yu‐Hsun , Chao Tze‐Fan , Lin Yung‐Kuo , Chen Shih‐Ann , Chen Yi‐Jen
Published: June 2019

Aim

Atrial fibrillation (AF) is an important cause of morbidity and mortality in the modern world. Loss‐of‐function mutation in the zinc finger homeobox 3 gene (ZFHX3) is associated with increased risk of AF. MicroRNAs (miRNAs) participate in arrhythmogenesis, and thus miRNA modulators may be applicable as therapeutic modalities for AF. However, the altered miRNA profiles after ZFHX3 knockdown (KD) remain unclear. This study aimed to analyse the changes of miRNA expression in loss‐of‐function of ZFHX3 and the effect of miRNA modulation on atrial arrhythmias in this model.

Methods

We performed small RNA deep sequencing on ZFHX3‐KD and control HL‐1 mouse atrial myocytes. The effect of miRNAs on ZFHX3‐dependent atrial arrhythmia was evaluated through in vitro and in vivo assays in mice.

Results

Among the differentially expressed miRNAs, 11 were down‐regulated and 6 were up‐regulated after ZFHX3 KD. Quantitative real‐time PCR analysis confirmed that after ZFHX3 KD, miR‐133a and miR‐133b were significantly down‐regulated, whereas miR‐184 was the most significantly up‐regulated. DIANA‐miRPath analysis suggested that miR‐133a/b down‐regulation increases the targeted signalling of miR‐133 (ie, adrenergic, Wnt/calcium and fibroblast growth factor receptor 1 signalling), which could contribute to pathological remodelling of cardiomyocytes. These results were confirmed through Western blotting. After transfection of miR‐133a/b mimics in ZFHX3‐KD cells, miR‐133a/b levels increased, accompanied by the inhibition of their target signalling. Treatment with miR‐133a/b mimics diminished ZFHX3 KD–induced atrial ectopy in mice.

Conclusion

ZFHX3‐KD promotes distinct miRNA expressional changes in atrial myocytes. MiR‐133a/b mimics may reverse signalling of ZFHX3 KD‐mediated cardiac remodelling and atrial arrhythmia.
A phenomenological case study on immigrant workers' gambling addiction in Korea
Authors: Kang Sun Kyung , Shin Seungnam
Published: June 2019

This study explores the experiences that have led some of Korea's immigrant workers into gambling addiction and examines possible social welfare services that could support treatment. Immigrant workers' gambling experience as aliens in Korea was analyzed through the methodology of a phenomenological case study. The participants, who voluntarily consented to the study, were five immigrant workers addicted to gambling. Data were collected through one‐on‐one, in‐depth interviews over 6 months, starting in July 2018. The essential themes that emerged in the interviews were “changing strategies for survival,” “forgetting oneself without any sense of responsibility or shame,” “gambling as routine daily life,” “obsession with making a fortune in one go,” and “no home to return to.” Based on its results, this study makes suggestions for the prevention of gambling addiction in immigrant workers. Further, future research needs to be broadened to analyze nationwide cases of immigrant workers with more diverse demographic backgrounds.
Low concordance between HbA1c and OGTT to diagnose prediabetes and diabetes in overweight or obesity
Authors: Chatzianagnostou Kyriazoula , Vigna Luisella , Di Piazza Silvana , Tirelli Amedea Silvia , Napolitano Filomena , Tomaino Laura , Bamonti Fabrizia , Traghella Irene , Vassalle Cristina
Published: June 2019

Background

Glycated haemoglobin (HbA1c) test, introduced for diagnosing prediabetes and diabetes by the American Diabetes Association for some years, is currently under extensive discussion for contradictory data on the concordance between this test and the oral glucose tolerance test (OGTT).

Hypothesis

To assess concordance between HbA1c and OGTT to diagnose prediabetes and diabetes in subjects with overweight or obesity, focusing on possible gender‐related differences.

Methods

A total of 949 outpatients with overweight or obesity at risk for diabetes (mean age 50 ± 15 years; 660 F) were enrolled and underwent HbA1c test and OGTT.

Results

In both genders, HbA1c test identified more patients with prediabetes than OGTT (42% vs 22% in males, 40% vs 18% in females, respectively): a slight concordance between HbA1c and OGTT (60% of total tests in both genders).

