bluuebunny/crossref_metadata_2025 huggingface dataset:
Case ascertainment in active paediatric surveillance systems: a report from the British Paediatric Surveillance Unit Ascertainment Group
Authors: Lynn Richard M , Reading Richard
Published: July 2019

The British Paediatric Surveillance Unit (BPSU) conducts surveillance of rare paediatric conditions using active, or prospective, case finding. The reliability of estimates of incidence, which is the primary outcome of public health importance, depends on ascertainment being as near complete as possible. This paper reviews evidence of the completeness of ascertainment in recent surveillance studies run through the BPSU. Ascertainment varied between 49% and 94% depending on the study. These are upper estimates. This was the basis of a discussion on barriers and facilitators of ascertainment which we have separated into factors related to the condition, factors related to the study methods, factors related to the study team and factors related to the surveillance system infrastructure. This leads to a series of recommendations to ensure continuing high levels of ascertainment in active surveillance studies.
Changes in hospital safety following penalties in the US Hospital Acquired Condition Reduction Program: retrospective cohort study
Authors: Sankaran Roshun , Sukul Devraj , Nuliyalu Ushapoorna , Gulseren Baris , Engler Tedi A , Arntson Emily , Zlotnick Hanna , Dimick Justin B , Ryan Andrew M
Published: July 2019

Objective

To evaluate the association between hospital penalization in the US Hospital Acquired Condition Reduction Program (HACRP) and subsequent changes in clinical outcomes.

Design

Regression discontinuity design applied to a retrospective cohort from inpatient Medicare claims.

Setting

3238 acute care hospitals in the United States.

Participants

Medicare fee-for-service beneficiaries discharged from acute care hospitals between 23 July 2014 and 30 November 2016 and eligible for at least one targeted hospital acquired condition (n=15 470 334).

Intervention

Hospital receipt of a penalty in the first year of the HACRP.

Main outcome measures

Episode level count of targeted hospital acquired conditions per 1000 episodes, 30 day readmissions, and 30 day mortality.

Results

Of 724 hospitals penalized under the HACRP in fiscal year 2015, 708 were represented in the study. Mean counts of hospital acquired conditions were 2.72 per 1000 episodes for penalized hospitals and 2.06 per 1000 episodes for non-penalized hospitals; 30 day readmissions were 14.4% and 14.0%, respectively, and 30 day mortality was 9.0% for both hospital groups. Penalized hospitals were more likely to be large, teaching institutions, and have a greater share of patients with low socioeconomic status than non-penalized hospitals. HACRP penalties were associated with a non-significant change of −0.16 hospital acquired conditions per 1000 episodes (95% confidence interval −0.53 to 0.20), −0.36 percentage points in 30 day readmission (−1.06 to 0.33), and −0.04 percentage points in 30 day mortality (−0.59 to 0.52). No clear patterns of clinical improvement were observed across hospital characteristics.

Conclusions

Penalization was not associated with significant changes in rates of hospital acquired conditions, 30 day readmission, or 30 day mortality, and does not appear to drive meaningful clinical improvements. By disproportionately penalizing hospitals caring for more disadvantaged patients, the HACRP could exacerbate inequities in care.
Prenatal diagnosis and prevalence of critical congenital heart defects: an international retrospective cohort study
Authors: Bakker Marian K , Bergman Jorieke E H , Krikov Sergey , Amar Emmanuelle , Cocchi Guido , Cragan Janet , de Walle Hermien E K , Gatt Miriam , Groisman Boris , Liu Shiliang , Nembhard Wendy N , Pierini Anna , Rissmann Anke , Chidambarathanu Shanthi , Sipek Jr Antonin , Szabova Elena , Tagliabue Giovanna , Tucker David , Mastroiacovo Pierpaolo , Botto Lorenzo D
Published: July 2019

Objectives

To assess international trends and patterns of prenatal diagnosis of critical congenital heart defects (CCHDs) and their relation to total and live birth CCHD prevalence and mortality.

Setting

Fifteen birth defect surveillance programmes that participate in the International Clearinghouse for Birth Defects Surveillance and Research from 12 countries in Europe, North and South America and Asia.

Participants

Live births, stillbirths and elective terminations of pregnancy for fetal anomaly diagnosed with 1 of 12 selected CCHD, ascertained by the 15 programmes for delivery years 2000 to 2014.

Results

18 243 CCHD cases were reported among 8 847 081 births. The median total prevalence was 19.1 per 10 000 births but varied threefold between programmes from 10.1 to 31.0 per 10 000. CCHD were prenatally detected for at least 50% of the cases in one-third of the programmes. However, prenatal detection varied from 13% in Slovak Republic to 87% in some areas in France. Prenatal detection was consistently high for hypoplastic left heart syndrome (64% overall) and was lowest for total anomalous pulmonary venous return (28% overall). Surveillance programmes in countries that do not legally permit terminations of pregnancy tended to have higher live birth prevalence of CCHD. Most programmes showed an increasing trend in prenatally diagnosed CCHD cases.

