Consensus on nomenclature for clinical staging models in bipolar disorder: A narrative review from the International Society for Bipolar Disorders (ISBD) Staging Task Force.

Abstract:
OBJECTIVES
Clinical staging is widely used in medicine to map disease progression, inform prognosis, and guide treatment decisions; in psychiatry, however, staging remains a hypothetical construct. To facilitate future research in bipolar disorders (BD), a well-defined nomenclature is needed, especially since diagnosis is often imprecise with blurred boundaries, and a full understanding of pathophysiology is lacking.

METHODS
Under the auspices of the International Society of Bipolar Disorders, a Task Force of international experts was convened to review, discuss, and integrate findings from the scientific literature relevant to the development of a consensus staging model and standardize a terminology that could be used to advance future research including staging of BD and related disorders.

RESULTS
Consensus opinion and areas of uncertainty or difference were identified in regard to terms referring to staging as it may apply to BD, to at-risk status and subthreshold stages, and to various clinical stages of BD as it is currently diagnosed.

CONCLUSION
The use of a standardized nomenclature about the clinical stages of BD will facilitate communication about research on clinical and pathological components of this heterogeneous group of disorders. The concepts presented are based on current evidence, but the template provided allows for further refinements as etiological advances come to light.

nomenclature
clinical staging
bipolar disorders


Serial block face scanning electron microscopy and the reconstruction of plant cell membrane systems.

Abstract: Serial block face imaging with the scanning electron microscope has been developed as an alternative to serial sectioning and transmission electron microscopy for the ultrastructural analysis of the three-dimensional organization of cells and tissues. An ultramicrotome within the microscope specimen chamber permits sectioning and imaging to a depth of many microns within resin-embedded specimens. The technology has only recently been adopted by plant microscopists and here we describe some specimen preparation procedures suitable for plant tissue, suggested microscope imaging parameters and discuss the software required for image reconstruction and analysis.

Osmium impregnation
SBFSEM
plant membranes
selective staining


Ubiquitination in Scleroderma Fibrosis and Its Treatment.

Abstract: Scleroderma (systemic sclerosis, SSc) is a highly heterogeneous rheumatic disease, and uncontrolled fibrosis in visceral organs is the major cause of death in patients. The transforming growth factor-β (TGF-β) and WNT/β-catenin signaling pathways, along with signal transducer and activator of transcription 3 (STAT3), play crucial roles in this fibrotic process. Currently, no therapy is available that effectively arrests or reverses the progression of fibrosis in patients with SSc. Ubiquitination is an important post-translational modification that controls many critical cellular functions. Dysregulated ubiquitination events have been observed in patients with systemic lupus erythematosus, rheumatoid arthritis and fibrotic diseases. Inhibitors targeting the ubiquitination pathway have considerable potential for the treatment of rheumatic diseases. However, very few studies have examined the role and mechanism of ubiquitination in patients with SSc. In this review, we will summarize the molecular mechanisms of ubiquitination in patients with SSc and explore the potential targets for treatment.

Long|Ying|Y| Chen|Weilin|W| Du|Qian|Q| Zuo|Xiaoxia|X| Zhu|Honglin|H|

ubiquitination SSc TGF-β WNT/β-catenin STAT3


Optimal experimental designs for dose-response studies with continuous endpoints.

Abstract: In most areas of clinical and preclinical research, the required sample size determines the costs and effort for any project, and thus, optimizing sample size is of primary importance. An experimental design of dose-response studies is determined by the number and choice of dose levels as well as the allocation of sample size to each level. The experimental design of toxicological studies tends to be motivated by convention. Statistical optimal design theory, however, allows the setting of experimental conditions (dose levels, measurement times, etc.) in a way which minimizes the number of required measurements and subjects to obtain the desired precision of the results. While the general theory is well established, the mathematical complexity of the problem so far prevents widespread use of these techniques in practical studies. The paper explains the concepts of statistical optimal design theory with a minimum of mathematical terminology and uses these concepts to generate concrete usable D-optimal experimental designs for dose-response studies on the basis of three common dose-response functions in toxicology: log-logistic, log-normal and Weibull functions with four parameters each. The resulting designs usually require control plus only three dose levels and are quite intuitively plausible. The optimal designs are compared to traditional designs such as the typical setup of cytotoxicity studies for 96-well plates. As the optimal design depends on prior estimates of the dose-response function parameters, it is shown what loss of efficiency occurs if the parameters for design determination are misspecified, and how Bayes optimal designs can improve the situation.