In subjects diagnosed by OGTT, post‐OGTT insulin levels and HOMA INDEX were significantly higher than those found in HbA1c(+) cases. Instead, those diagnosed with HbA1c were significantly older and showed higher uric acid than those with both tests (−).

Conclusions

HbA1c test and OGTT did not reach full concordance for the diagnosis of diabetes and prediabetes in both genders. The two tests likely reflect different physiopathological aspects of dysglycaemia, suggesting that the ‘diagnostic thresholds’ could be reconsidered in light of the discordance observed.
Integrating opportunistic glaucoma screening into general health examinations in China: A pilot study
Authors: Zhang Shaodan , Sun Jing , Liu Shanshan , Liang Yuanbo , Hu Ying , Congdon Nathan , Pang Chi Pui , Wang Hailin
Published: June 2019

Importance

Under‐detection and late diagnosis are major causes of glaucoma‐related visual impairment. Cost‐effective opportunistic glaucoma screening is of great interest in the early identification and prevention of glaucoma.

Background

To describe the results of a health examination centre‐based opportunistic glaucoma screening and referral model.

Design

This single centre cross‐sectional study was conducted in a health examination centre affiliated to a tertiary hospital in Shenyang, northeastern China.

Participants

From 21 March to 30 September 2016, 14 367 individuals aged ≥ 30 years undergoing routine physical examinations were invited for this glaucoma screening.

Methods

Presenting visual acuity, non‐contact pneumotonometry and non‐mydriatic fundus photography were evaluated. Fundus photographs were classified as non‐glaucoma, possible, probable and definitive glaucoma. Participants with probable and definite glaucomatous discs or intraocular pressure ≥ 24 mmHg were referred for definitive examinations.

Main Outcome Measures

Detection rate of glaucoma suspects and ocular hypertension (OHT). Cost to identify a single case with suspected and diagnosed glaucoma was also calculated.

Results

Altogether, 277 glaucoma suspects and 327 ocular hypertension suspects were identified. Among 190 participants with probable/definite glaucomatous discs, 93 (48.9%) accepted further examination. Among these, 78 were diagnosed as glaucoma, seven as suspects and eight were excluded. Only 98 ocular hypertension suspects (30.0%) accepted further examinations: eight had primary angle closure and 23 had confirmed ocular hypertension. The cost to identify a single glaucoma suspect and definite glaucoma case were US$135 and US$857, respectively.

Conclusions and Relevance

This novel screening model provides opportunities to improve glaucoma detection at low cost. Interventions to improve follow‐up are needed.
Hypothermia protects retinal ganglion cells against hypoxia‐induced cell death in a retina organ culture model
Authors: Klemm Patricia , Hurst José , Dias Blak Matthias , Herrmann Thoralf , Melchinger Marion , Bartz‐Schmidt Karl U. , Zeck Günther , Schultheiss Maximilian , Spitzer Martin S. , Schnichels Sven
Published: June 2019

Background

Hypoxia contributes to retinal damage in several retinal diseases, including central retinal artery occlusion, with detrimental consequences like painless, monocular loss of vision. Currently, the treatment options are severely limited due to the short therapy window, as the neuronal cells, especially the retinal ganglion cells (RGCs), are irreversibly damaged within the first few hours. Hypothermia might be a possible treatment option or at least might increase the therapy window.

Methods

To investigate the neuroprotective effect of hypothermia after retinal hypoxia, an easy‐to‐use ex vivo retinal hypoxia organ culture model developed in our laboratory was used that reliably induced retinal damage on a structural, molecular and functional level. The neuroprotective effect of hypothermia after retinal hypoxia was analysed using optical coherence tomography scans, histological stainings, quantitative real‐time polymerase chain reaction, western blotting and microelectrode array recordings.

Results

Two different hypothermic temperatures (30°C and 20°C) were evaluated, both exhibited strong neuroprotective effects. Most importantly, hypothermia increased RGC survival after retinal hypoxia. Furthermore, hypothermia counteracted the hypoxia‐induced RGC death, reduced macroglia activation, attenuated retinal thinning and protected from loss of spontaneous RGC activity.