Discussion and conclusions

Prenatal detection already accounts for 50% or more of CCHD detected in many programmes and is increasing. Local policies and access likely account for the wide variability of reported occurrence and prenatal diagnosis. Detection rates are high especially for CCHD that are more easily diagnosed on a standard obstetric four-chamber ultrasound or for fetuses that have extracardiac anomalies. These ongoing trends in prenatal diagnosis, potentially in combination with newborn pulse oximetry, are likely to modify the epidemiology and clinical outcomes of CCHD in the near future.
Independent associations of blood pressure and body mass index with interatrial block: a cross-sectional study in general Chinese population
Authors: Sun Guozhe , Zhou Ying , Ye Ning , Wu Shaojun , Sun Yingxian
Published: July 2019

Objectives

This current study was performed to characterise the independent associations of obesity and hypertension with interatrial block (IAB) after adjusting for cardiovascular risk factors, echocardiographic left atrial diameter (LAD) and left ventricular mass index (LVMI) in a large general Chinese population.

Design

A cross-sectional study.

Setting and participants

A total of 11 956 permanent residents (≥35 years of age) from Liaoning Province in China were included in this study. Following the completion of a questionnaire, the enrolled participants were subjected to physical examinations, laboratory analyses, ECG and echocardiogram. Linear and logistic regression analyses were performed to evaluate the associations of hypertension and obesity with IAB.

Outcome measures

IAB was defined as a prolongation of the P wave duration ≥120 ms on a digital 12-lead ECG.

Results

The prevalence of IAB in hypertensive individuals was higher than the normotensive in both men (9.5 vs 5.9%; p<0.001) and women (6.6 vs 3.6%; p<0.001). In addition, the prevalence of IAB exhibited a sharp increase with advancing body mass index (BMI) in both men (from 4.9% to 13.0%) and women (from 3.5% to 6.9%) (ps- for trend <0.001). Multiple relevant clinical covariates, echocardiographic LAD and LVMI were adjusted in the multivariate linear and logistic regression analyses. The results revealed that systolic blood pressure, diastolic blood pressure and BMI were all independently associated with P wave duration (β=0.02, 0.09 and 0.25, respectively; all ps <0.005). Furthermore, hypertension was found to be independently associated with IAB (OR=1.27; p=0.018), while both overweight and obesity exhibited higher odds of IAB (OR=1.42 and 1.67, respectively; ps <0.005), compared with BMI <24.0 kg/m2.

Conclusions

The key findings of this study highlighted that hypertension and overweight/obesity were independently and significantly associated with IAB in general Chinese population.
Wearable inertial sensors and pressure MAT detect risk factors associated with ACL graft failure that are not possible with traditional return to sport assessments
Authors: Dan Michael J , Lun Kimberly Kai , Dan Luke , Efird Jimmy , Pelletier Matthew , Broe David , Walsh William R
Published: July 2019

Introduction

Anterior cruciate ligament reconstruction (ACLR) is associated with poor return to sport and high graft re-rupture rates. This study explored the use of a wearable inertial sensor (ViMove) that incorporates an accelerometer and gyroscope, and MatScan pressure sensing mat (TekScan, South Boston, Massachusetts, USA) to provide objective return-to-sport measures.

Methods

Three cohorts’ ACLR patients, non-athletic controls and elite athletes (Australian seven’s rugby Olympic Gold medallist). Patients performed biometric and functional tests (thigh circumference and triple hop) and the ViMove knee module (consisting of single and double leg squats, hops and box drops) for lower limb alignment assessment, concurrently with force plate.

Results

Elite athletes had less varus/valgus (VV) movement during ViMove exercises compared with the ACLR cohort, who in turn had less VV malalignment than controls. When analysing side-to-side differences, single leg squats and box drop were asymmetrical in the ACL group, with greater malalignment in the reconstructed leg (p<0.05). Subgroup analysis failed to differentiate who passed or failed current return to sport assessment. TekScan pressure plate detected differences in double leg landing and flight time while hopping not detected with ViMove, suggesting ACL patients compensate by offloading the reconstructed leg to improve coronal alignment during double leg activity.

Conclusion

The inertial sensor detected differences in motion for patients following ACLR, which are known to be associated with graft rupture and were not detected with functional return to sport testing. Coupling the device with data from a pressure plate provides a powerful assessment tool detecting alignment differences known to be associate with graft failure only previously detected in formal gait analysis.
Characterising JUUL-related posts on Instagram
Authors: Czaplicki Lauren , Kostygina Ganna , Kim Yoonsang , Perks Siobhan N , Szczypka Glen , Emery Sherry L , Vallone Donna , Hair Elizabeth C
Published: July 2019

Background

JUUL, a high-tech, popular vaping device, was the first major electronic cigarette (e-cigarette) brand to incorporate social media into its marketing strategy. There is growing concern around the increasing use of JUUL and other electronic nicotine delivery devices among youth, and their potential to addict a new generation to nicotine. The current study analysed the amount and characteristics of JUUL-related posts on Instagram, a social media platform used frequently among youth and young adults.

Methods

Hashtag-based keyword queries (n=50) were used to collect JUUL-related posts from the Instagram application programming interface, March 2018–May 2018. Using a combination of machine learning methods, keyword algorithms and human coding, posts were characterised as featuring content related to product promotion, nicotine and addiction, youth culture and lifestyle.

Results

Keyword queries captured 14 838 JUUL-relevant posts by 5201 unique users. Over one-third of posts were promotional (eg, linked to commercial website) and 11% contained nicotine and addiction-related information. Approximately half of posts featured content related to youth (55%) or lifestyle (57%). Youth-related content or lifestyle appeals were also notably present within promotional posts and nicotine and addiction-related posts, respectively. Nicotine and addiction-related posts featured memes, hashtags (eg, #nichead, #juulbuzz) and tag lines (eg, ‘more flavor, more buzz’).