Weibull function
3T3/NHK guideline
D-optimal design
Dose response modelling
Log-logistic function
Log-normal function


Risk Factors for Primary Middle East Respiratory Syndrome Coronavirus Infection in Camel Workers in Qatar During 2013-2014: A Case-Control Study.

Abstract: The transmission routes and risk factors for zoonotic Middle East respiratory syndrome coronavirus (MERS-CoV) infections are still unknown. We used the World Health Organization questionnaire for MERS-CoV case-control studies to assess risk factors for human MERS-CoV seropositivity at a farm complex in Qatar. Nine camel workers with MERS-CoV antibodies and 43 workers without antibodies were included. Some camel-related activities may pose a higher risk of MERS-CoV infection, as may cross-border movements of camels, poor hand hygiene, and overnight hospital stays with respiratory complaints. The risk factors identified in this study can be used to develop infection prevention and control measures for human MERS-CoV infections.

Sikkema|Reina S|RS|
Farag|Elmoubasher A B A|EABA|
Himatt|Sayed|S|
Ibrahim|Adel K|AK|
Al-Romaihi|Hamad|H|
Al-Marri|Salih A|SA|
Al-Thani|Mohamed|M|
El-Sayed|Ahmed M|AM|
Al-Hajri|Mohammed|M|
Haagmans|Bart L|BL|
Koopmans|Marion P G|MPG|
Reusken|Chantal B E M|CBEM|

D065207:Middle East Respiratory Syndrome Coronavirus

risk factors
coronavirus
transmission
zoonotic
MERS-CoV


Lipid metabolism-related proteins of relevant evolutionary and lymphoid interest (PRELI) domain containing family proteins in cancer.

Abstract: Metabolic reprogramming of tumor cells plays a critical role in the tumor microenvironment, including disorder of lipid metabolism. Recently, lipid metabolism has received increasing attention in cancer research. The proteins of relevant evolutionary and lymphoid interest (PRELI) domain containing family contains 6 proteins. Functionally, the PRELI-like family proteins were mainly involved in mitochondrial lipid transport and correlated with several types of diseases and malignant tumors. Here we review current knowledge of the functions, structures, biological functions and underlying mechanisms of the PRELI-like family proteins in cancer progression, which provide insights into the clinical translational application.

Zhu|Yue|Y| Zou|Renrui|R| Sha|Huanhuan|H| Lu|Ya|Y| Zhang|Yuan|Y| Wu|Jianzhong|J| Feng|Jifeng|J| Wang|Dongfeng|D|

tumor
Lipid metabolism
the PRELI-like family


Risk of Cardiomyopathy in Breast Cancer: How Can We Attenuate the Risk of Heart Failure from Anthracyclines and Anti-HER2 Therapies?

Abstract:
PURPOSE OF REVIEW
To review cardiotoxicity of and strategies to prevent cardiotoxicity from anthracyclines and anti-HER2 agents used to treat breast cancer.