Conclusions

These results indicate that already a mild reduction in temperature protects the RGCs against damage and could function as a promising therapeutic option for hypoxic diseases.
Achieving conservation impact by shifting focus from human attitudes to behaviors
Authors: Nilsson Danielle , Fielding Kelly , Dean Angela J.
Published: June 2019

Attitudes have been a commonly used psychological measure of program effectiveness in conservation social science research. The major limitation of this approach is that attitudes do not always translate into behavior and therefore may not provide an accurate assessment of program success. Given that achieving conservation goals generally relies on understanding and changing human behavior, we argue for the need to assess behavior rather than attitudes as an indicator of conservation outcomes. Psychological theory shows that attitudes and behavior are distinct, but related, concepts. Measuring conservation behaviors involves identifying the target behavior or behaviors and the optimal time to measure and then selecting the most appropriate method of measurement (i.e., direct observation, objective indicators, self‐reported behavior, and behavioral intentions) that considers the strengths and weaknesses of each approach. We call for conservation programs to focus on influencing behavior rather than attitudes alone and encourage conservation practitioners and researchers to collect high‐quality behavioral data to more effectively inform policy and programs.
The effect of pre–heart transplant body mass index on posttransplant outcomes: An analysis of the ISHLT Registry Data
Authors: Doumouras Barbara S. , Fan Chun‐Po S. , Mueller Brigitte , Dipchand Anne I. , Manlhiot Cedric , Stehlik Josef , Ross Heather J. , Alba Ana C.
Published: June 2019

We evaluated the effect of pre–heart transplant body mass index (BMI) on posttransplant outcomes using the International Society for Heart and Lung Transplantation Registry. Kaplan‐Meier analysis and a multivariable Cox proportional hazard regression model were used for all‐cause mortality, and cause‐specific hazard regression for cause‐specific mortality and morbidity. We assessed 38 498 recipients from 2000 to 2014 stratified by pretransplant BMI. Ten‐year survival was 56% in underweight, 59% in normal weight, 57% in overweight, 52% in obese class I, 54% in class II, and 47% in class III patients (P < 0.001). Mortality was increased in underweight (HR 1.29, 95% CI 1.24‐1.35), obese class I (HR 1.19, 95% CI 1.13‐1.26), class II (HR 1.20, 95% CI 1.08‐1.32), and class III patients (HR 1.45, 95% CI 1.15‐1.83). Obesity was independently associated with increased death from myocardial infarction, chronic rejection, infection, and renal dysfunction. An underweight BMI lead to increased death from infection, acute and chronic rejection, malignancy, and bleeding. Obese patients had a higher incidence of renal dysfunction, diabetes, stroke, acute rejection, cardiac allograft vasculopathy, and malignancy, and underweight recipients had increased acute rejection. We have shown that pretransplant obese and underweight patients have increased post–heart transplant mortality and morbidity. This has implications for candidate selection and posttransplant management.
Ageing significantly impacts the biomechanical function and structural composition of skin
Authors: Langton Abigail K. , Graham Helen K. , Griffiths Christopher E. M. , Watson Rachel E. B.
Published: June 2019

Skin ageing is a complex process involving the additive effects of skin's interaction with its external environment, predominantly chronic sun exposure, upon a background of time‐dependent intrinsic ageing. Here, using non‐invasive cutometry and ballistometry, we explore the consequences of ageing on the biomechanical function of skin in otherwise healthy White Northern European volunteers. Intrinsic skin ageing caused biomechanical decline; skin loses both resilience (P < 0.01) and elasticity (P < 0.001), which is characterised histologically by modest effacement of rete ridges (P < 0.05) and disorganisation of papillary dermal elastic fibres. At photoexposed sites, biomechanical testing identified significant loss of biomechanical function—particularly in the aged cohort. Photoaged forearm displayed severe loss of resilience (P < 0.001) and elasticity (P < 0.001); furthermore with repetitive testing, fatigue (P < 0.001), hysteresis (P < 0.001) and viscous “creep” (P < 0.001) were exacerbated. Histologically, both young and aged forearm displayed flattening of rete ridges and disruption to the arrangement of elastic fibres. We conclude that maintenance of skin architecture is inherently associated with optimal biomechanical properties. Modest perturbations to skin architecture—as exemplified by intrinsic ageing—result in moderate functional decline. Chronic sun exposure causes fundamental changes to the clinical and histological appearance of skin, and these are reflected by an extreme alteration in biomechanical function.
Why does sweat lead to the development of itch in atopic dermatitis?
Authors: Murota Hiroyuki , Yamaga Kosuke , Ono Emi , Murayama Naoya , Yokozeki Hiroo , Katayama Ichiro
Published: June 2019