Conclusions

Findings reveal a proliferation of JUUL-related content on Instagram, which focused on product promotion and nicotine and addiction that included youth culture and lifestyle appeals. Regulatory actions should focus on restricting promotional efforts for e-cigarette products, particularly on social media platforms where young people are a primary audience.
Arachidonic acid status negatively associates with forearm bone outcomes and glucose homeostasis in children with an overweight condition or obesity
Authors: Mak Ivy L. , Cohen Tamara R. , Vanstone Catherine A. , Weiler Hope A.
Published: July 2019

Long-chain polyunsaturated fatty acids are implicated in musculoskeletal health in adults. This study examined whether fatty acid status relates to bone health outcomes in children with overweight condition or obesity (body mass index z score, 3.1 ± 0.1; age, 9.0 ± 0.2 years; n = 108). Nondominant forearm bone density (distal one-third), geometry (4% site), and soft tissue composition (66%) were assessed using dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. Red blood cell (RBC) fatty acid profile and indices of glucose homeostasis were measured. Differences in outcomes among RBC arachidonic acid (AA, C20:4n-6) tertiles were tested using mixed-model ANOVA. Ultra-, mid-, and total-distal forearm bone mineral content, adjusted for sex, age, percentage body fat, race, and forearm length, were 10% to 13% greater in children in the first AA tertile relative to the third. Children in the second tertile had the highest bone cross-sectional area and estimated strength at the 66% radius. Muscle cross-sectional area was 15% lower in the third tertile compared with the first, along with higher fasting insulin concentrations (27%) and homeostasis model of assessment estimate of insulin resistance (31%). Higher RBC AA status aligns with deficits in forearm bone mass, geometry, and muscle mass in children with excess adiposity and early signs of insulin resistance.

Novelty Higher arachidonic acid status is associated with lower forearm bone mass in children with overweight condition or obesity. Children with higher arachidonic acid status had increased fasting insulin concentrations and indices of insulin resistance.
Calibration of reliability-based safety factors for sand boiling in excavations
Authors: Pratama Ignatius Tommy , Ou Chang-Yu , Ching Jianye
Published: July 2019

This study calibrated the required factors of safety of five analysis methods for sand boiling using reliability theory. The factors of safety computed by the five analysis methods were compared with the results of a series of sand boiling model tests. The comparison shows that rigorous methods (Terzaghi’s and Harza’s methods) were more accurate in predicting the factors of safety compared to the simplified methods (Harr’s, simplified Terzaghi’s, and simplified Harza’s methods). The statistics of the model factor for each method, defined as the actual factor of safety divided by the computed one, was calibrated by the model test results. These statistics were then used to establish the relationship between the target probability of failure and the required factor of safety by reliability theory. Verification using a full-scale sand boiling case history shows that the required factor of safety calibrated by the reliability theory was more reasonable than the required factors of safety in references and design codes.
Étude structurale des systèmes dissymétriques de structure D-π-A à base de thiénopyrazine destinés aux cellules solaires organiques de type « bulk heterojunction » (BHJ)
Authors: Bourass Mohamed , Bouachrine Mohammed
Published: July 2019

Onze nouvelles molécules organiques de structure donneurs-espaceur-accepteurs (D-π-A) utilisées pour les cellules solaires organiques (OSC) basées sur la thiénopyrazine et le thiophène ont été étudiées par la théorie de la densité fonctionnelle (DFT) et la théorie de la densité fonctionnelle dépendante de temps DFT (TD-DFT), pour expliquer comment l’ordre de conjugaison influe sur les performances des cellules solaires. Le groupe accepteur d’électrons (ancrage) était composé de 2-cyanoacrylique pour tous les composés, tandis que l’unité donneuse d’électrons était variée et que son influence fut étudiée. Les résultats théoriques ont montré que les calculs TD-DFT, avec une fonction hybride d’échange – corrélation utilisant la méthode d’atténuation de Coulomb (CAM-B3LYP) en conjonction avec un modèle de solvatation à cycle continu polarisable (modèle de continuum polarisable, PCM) combinée avec la base 6-31G(d,p), était raisonnablement capable de prédire les énergies d’excitation, les spectres d’absorption et d’émission des molécules étudiées. Les niveaux d’énergie des orbitales moléculaires frontières (orbitale moléculaire occupée de plus haute énergie (HOMO) et orbitale moléculaire inoccupée de plus basse énergie (LUMO) de ces composés peuvent avoir un effet positif sur le processus d’injection et de régénération d’électrons. La tendance des lacunes calculées HOMO-LUMO se compare bien avec les données spectrales. En outre, les valeurs estimées de photovoltage en circuit ouvert (Voc) pour ces composés ont été présentées. L’étude des propriétés structurelles, électroniques et optiques de ces composés pourrait aider à concevoir des matériaux organiques photovoltaïques fonctionnels plus efficaces.
Pack-year Smoking Associated with Poorer Functional Status, Worsened Spinal Mobility and More Radiological Damages
Authors: Tsang Helen Hoi Lun , Chung Ho Yin
Published: July 2019

Introduction: To study the dose-response relationship between smoking and axial Spondyloarthritis (axSpA) disease outcome.

Method: One hundred and sixty participants with axSpA were recruited from a single rheumatology center. All of them fulfilled the classification criteria for axSpA by the Assessment of SpondyloArthritis International Society (ASAS). Clinical, demographic and biochemical data was collected. Participants were asked for detailed smoking histories including past and current smoking, smoking duration and quantity. Radiographs of cervical and lumbar spine were performed for modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) and modified New York (MNY) criteria for radiological sacroiliitis. Ankylosing Spondylitis Disease Activity Score (ASDAS) was calculated based on C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Univariate and multivariate regression models were performed to determine the associations between pack-year smoking and different disease outcomes.