RECENT FINDINGS
Although not common, cardiotoxicity from anthracyclines and anti-HER2 therapies is a major consideration in the use of these agents, especially in the adjuvant setting. Modifications in anthracycline agent, dosing, or schedule or use of Dexrazoxane have been shown to ameliorate the mostly irreversible cardiotoxicity from anthracyclines. Dose delays have been the primary means of addressing the possibly reversible cardiotoxicity from the anti-HER2 agent, trastuzumab, whereas the other anti-HER2 therapies, pertuzumab, lapatinib, and neratinib, are relatively nontoxic to the myocardium. Data from recent randomized clinical trials suggest that the use of angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), and beta blockers may prevent subclinical cardiotoxicity, as measured by decline in the left ventricular ejection fraction, associated with these agents. Longer-term follow-up will be needed to confirm their role in prevention of symptomatic cardiomyopathy and subsequent cardiovascular disease in women with breast cancer. Preliminary evidence suggests that the use of ACEi, ARB, and beta blockers during treatment with anthracyclines and trastuzumab may prevent subsequent cardiomyopathy. Larger trials with meaningful clinical endpoints are needed.

Breast cancer
Anthracyclines
Anti-HER2 therapies
Trastuzumab
Cardiotoxicity, cardiomyopathy


Expression of Foxp3, CD25 and IL-2 in the B16F10 cancer cell line and melanoma is correlated with tumor growth in mice.

Abstract: The forkhead box P3 (Foxp3) transcription factor is one of the most studied markers used to identify CD4+CD25+ regulatory T cells (Tregs), and has been identified as a key regulator in the development and function of Tregs. Foxp3 expression has been reported in a variety of solid human tumors, including melanoma. The aims of the present study were to analyze Foxp3 expression in B16F10 melanoma cells in vitro, to determine whether this expression was affected during tumor growth in a murine melanoma model and to correlate Foxp3 expression with CD25 expression, interleukin (IL)-2 production and tumor weight. Foxp3 expression was analyzed with quantitative (q)PCR, flow cytometry and confocal microscopy. CD25 expression was analyzed by flow cytometry, and cytokine production was measured by ELISA [IL-2, interferon (IFN)-γ, transforming growth factor (TGF)-β and IL-10] and flow cytometry (IL-2, IFN-γ, IL-4 and IL-5). Foxp3 and CD25 expression was detected in the B16F10 cells in culture and in the intratumoral B16F10 cells. An increase in Foxp3 and CD25 expression was observed in a time-dependent manner during tumor growth at 7, 14 and 21 days. The production of the IL-2, IL-10, IFN-γ and TGF-β cytokines was observed in the B16F10 cells and also detected in the tumoral microenvironment during tumor growth (7, 14 and 21 days). An increase in IL-2 and IL-10 production was observed, whereas IFN-γ production decreased in a time-dependent manner. The production of tumor necrosis factor (TNF)-α was not observed in culture, but was detected during tumor growth, whereas the production of IL-4 and IL-5 was not detected. These data showed a positive correlation between the expression of Foxp3, CD25 and IL-2 and tumor weight in murine melanoma. From these data, it may be suggested that Foxp3 participates in melanoma growth, the modulation of the IL-2, IFN-γ and TNF-α cytokines and CD25 expression, and that it also plays a possible role in immunosuppression.

Miranda-Hernández|D F|DF|
Franco-Molina|M A|MA|
Mendoza-Gamboa|E|E|
Zapata-Benavides|P|P|
Sierra-Rivera|C A|CA|
Coronado-Cerda|E E|EE|
Rosas-Taraco|A G|AG|
Taméz-Guerra|R S|RS|
Rodríguez-Padilla|C|C|

CD25
melanoma
forkhead box P3
regulatory T cells
cytokines
interleukin-2


Multigrid MALDI mass spectrometry imaging (mMALDI MSI).

Abstract: Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) is an important technique for the spatially resolved molecular analysis of tissue sections. The selection of matrices influences the resulting mass spectra to a high degree. For extensive and simultaneous analysis, the application of different matrices to one tissue sample is desirable. To date, only a single matrix could be applied to a tissue section per experiment. However, repetitive removal of the matrix makes this approach time-consuming and damaging to tissue samples. To overcome these drawbacks, we developed a multigrid MALDI MSI technique (mMALDI MSI) that relies on automated inkjet printing to place differing matrices onto predefined dot grids. We used a cooled printhead to prevent cavitation of low viscosity solvents in the printhead nozzle. Improved spatial resolution of the dot grids was achieved by using a triple-pulse procedure that reduced droplet volume. The matrices can either be applied directly to the thaw-mounted tissue sample or by precoating the slide followed by mounting of the tissue sample. During the MALDI imaging process, we were able to precisely target different matrix point grids with the laser to simultaneously produce distinct mass spectra. Unlike the standard method, the prespotting approach optimizes the spectra quality, avoids analyte delocalization, and enables subsequent hematoxylin and eosin (H&E) staining. Graphical Abstract Scheme of the pre-spotted multigrid MALDI MSI workflow.