Sweating plays an important role in maintaining temperature homeostasis in humans. However, under certain circumstances, sweat can cause itching. For example, when excessive sweat accumulates on the skin surface for a long period, miliaria can develop and cause itching. Subjects with dermatoses, such as atopic dermatitis (AD), suffer from itch when exposed to heat or psychological stresses, which are also known perspiration stimuli. Recently, some mechanisms of sweat‐induced itch have been revealed. For instance, attenuated sweating ability is observed in subjects with AD, causing heat retention, skin dryness, and high susceptibility to itch. Furthermore, the decreased tight junction of the sweat gland in AD leads to sweat leakage in the dermis, which could be designated as a “sweat endocrine response” and may be the cause of tingling itch during sweating. Additionally, metabolomic analysis of sweat from patients with AD revealed that glucose concentration in sweat increases according to disease severity. Sweat with elevated glucose concentration retards the recovery of the damaged skin barrier and may promote itching. This viewpoint essay outlines the relationship between sweat and itch based on recent evidence.
The dorsal skinfold chamber: A valuable model for the in vivo evaluation of topical formulations
Authors: Dahmke Indra N. , Ampofo Emmanuel , Menger Michael D. , Laschke Matthias W.
Published: June 2019

In this study, we introduce the mouse dorsal skinfold chamber model as a valuable approach for the in vivo evaluation of topical formulations. For this purpose, dorsal skinfold chambers were implanted into BALB/c mice. Tumor necrosis factor (TNF)‐α was administered to the chamber tissue for the local induction of inflammation followed by the application of diclofenac‐containing or diclofenac‐free (control) gel onto the skin of the chamber backside. Intravital fluorescence microscopy was repetitively performed throughout an observation period of 24 hours to study macromolecular leakage, leucocyte‐endothelial cell interactions and microhaemodynamic parameters. In addition, infiltration of the inflamed tissue with different immune cell subtypes was assessed by immunohistochemistry. In a second set of experiments, the effect of dermal application of a diclofenac‐containing gel on photochemically induced thrombus formation was analysed. It was observed that macromolecular leakage, numbers of adherent leucocytes and tissue infiltrating myeloperoxidase (MPO)‐positive neutrophilic granulocytes and CD68‐positive macrophages were significantly reduced in dorsal skinfold chambers treated with diclofenac‐containing gel when compared to controls. Moreover, the diclofenac‐containing gel exerted an anti‐thrombotic activity, as indicated by a significantly prolonged complete vessel occlusion time. These findings demonstrate that the mouse dorsal skinfold chamber represents a valid and versatile tool to evaluate the effects of topical formulations in vivo.
Structural characterization and directed modification of Sus scrofa SAMHD1 reveal the mechanism underlying deoxynucleotide regulation
Authors: Kong Jia , Wang Mei‐mei , He Shuang‐yi , Peng Xin , Qin Xiao‐hong
Published: June 2019

Sterile α‐motif/histidine–aspartate domain‐containing protein 1 (SAMHD1) is an intrinsic antiviral restriction factor known to play a vital role in preventing multiple viral infections and in the control of the cellular deoxynucleoside triphosphate (dNTP) pool. Human and mouse SAMHD1 have both been extensively studied; however, our knowledge on porcine SAMHD1 is limited. Here, we report our findings from comprehensive structural and functional studies on porcine SAMHD1. We determined the crystal structure of porcine SAMHD1 and showed that it forms a symmetric tetramer. Moreover, we modified the deoxynucleotide triphosphohydrolase (dNTPase) activity of SAMHD1 by site‐directed mutagenesis based on the crystal structure, and obtained an artificial dimeric enzyme possessing high dNTPase activity. Taken together, our results define the mechanism underlying dNTP regulation and provide a deeper understanding of the regulation of porcine SAMHD1 functions. Directed modification of key residues based on the protein structure enhances the activity of the enzyme, which will be beneficial in the search for new antiviral strategies and for future translational applications.