Results: Among the participants, 62 (38.7%) were either current (N [Formula: see text] 39) or former smokers (N [Formula: see text] 23). Ex-smokers quit smoking by 18.8 ± 12.4 years. The mean pack-year for patients who had ever smoked was 19.4 ± 23.1. In univariate analyses, pack-year smoking was associated with BASFI (p <0.001), modified Schober test (p [Formula: see text] 0.01) and mSASSS (p <0.001). Multivariate regression models showed independent dose-response associations between pack-year of smoking and BASFI (SC 0.23; 95% CI 0.01 to 0.06; p [Formula: see text] 0.004), modified Schober test (SC −0.16; 95% CI −0.03 to 0.00; p [Formula: see text] 0.049) and mSASSS (SC 0.22; 95% CI 0.09 to 0.47; p [Formula: see text] 0.01).

Conclusion: In Chinese axSpA patients, pack-year smoking was independently associated with poorer functional status, worsened spinal mobility and more radiological damages. Smoking cessation should be encouraged in patients with axSpA.
Features of radioactive element distribution within the Arkhangelsk diamondiferous province: possible directions for development of isotope–radiogeochemical methods for kimberlite prospecting in complex landscape–geology and climate conditions of the subarctic zone
Authors: Yakovlev Evgeny Yu.
Published: July 2019

The effectiveness of traditional methods of searching for kimberlite pipes in the Arkhangelsk diamondiferous province (in the subarctic zone of Russia) has decreased greatly in recent years, and new methods of kimberlite exploration must therefore be developed. This study discusses new patterns of the distribution of natural radioactive isotopes within the Arkhangelsk diamondiferous province (Zolotitskoe kimberlite field), and the uranium isotopes
234
U and
238
U in particular. A variety of isotope radiogeochemical studies has shown that the kimberlite pipes are characterized by local radioisotope anomalies, on the surface and in exploration drill cores. These irregularities are clearly manifested in the formation of a non-equilibrium anomalous uranium isotope composition in the surrounding rocks and groundwater of the near-contact zone of the pipes. These uranium isotopes can be used to explore for kimberlites in other areas with similar complex landscape–geology and climate conditions of the subarctic zone.
Security and Privacy on Blockchain
Authors: Zhang Rui , Xue Rui , Liu Ling
Published: July 2019

Blockchain offers an innovative approach to storing information, executing transactions, performing functions, and establishing trust in an open environment. Many consider blockchain as a technology breakthrough for cryptography and cybersecurity, with use cases ranging from globally deployed cryptocurrency systems like Bitcoin, to smart contracts, smart grids over the Internet of Things, and so forth. Although blockchain has received growing interests in both academia and industry in the recent years, the security and privacy of blockchains continue to be at the center of the debate when deploying blockchain in different applications. This article presents a comprehensive overview of the security and privacy of blockchain. To facilitate the discussion, we first introduce the notion of blockchains and its utility in the context of Bitcoin-like online transactions. Then, we describe the basic security properties that are supported as the essential requirements and building blocks for Bitcoin-like cryptocurrency systems, followed by presenting the additional security and privacy properties that are desired in many blockchain applications. Finally, we review the security and privacy techniques for achieving these security properties in blockchain-based systems, including representative consensus algorithms, hash chained storage, mixing protocols, anonymous signatures, non-interactive zero-knowledge proof, and so forth. We conjecture that this survey can help readers to gain an in-depth understanding of the security and privacy of blockchain with respect to concept, attributes, techniques, and systems.
Control of lysosomal TRPML1 channel activity and exosome release by acid ceramidase in mouse podocytes
Authors: Li Guangbi , Huang Dandan , Hong Jinni , Bhat Owais M. , Yuan Xinxu , Li Pin-Lan
Published: July 2019

The transient receptor potential mucolipin 1 (TRPML1) channel has been reported to mediate lysosomal Ca2+ release that is involved in Ca2+-dependent lysosome trafficking and autophagic flux. However, this regulatory mechanism of lysosomal TRPML1 channel activity in podocytes remains poorly understood. In the present study, we tested whether the TRPML1 channel in podocytes mediates lysosome trafficking, which is essential for multivesicular body (MVB) degradation by lysosomes. We first demonstrated the abundant expression of TRPML1 channel in podocytes. By GCaMP3 Ca2+ imaging, we characterized the lysosomal specificity of TRPML1 channel-mediated Ca2+ release in podocytes. Given the important role of acid ceramidase (AC) in lysosome function and podocyte injury, we tested whether AC regulates this TRPML1 channel-mediated Ca2+ release and consequent lysosome-dependent MVB degradation in podocytes. Pharmacologically, it was found that TRPML1 channel activity was remarkably attenuated by the AC inhibitor carmofur. Sphingosine, as an AC product, was demonstrated to induce TRPML1-mediated Ca2+ release, which was inhibited by a TRPML1 blocker, verapamil. Using a Port-a-Patch planar patch-clamp system, we found that AC-associated sphingolipids, sphingomyelin, ceramide, and sphingosine had different effects on TRPML1 channel activity in podocytes. Functionally, the inhibition of AC or blockade of TRPML1 channels was found to suppress the interaction of lysosomes and MVBs, leading to increased exosome release from podocytes. These results suggest that AC is critical for TRPML1 channel-mediated Ca2+ release, which controls lysosome-MVB interaction and exosome release in podocytes.
Alcohol-induced adipose tissue macrophage phenotypic switching is independent of myeloid Toll-like receptor 4 expression
Authors: Fulham Melissa A. , Ratna Anuradha , Gerstein Rachel M. , Kurt-Jones Evelyn A. , Mandrekar Pranoti
Published: July 2019