Urbanek|Annett|A|
Hölzer|Stefan|S|
Knop|Katrin|K|
Schubert|Ulrich S|US|
von Eggeling|Ferdinand|F|

D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Multigrid
Mass spectrometry imaging
Simultaneous analysis
Inkjet printing
Multiplex
Sub-pixel


Changes in function but not oligomeric size are associated with αB-crystallin lysine substitution.

Abstract: αB-Crystallin, ubiquitously expressed in many tissues including the ocular lens, is a small heat shock protein that can prevent protein aggregation. A number of post-translation modifications are reported to modify αB-crystallin function. Recent studies have identified αB-crystallin lysine residues are modified by acetylation and ubiquitination. Therefore, we sought to determine the effects of lysine to alanine substitution on αB-crystallin functions including chaperone activity and modulation of actin polymerization. Analysis of the ten substitution mutants as recombinant proteins indicated all the proteins were soluble and formed oligomeric complexes similar to wildtype protein. Lysozyme aggregation induced by chemical treatment indicated that K82, K90, K121, K166 and K174/K175 were required for efficient chaperone activity. Thermal induction of γ-crystallin aggregation could be prevented by all αB-crystallin substitution mutants. These αB-crystallin mutants also were able to mediate wildtype levels of actin polymerization. Further analysis of two clones with either enhanced or reduced chaperone activity on individual client substrates or actin polymerization indicated both retained broad chaperone activity and anti-apoptotic activity. Collectively, these studies show the requirements for lysine residues in αB-crystallin function.

Droho|Steven|S|
Keener|Mitchell E|ME|
Mueller|Niklaus H|NH|

αB-crystallin
Ocular lens
Small heat shock proteins
sHSP


Substances of abuse consumption among patients seeking medical help for uro-andrological purposes: a sociobehavioral survey in the real-life scenario.

Abstract: Substances of abuse (SoA), as well as smoking and alcohol consumption, are well known for their impact on male fertility status, erectile function, and ejaculation. We assessed SoA consumption habits in a cohort of men seeking medical attention for uro-andrological purposes. Data from 7447 men seeking medical attention for the first time for uro-andrological purposes were analyzed. A complete medical and sexual history was collected for each patient. Smoking, alcohol, and SoA consumption were investigated. Descriptive statistics was used to describe the whole cohort. The primary motivations for their evaluation were lower urinary tract symptoms (LUTS), erectile dysfunction (ED), and infertility in 1912 (25.7%), 2944 (39.5%), and 2591 (34.8%) men, respectively. Previous use of SoA was reported by 378 (5.1%) men, and 190 (2.6%) individuals were current users. Patients seeking medical attention for infertility were more frequently current SoA users (107; 4.1%) than men with ED (66; 2.2%) and LUTS (17; 0.9%) (both P < 0.001). Current users of SoA were younger than those with past or no SoA history (P < 0.001). Current SoA users were more frequently smokers (P < 0.001) and alcohol consumers (P < 0.001) than those with a previous history or those who had never tried SoA. In conclusion, approximately 3% of men seeking medical attention for uro-andrological purposes were current SoA consumers. Infertile men reported a higher use of SoA than those with ED or LUTS. Current SoA users were younger and more frequently concomitant smokers and alcohol consumers compared to those who did or had never used SoA.