Alcoholic liver disease results from a combination of immune and metabolic pathogenic events. In addition to liver injury, chronic alcohol consumption also causes adipose tissue inflammation. The specific immune mechanisms that drive this process are unknown. Here, we sought to determine the role of the innate immune receptor Toll-like receptor 4 (TLR4) in alcohol-induced adipose tissue inflammation. Using a model of chronic, multiple-binge alcohol exposure, we showed that alcohol-mediated accumulation of proinflammatory adipose tissue macrophages was absent in global TLR4 knockout mice. Proinflammatory macrophage accumulation did not depend on macrophage TLR4 expression; LysMCre-driven deletion of Tlr4 from myeloid cells did not affect circulating endotoxin or the accumulation of M1 macrophages in adipose tissue following alcohol exposure. Proinflammatory cytokine/chemokine production in the adipose stromal vascular fraction also occurred independently of TLR4. Finally, the levels of other adipose immune cells, such as dendritic cells, neutrophils, B cells, and T cells, were modulated by chronic, multiple-binge alcohol and the presence of TLR4. Together, these data indicate that TLR4 expression on cells, other than myeloid cells, is important for the alcohol-induced increase in proinflammatory adipose tissue macrophages.
G protein-coupled receptor kinase 2 regulates mitochondrial bioenergetics and impairs myostatin-mediated autophagy in muscle cells
Authors: Manfredi Leandro Henrique , Ang Joshur , Peker Nesibe , Dagda Ruben K. , McFarlane Craig
Published: July 2019

G protein-coupled receptor kinase 2 (GRK2) is an important protein involved in β-adrenergic receptor desensitization. In addition, studies have shown GRK2 can modulate different metabolic processes in the cell. For instance, GRK2 has been recently shown to promote mitochondrial biogenesis and increase ATP production. However, the role of GRK2 in skeletal muscle and the signaling mechanisms that regulate GRK2 remain poorly understood. Myostatin is a well-known myokine that has been shown to impair mitochondria function. Here, we have assessed the role of myostatin in regulating GRK2 and the subsequent downstream effect of myostatin regulation of GRK2 on mitochondrial respiration in skeletal muscle. Myostatin treatment promoted the loss of GRK2 protein in myoblasts and myotubes in a time- and dose-dependent manner, which we suggest was through enhanced ubiquitin-mediated protein loss, as treatment with proteasome inhibitors partially rescued myostatin-mediated loss of GRK2 protein. To evaluate the effects of GRK2 on mitochondrial respiration, we generated stable myoblast lines that overexpress GRK2. Stable overexpression of GRK2 resulted in increased mitochondrial content and enhanced mitochondrial/oxidative respiration. Interestingly, although overexpression of GRK2 was unable to prevent myostatin-mediated impairment of mitochondrial respiratory function, elevated levels of GRK2 blocked the increased autophagic flux observed following treatment with myostatin. Overall, our data suggest a novel role for GRK2 in regulating mitochondria mass and mitochondrial respiration in skeletal muscle.
Activity within specific enteric neurochemical subtypes is correlated with distinct patterns of gastrointestinal motility in the murine colon
Authors: Gould Thomas W. , Swope William A. , Heredia Dante J. , Corrigan Robert D. , Smith Terence K.
Published: July 2019

The enteric nervous system in the large intestine generates two important patterns relating to motility: 1) propagating rhythmic peristaltic smooth muscle contractions referred to as colonic migrating motor complexes (CMMCs) and 2) tonic inhibition, during which colonic smooth muscle contractions are suppressed. The precise neurobiological substrates underlying each of these patterns are unclear. Using transgenic animals expressing the genetically encoded calcium indicator GCaMP3 to monitor activity or the optogenetic actuator channelrhodopsin (ChR2) to drive activity in defined enteric neuronal subpopulations, we provide evidence that cholinergic and nitrergic neurons play significant roles in mediating CMMCs and tonic inhibition, respectively. Nitrergic neurons [neuronal nitric oxide synthase (nNOS)-positive neurons] expressing GCaMP3 exhibited higher levels of activity during periods of tonic inhibition than during CMMCs. Consistent with these findings, optogenetic activation of ChR2 in nitrergic neurons depressed ongoing CMMCs. Conversely, cholinergic neurons [choline acetyltransferase (ChAT)-positive neurons] expressing GCaMP3 markedly increased their activity during the CMMC. Treatment with the NO synthesis inhibitor Nω-nitro-l-arginine also augmented the activity of ChAT-GCaMP3 neurons, suggesting that the reciprocal patterns of activity exhibited by nitrergic and cholinergic enteric neurons during distinct phases of colonic motility may be related.