Belladelli|Federico|F| Boeri|Luca|L| Capogrosso|Paolo|P| Cazzaniga|Walter|W| Ventimiglia|Eugenio|E| Candela|Luigi|L| Pozzi|Edoardo|E| Baudo|Andrea|A| Alfano|Massimo|M| Abbate|Costantino|C| Montorsi|Francesco|F| Salonia|Andrea|A|

substances of abuse
erectile dysfunction
cannabis
cocaine
male infertility
risk factors


Fatal Neonatal Herpes Simplex Infection Likely from Unrecognized Breast Lesions.

Abstract: Type 1 herpes simplex virus (HSV-1) is very prevalent yet in rare circumstances can lead to fatal neonatal disease. Genital acquisition of type 2 HSV is the usual mode for neonatal herpes, but HSV-1 transmission by genital or extragenital means may result in greater mortality rates. A very rare scenario is presented in which the mode of transmission was likely through breast lesions. The lesions were seen by nurses as well as the lactation consultant and obstetrician in the hospital after delivery of the affected baby but not recognized as possibly being caused by herpes. The baby died 9 days after birth with hepatic failure and disseminated intravascular coagulation. Peripartum health care workers need to be aware of potential nongenital (including from the breast[s]) neonatal herpes acquisition, which can be lethal.

D018445:Infectious Disease Transmission, Vertical

neonatal herpes simplex
type 1 herpes
breastfeeding


Laccase Directed Lignification Is One of the Major Processes Associated With the Defense Response Against Pythium ultimum Infection in Apple Roots.

Abstract: Apple replant disease (ARD), incited by a pathogen complex including Pythium ultimum, causes stunted growth or death of newly planted trees at replant sites. Development and deployment of resistant or tolerant rootstocks offers a cost-effective, ecologically friendly, and durable approach for ARD management. Maximized exploitation of natural resistance requires integrated efforts to identify key regulatory mechanisms underlying resistance traits in apple. In this study, miRNA profiling and degradome sequencing identified major miRNA pathways and candidate genes using six apple rootstock genotypes with contrasting phenotypes to P. ultimum infection. The comprehensive RNA-seq dataset offered an expansive view of post-transcriptional regulation of apple root defense activation in response to infection from P. ultimum. Several pairs of miRNA families and their corresponding targets were identified for their roles in defense response in apple roots, including miR397-laccase, miR398-superoxide dismutase, miR10986-polyphenol oxidase, miR482-resistance genes, and miR160-auxin response factor. Of these families, the genotype-specific expression patterns of miR397 indicated its fundamental role in developing defense response patterns to P. ultimum infection. Combined with other identified copper proteins, the importance of cellular fortification, such as lignification of root tissues by the action of laccase, may critically contribute to genotype-specific resistance traits. Our findings suggest that quick and enhanced lignification of apple roots may significantly impede pathogen penetration and minimize the disruption of effective defense activation in roots of resistant genotypes. The identified target miRNA species and target genes consist of a valuable resource for subsequent functional analysis of their roles during interaction between apple roots and P. ultimum.

Zhu|Yanmin|Y| Li|Guanliang|G| Singh|Jugpreet|J| Khan|Awais|A| Fazio|Gennaro|G| Saltzgiver|Melody|M| Xia|Rui|R|

apple root
degradome sequencing
post-transcriptional regulation
defense activation
plant resistance
small RNA profiling
soilborne pathogens


An Industry in Transition: The Chemical Industry and the Megatrends Driving Its Forthcoming Transformation.

Abstract: Significant product and process innovation is taking place in the chemical industry. Rather than making bold predictions, this Essay emphasizes that this change, due to impact both main segments of the industry, is driven by societal megatrends concerning the environment, health, and energy which permeate societies on a global scale.

chemical industry
green chemistry
sustainability


Short-term Outcomes of Saffron Supplementation in Patients with Age-related Macular Degeneration: A Double-blind, Placebo-controlled, Randomized Trial.