NEW & NOTEWORTHY Correlating the activity of neuronal populations in the myenteric plexus to distinct periods of gastrointestinal motility is complicated by the difficulty of measuring the activity of specific neuronal subtypes. Here, using mice expressing genetically encoded calcium indicators or the optical actuator channelrhodopsin-2, we provide compelling evidence that cholinergic and nitrergic neurons play important roles in mediating coordinated propagating peristaltic contractions or tonic inhibition, respectively, in the murine colon.
Inhibition of retinoic acid signaling induces aberrant pericyte coverage and differentiation resulting in vascular defects in congenital diaphragmatic hernia
Authors: Kool Heleen M. , Bürgisser Petra E. , Edel Gabriëla G. , de Kleer Ismé , Boerema-de Munck Anne , de Laat Inge , Chrifi Ihsan , Cheng Caroline , van Cappellen Wiggert A. , Kremers Gert-Jan , Tibboel Dick , Rottier Robbert J.
Published: July 2019

The mortality and morbidity of patients with congenital diaphragmatic hernia (CDH) is primarily caused by treatment-resistant, persistent pulmonary hypertension. Structural vascular changes, exemplified by extensive muscularization, are already present early in gestation, but the origin of these abnormalities is unknown. Understanding the origin of the vascular defects is important to improve treatment modalities. Here, we show that the distribution of pericytes is different and may thereby potentially initiate the vascular pathology in CDH. Transient inhibition of retinoic acid (RA) signaling early during pregnancy, the basis of the CDH mouse model, led to an increase in the number of pericytes, thereby affecting the angiogenic potential of pericytes in the fetuses. Pericytes of CDH lungs showed reduced proliferation and an increased ACTA2 expression, which indicates that these pericytes are more contractile than in control lung pericytes. This resulted in increased pericyte coverage of pulmonary vessels and reduced expansion of the capillary bed, the earliest pathological sign of the structural changes in CDH. Furthermore, the pericytes had reduced and altered collagen IV deposition in CDH, pointing to a loss of basal membrane integrity between pericytes and endothelial cells. Inhibition of RA signaling in vitro resulted in reduced migration of pericytes, reduced angiogenesis, and loss of collagen IV expression. Importantly, we confirmed our findings in lungs of human CDH patient samples. In summary, inhibition of RA signaling affects the lung pericyte population, leading to increased contractility, reduced pulmonary angiogenesis, and aberrant lung development, as observed in CDH.
Histone deacetylase 6 regulates endothelial MyD88-dependent canonical TLR signaling, lung inflammation, and alveolar remodeling in the developing lung
Authors: Menden Heather , Xia Sheng , Mabry Sherry M. , Noel-MacDonnell Janelle , Rajasingh Johnson , Ye Shui Qing , Sampath Venkatesh
Published: July 2019

Lung endothelial cell (EC) immune activation during bacterial sepsis contributes to acute lung injury and bronchopulmonary dysplasia in premature infants. The epigenetic regulators of sepsis-induced endothelial immune activation, lung inflammation, and alveolar remodeling remain unclear. Herein, we examined the role of the cytoplasmic histone deacetylase, HDAC6, in regulating EC Toll-like receptor 4 (TLR4) signaling and modulating sepsis-induced lung injury in a neonatal model of sterile sepsis. In human primary microvascular endothelial cells (HPMEC), lipopolysaccharide (LPS)-induced MAPK, IKK-β, and p65 phosphorylation as well as inflammatory cytokine expression were exaggerated with the HDAC6 inhibitor tubastatin A, and by dominant-negative HDAC6 with a mutated catalytic domain 2. Expression of HDAC6 wild-type protein suppressed LPS-induced myeloid differentiation primary response 88 (MyD88) acetylation, p65 (Lys310) acetylation, MyD88/TNF receptor-associated factor 6 (TRAF6) coimmunoprecipitation, and proinflammatory TLR4 signaling in HPMEC. In a neonatal mouse model of sepsis, the HDAC6 inhibitor tubastatin A amplified lung EC TLR4 signaling and vascular permeability. HDAC6 inhibition augmented LPS-induced MyD88 acetylation, MyD88/TRAF6 binding, p65 acetylation, canonical TLR4 signaling, and inflammation in the developing lung. Sepsis-induced decreases in the fibroblast growth factors FGF2 and FGF7 and increase in matrix metalloproteinase-9 were worsened with HDAC6 inhibition, while elastin expression was equally suppressed. Exaggerated sepsis-induced acute lung inflammation observed with HDAC6 inhibition worsened alveolar simplification evidenced by increases in mean linear intercepts and decreased radial alveolar counts. Our studies reveal that HDAC6 is a constitutive negative regulator of cytoplasmic TLR4 signaling in EC and the developing lung. The therapeutic efficacy of augmenting HDAC6 activity in neonatal sepsis to prevent lung injury needs to be evaluated.
Mitochondrial activity contributes to impaired renal metabolic homeostasis and renal pathology in STZ-induced diabetic mice
Authors: Wu Mengqiu , Li Shuzhen , Yu Xiaowen , Chen Weiyi , Ma Haoyang , Shao Chang , Zhang Yue , Zhang Aihua , Huang Songming , Jia Zhanjun
Published: July 2019