Abstract: In modern pharmacological medicine, saffron is used for various purposes due to its antioxidant effect. This study evaluated retinal function after treatment with saffron supplementation during a follow-up period of 6 months to provide further insight into the efficacy and safety considerations of this treatment. Sixty patients with wet or dry age-related macular degeneration (AMD) were randomly assigned to receive oral saffron 30 mg/d or placebo supplementation for 6 months. Optical coherence tomography (OCT), electroretinography (ERG), fluorescein angiography, and visual acuity testing were performed at baseline and 3 and 6 months after treatment. The main outcome measures were OCT, ERG amplitude, and implicit time. Six months after treatment, no statistically significant decrease in OCT results was observed between the groups with dry AMD (P = 0.282). However, there was a statistically significant increase in ERG results between the groups at 3 months after treatment (P = 0.027). In addition, there was a significant decrease in OCT results between groups with wet AMD at the follow-up (P = 0.05). Finally, there was a significant increase in ERG findings between the groups with wet AMD at 3 months after treatment (P = 0.01), but these changes decreased at 6 months after treatment (P = 0.213). Daily supplementation with 30 mg of saffron for 6 months may result in a mid-term, significant improvement in retinal function in patients with AMD.

Lashay|Alireza|A| Sadough|Gholamreza|G| Ashrafi|Elham|E| Lashay|Mohammadreza|M| Movassat|Morteza|M| Akhondzadeh|Shahin|S|

Saffron Supplementation
Age-related Macular Degeneration
Randomized Trial


A modular approach to the total synthesis of tunicamycins.

Abstract: The tunicamycins constitute a delicate mimic of the bisubstrate intermediates of N-acetyl-D-hexosamine-1-phosphate translocases and thus inhibit bacterial cell-wall synthesis and the N glycosylation of eukaryotic proteins. An efficient approach to the synthesis of this unique type of nucleoside antibiotics is now reported and features the assembly of five modules in a highly stereoselective and robust manner. A Mukaiyama aldol reaction, intramolecular acetal formation, gold(I)-catalyzed O and N glycosylation, and final N acylation were used as the key steps.

total synthesis
tunicamycin
glycosylation
nucleosides
gold


The Lateral Preoptic Area and Its Projection to the VTA Regulate VTA Activity and Drive Complex Reward Behaviors.

Abstract: The ventral tegmental area (VTA) underlies motivation and reinforcement of natural rewards. The lateral preoptic area (LPO) is an anterior hypothalamic brain region that sends direct projections to the VTA and to other brain structures known to regulate VTA activity. Here, we investigated the functional connection between the LPO and subpopulations of VTA neurons and explored the reinforcing and valence qualities of the LPO in rats. We found that the LPO and the LPO→VTA pathway inhibit the activity of VTA GABA neurons and have mixed effects on VTA dopamine neurons. Furthermore, we found that the LPO supports operant responding but drives avoidance, and we explored the apparent discrepancy between these two results. Finally, using fiber photometry, we show that the LPO signals aversive events but not rewarding events. Together, our findings demonstrate that the LPO modulates the activity of the VTA and drives motivated behavior and represents an overlooked modulator of reinforcement.

Gordon-Fennell|Adam|A| Gordon-Fennell|Lydia|L| Desaivre|Stève|S| Marinelli|Michela|M|

lateral preoptic area
ventral tegmental area
reinforcement
valence
dopamine
hypothalamus


Retrieval and classification of food images.

Abstract: Automatic food understanding from images is an interesting challenge with applications in different domains. In particular, food intake monitoring is becoming more and more important because of the key role that it plays in health and market economies. In this paper, we address the study of food image processing from the perspective of Computer Vision. As first contribution we present a survey of the studies in the context of food image processing from the early attempts to the current state-of-the-art methods. Since retrieval and classification engines able to work on food images are required to build automatic systems for diet monitoring (e.g., to be embedded in wearable cameras), we focus our attention on the aspect of the representation of the food images because it plays a fundamental role in the understanding engines. The food retrieval and classification is a challenging task since the food presents high variableness and an intrinsic deformability. To properly study the peculiarities of different image representations we propose the UNICT-FD1200 dataset. It was composed of 4754 food images of 1200 distinct dishes acquired during real meals. Each food plate is acquired multiple times and the overall dataset presents both geometric and photometric variabilities. The images of the dataset have been manually labeled considering 8 categories: Appetizer, Main Course, Second Course, Single Course, Side Dish, Dessert, Breakfast, Fruit. We have performed tests employing different representations of the state-of-the-art to assess the related performances on the UNICT-FD1200 dataset. Finally, we propose a new representation based on the perceptual concept of Anti-Textons which is able to encode spatial information between Textons outperforming other representations in the context of food retrieval and Classification.