Diabetic nephropathy (DN) has become the main cause of end-stage renal disease worldwide, but the efficacy of current therapeutic strategies on DN remains unsatisfactory. Recent research has reported the involvement of metabolic rearrangement in the pathological process of DN, and of all the disturbances in metabolism, mitochondria serve as key regulatory hubs. In the present study, high-resolution mass spectrometry-based nontarget metabolomics was used to uncover the metabolic characteristics of the early diabetic kidney with or without the inhibition of mitochondrial activity. At first, we observed a moderate enhancement of mitochondrial complex-1 activity in the diabetic kidney, which was completely normalized by the specific mitochondrial complex-1 inhibitor rotenone (ROT). Meanwhile, metabolomics data indicated an overactivated pentose phosphate pathway, purine and pyrimidine metabolism, hexosamine biosynthetic pathway, and tricarboxylic acid cycle, which were strikingly corrected by ROT. In addition, ROT also strikingly corrected imbalanced redox homeostasis, possibly by increasing the ratio of antioxidant metabolites glutathione and NADPH against their oxidative form. In agreement with the improved metabolic status and oxidative response, ROT attenuated glomerular and tubular injury efficiently. Fibrotic markers (fibronectin, α-smooth muscle actin, collagen type I, and collagen type III), inflammatory factors (TNF-α, IL-1β, and ICAM-1), and oxidative stress were all markedly blocked by ROT. In vitro, ROT dose dependently attenuated high glucose-induced proliferation and extracellular matrix production in mesangial cells. Collectively, these findings revealed that the overactivation of mitochondrial activity in the kidney could contribute to metabolic disorders and the pathogenesis of early DN.
New opportunities: Drosophila as a model system for exercise research
Authors: Watanabe Louis P. , Riddle Nicole C.
Published: July 2019

Because of the growing rates of obesity in much of the world, exercise as a treatment option for obesity and as part of a healthy lifestyle is of great interest to the general public, health policy makers, and scientists alike. Despite the long history of exercise promotion and exercise research, there are still significant gaps in our understanding of how exercise impacts individuals and what role genetics plays in determining an individual’s response to exercise. Model organisms are positioned uniquely to help address these questions because of the challenges associated with carrying out large-scale, well-controlled studies in humans. The fruit fly model system, Drosophila melanogaster, has joined the models used for exercise research only recently but already has made significant contributions to the field. In this review, we highlight the opportunities for exercise research in Drosophila. We review the resources available to researchers interested in using Drosophila for exercise research, focusing on the existing systems to induce exercise in Drosophila, to measure the amount of exercise performed, and to assess physical fitness. We illustrate the potential of the Drosophila system by drawing attention to pioneering studies in Drosophila exercise research and emphasize the unique opportunities this model system represents.
Active membrane conductances and morphology of a collision detection neuron broaden its impedance profile and improve discrimination of input synchrony
Authors: Dewell Richard B. , Gabbiani Fabrizio
Published: July 2019

How neurons filter and integrate their complex patterns of synaptic inputs is central to their role in neural information processing. Synaptic filtering and integration are shaped by the frequency-dependent neuronal membrane impedance. Using single and dual dendritic recordings in vivo, pharmacology, and computational modeling, we characterized the membrane impedance of a collision detection neuron in the grasshopper Schistocerca americana. This neuron, the lobula giant movement detector (LGMD), exhibits consistent impedance properties across frequencies and membrane potentials. Two common active conductances gH and gM, mediated respectively by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and by muscarine-sensitive M-type K+ channels, promote broadband integration with high temporal precision over the LGMD’s natural range of membrane potentials and synaptic input frequencies. Additionally, we found that a model based on the LGMD’s branching morphology increased the gain and decreased the delay associated with the mapping of synaptic input currents to membrane potential. More generally, this was true for a wide range of model neuron morphologies, including those of neocortical pyramidal neurons and cerebellar Purkinje cells. These findings show the unexpected role played by two widespread active conductances and by dendritic morphology in shaping synaptic integration.

NEW & NOTEWORTHY Neuronal filtering and integration of synaptic input patterns depend on the electrochemical properties of dendrites. We used an identified collision detection neuron in grasshoppers to examine how its morphology and two conductances affect its membrane impedance in relation to the computations it performs. The neuronal properties examined are ubiquitous and therefore promote a general understanding of neuronal computations, including those in the human brain.
Case studies in neuroscience: subcortical origins of the frequency-following response
Authors: White-Schwoch Travis , Anderson Samira , Krizman Jennifer , Nicol Trent , Kraus Nina
Published: July 2019

The auditory frequency-following response (FFR) reflects synchronized and phase-locked activity along the auditory pathway in response to sound. Although FFRs were historically thought to reflect subcortical activity, recent evidence suggests an auditory cortex contribution as well. Here we present electrophysiological evidence for the FFR’s origins from two cases: a patient with bilateral auditory cortex lesions and a patient with auditory neuropathy, a condition of subcortical origin. The patient with auditory cortex lesions had robust and replicable FFRs, but no cortical responses. In contrast, the patient with auditory neuropathy had no FFR despite robust and replicable cortical responses. This double dissociation shows that subcortical synchrony is necessary and sufficient to generate an FFR.

NEW & NOTEWORTHY The frequency-following response (FFR) reflects synchronized and phase-locked neural activity in response to sound.  The authors present a dual case study, comparing FFRs and cortical potentials between a patient with auditory neuropathy (a condition of subcortical origin) and a patient with bilateral auditory cortex lesions. They show that subcortical synchrony is necessary and sufficient to generate an FFR.
Disruption of peripheral nerve development in a zebrafish model of hyperglycemia
Authors: Ennerfelt Hannah , Voithofer Gabrielle , Tibbo Morgan , Miller Derrick , Warfield Rebecca , Allen Samantha , Kennett Clark Jessica
Published: July 2019