Farinella|Giovanni Maria|GM|
Allegra|Dario|D|
Moltisanti|Marco|M|
Stanco|Filippo|F|
Battiato|Sebastiano|S|

D016247:Information Storage and Retrieval

Food retrieval
Anti-Textons
Textons
Food classification
Food representation


MicroRNA-186 targets SKP2 to induce p27Kip1-mediated pituitary tumor cell cycle deregulation and modulate cell proliferation.

Abstract: Pituitary tumors are usually benign but can occasionally exhibit hormonal and proliferative behaviors. Dysregulation of the G1/S restriction point largely contributes to the over-proliferation of pituitary tumor cells. F-box protein S-phase kinase-interacting protein-2 (SKP2) reportedly targets and inhibits the expression of p27Kip1, a well-known negative regulator of G1 cell cycle progression. In this study, SKP2 expression was found to be upregulated while p27Kip1 expression was determined to be downregulated in rat and human pituitary tumor cells. Furthermore, SKP2 knockdown induced upregulation of p27Kip1 and cell growth inhibition in rat and human pituitary tumor cells, while SKP2overexpression elicited opposite effects on p27Kip1 expression and cell growth. The expression of microRNA-186 (miR-186) was reported to be reduced in pituitary tumors. Online tools predicted SKP2 to be a direct downstream target of miR-186, which was further confirmed by luciferase reporter gene assays. Moreover, miR-186 could modulate the cell proliferation and p27Kip1-mediated cell cycle alternation of rat and human pituitary tumor cells through SKP2. As further confirmation of these findings, miR-186 and p27Kip1 expression were downregulated, while SKP2 expression was upregulated in human pituitary tumor tissue samples; thus, SKP2 expression negatively correlated with miR-186 and p27Kip1 expression. In contrast, miR-186 expression positively associated with p27Kip1 expression. Taken together, we discovered a novel mechanism by which miR-186/SKP2 axis modulates pituitary tumor cell proliferation through p27Kip1-mediated cell cycle alternation.

He|Zongze|Z| Chen|Longyi|L| Wang|Qi|Q| Yin|Cheng|C| Hu|Junting|J| Hu|Xiao|X| Fei|Fan|F| Tang|Jian|J|

microRNA-186
Cell proliferation
S-phase kinase-interacting protein-2
Cyclin-dependent kinase inhibitor p27
Pituitary neoplasms


How does brain insulin resistance develop in Alzheimer's disease?

Abstract: Compelling preclinical and clinical evidence supports a pathophysiological connection between Alzheimer's disease (AD) and diabetes. Altered metabolism, inflammation, and insulin resistance are key pathological features of both diseases. For many years, it was generally considered that the brain was insensitive to insulin, but it is now accepted that this hormone has central neuromodulatory functions, including roles in learning and memory, that are impaired in AD. However, until recently, the molecular mechanisms accounting for brain insulin resistance in AD have remained elusive. Here, we review recent evidence that sheds light on how brain insulin dysfunction is initiated at a molecular level and why abnormal insulin signaling culminates in synaptic failure and memory decline. We also discuss the cellular basis underlying the beneficial effects of stimulation of brain insulin signaling on cognition. Discoveries summarized here provide pathophysiological background for identification of novel molecular targets and for development of alternative therapeutic approaches in AD.

De Felice|Fernanda G|FG|
Lourenco|Mychael V|MV|
Ferreira|Sergio T|ST|

Insulin resistance
Alzheimer's disease
Amyloid-β oligomers
GLP-1R agonists
Insulin therapy


The impact of COVID-19 on the ride-sharing industry and its recovery: Causal evidence from China.