Diabetes mellitus-induced hyperglycemia is associated with a number of pathologies such as retinopathy, nephropathy, delayed wound healing, and diabetic peripheral neuropathy (DPN). Approximately 50% of patients with diabetes mellitus will develop DPN, which is characterized by disrupted sensory and/or motor functioning, with treatment limited to pain management. Zebrafish ( Danio rerio) are an emerging animal model used to study a number of metabolic disorders, including diabetes. Diabetic retinopathy, nephropathy, and delayed wound healing have all been demonstrated in zebrafish. Recently, our laboratory has demonstrated that following the ablation of the insulin-producing β-cells of the pancreas (and subsequent hyperglycemia), the peripheral nerves begin to show signs of dysregulation. In this study, we take a different approach, taking advantage of the transdermal absorption abilities of zebrafish larvae to extend the period of hyperglycemia. Following 5 days of 60 mM d-glucose treatment, we observed motor axon defasciculation, disturbances in perineurial glia sheath formation, decreased myelination of motor axons, and sensory neuron mislocalization. This study extends our understanding of the structural changes of the peripheral nerve following induction of hyperglycemia and does so in an animal model capable of potential DPN drug discovery in the future.

NEW & NOTEWORTHY Zebrafish are emerging as a robust model system for the study of diabetic complications such as retinopathy, nephropathy, and impaired wound healing. We present a novel model of diabetic peripheral neuropathy in zebrafish in which the integrity of the peripheral nerve is dysregulated following the induction of hyperglycemia. By using this model, future studies can focus on elucidating the underlying molecular mechanisms currently unknown.
Phytochemical Analysis and Toxicity Study of Aristolochia paucinervis Rhizomes Decoction Used in Moroccan Alternative Medicine: Histopathological and Biochemical Profiles
Authors: Bourhia Mohammed , Lahmadi Ayoub , Achtak Hafid , Touis Ayoub , Elbrahmi Jamal , Ullah Riaz , Shahat Abdelaaty A. , Mahmood Hafiz Majid , Aboudkhil Souad , Benbacer Laila , Khlil Naima
Published: July 2019

Ethnopharmacological Relevance. Aristolochia paucinervis (A. paucinervis) (Aristolochiaceae) is a plant frequently used in Moroccan alternative medicine. The aim of the current study is to investigate the phytochemical composition of rhizomes decoction of A. paucinervis (RDA) and to evaluate its acute and subacute toxicity following the OECD guidelines. Materials and Methods. The qualitative phytochemical analysis of A. paucinervis was performed using standard qualitative phytochemical procedures. The acute toxicity of rhizomes decoction of the studied plant was evaluated in mice at single doses of 1, 2, and 4 g/kg of body weight for 14 days. In subacute toxicity study, the decoction was orally administered to mice at three different doses (0.5, 1, and 1.5 g/kg/day) for 28 days. Histopathological and biochemical parameters were investigated. Results. The preliminary phytochemical screening showed the presence of flavonoids, saponins, alkaloids, and polyphenols and the absence of anthraquinones, sterols, and terpenes. There was no mortality and no significant changes occurred in animals treated with 1 and 2 g/kg in the acute toxicity model. The signs of toxicity and morbidity were remarkable with the highest tested dose (4g/kg). LD50 (dose required to kill 50% of the test population) was determined as 4 g/kg. Repeated oral administration of 1 and 1.5 g/kg/day of RDA for 28 days induced significant disturbance of serum parameters (AST, ALT, LDH, urea, creatinine). Kidney and liver extracted from mice fed with 1 and 1.5 g/kg/day showed significant histopathological injuries as tubular necrosis, inflammatory infiltrate, tubular degeneration, necrosis, and hepatic cholestasis. Meanwhile, neither histopathological nor biochemical alterations were observed in mice treated with 0.5 g/kg/day of body weight in comparison to the control group. Conclusion. RDA showed toxicity in mice at a dose of 1 g/kg/day under subacute toxicity conditions. RDA is safe at a single dose inferior to 4 g/kg of body weight. The plant extract prepared by decoction showed more poisonous effect than the extract prepared by maceration at room temperature.
Optimization of Scanning Parameters in Coordinate Metrology Using Grey Relational Analysis and Fuzzy Logic
Authors: Mian Syed Hammad , Umer Usama , Alkhalefah Hisham
Published: July 2019

The phenomenon of coordinate measuring machines has led to a significant improvement in accuracy, adaptability, and reliability for measurement jobs. The coordinate measuring machines with scanning capabilities provide the alternative to output precise acquisition at a faster rate. However, they are less accurate as compared to discrete probing systems and slower than the noncontact techniques. Therefore, the data acquisition using a scanning touch probe needs improvement, so that it can provide commendable performance both in terms of accuracy and scanning time. The determination of appropriate scanning parameters is crucial to minimize the inaccuracy and time associated with the scanning process. However, it can be demanding as well as unreliable owing to the presence of uncertainty from a multitude of factors that may influence the measurement process. The optimization of data acquisition using a scanning touch probe is a multiresponse process which involves definite uncertainties from various sources. Therefore, multioptimization tools based on grey relational analysis coupled with principal component analysis and fuzzy logic were employed to enhance the utilization of the scanning touch probe. The work described here has the objective to identify the appropriate combination of scanning factors which can simultaneously boost the accuracy and lessen the scanning time. This study demonstrates the capability and effectiveness of the uncertainty theory based optimization methods in coordinate metrology. It also suggests that the uncertainty associated with the parameter optimization can be significantly reduced using these techniques. It has also been noticed that the results from the two techniques are in accord, which corroborates their application in coordinate metrology. The result from this study can be applied to other probing systems and can be broadened to include more experiments and parameters in various scenarios as needed by the specific application.