Abstract: The COVID-19 pandemic has brought unprecedented disruptions to many industries, and the transportation industry is among the most disrupted ones. We seek to address, in the context of a ride-sharing platform, the response of drivers to the pandemic and the post-pandemic recovery. We collected comprehensive trip data from one of the leading ride-sharing companies in China from September 2019 to August 2020, which cover pre-, during-, and post-pandemic phases in three major Chinese cities, and investigate the causal effect of the COVID-19 pandemic on driver behavior. We find that drivers only slightly reduce their number of shifts in response to increased COVID-19 cases, likely because they have to make a living from providing ride-sharing services. Nevertheless, conditional on working, drivers exhibit strong risk aversion: As the number of new cases increases, drivers strategically adjust the scope of their search for passengers, complete fewer trips, and as a result, make lower daily earnings. Finally, our heterogeneity analyses indicate that the effects appear to vary both across drivers and over time, with generally stronger effects on drivers who are older, more experienced, more active before the pandemic, and higher-status within the firm. Our findings have strong policy implications: These drivers tend to contribute more to the focal company, and also rely more on providing ride-sharing services to make a living. Therefore, they should be prioritized in stimulus plans offered by the government or the ride-sharing company.

Wang|Wei|W| Miao|Wei|W| Liu|Yongdong|Y| Deng|Yiting|Y| Cao|Yunfei|Y|

COVID-19
Ride-sharing
Recovery
Causal inference
Instrumental variables


White matter hyperintensities and cognition across different Alzheimer's biomarker profiles.

Abstract:
BACKGROUND/OBJECTIVES
To examine the association between white matter hyperintensities (WMH) and cognitive domains such as memory and executive function (EF) across different clinical and biomarker categories of Alzheimer's disease (AD).

DESIGN
Cross-sectional study.

SETTING
Alzheimer's Disease Neuroimaging Initiative.

PARTICIPANTS
A total of 216 cognitively normal (CN) participants and 407 participants with mild cognitive impairment (MCI) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) at baseline.

MEASUREMENTS
Based on the 2018 research framework, participants were classified using AT(N) (amyloid-β deposition [A], pathologic tau [T], and neurodegeneration [(N)]) biomarkers into one of three categories: biomarker negative [A - T- (N)-], amyloid negative but other biomarker positive [A - T ± (N)+ or A - T + (N)±] or amyloid positive [A + T ± (N)±]. Linear regression models were then used to examine the association between WMH and memory composite scores and EF composite scores.

RESULTS
Higher WMH burden was associated with worse EF in both CN and MCI subgroups while a significant association between WMH and memory was only found in the MCI subgroup. Furthermore, WMH was associated with EF in the group with A - T ± (N)+ or A - T + (N)± biomarker category, but not for A - T - (N)- (normal biomarker) and A + T ± (N) ± (AD pathology). The association between higher WMH and worse memory was independent of amyloid levels in individuals with MCI with evidence of AD pathology.

CONCLUSION
Vascular disease, as indexed by WMH, independent of AD pathology affects cognitive function in both CN and MCI subgroups. Future studies using the AT(N) research framework should consider white matter lesions as a key biomarker contributing to the clinical presentation of AD.

Lam|Sharon|S|0000-0002-9558-7670
Lipton|Richard B|RB|
Harvey|Danielle J|DJ|
Zammit|Andrea R|AR|
Ezzati|Ali|A|
|||

white matter hyperintensities
AT(N) research framework
Alzheimer's disease pathology
cognitive decline


10,12 Conjugated Linoleic Acid-Driven Weight Loss Is Protective against Atherosclerosis in Mice and Is Associated with Alternative Macrophage Enrichment in Perivascular Adipose Tissue.

Abstract: The dietary fatty acid 10,12 conjugated linoleic acid (10,12 CLA) promotes weight loss by increasing fat oxidation, but its effects on atherosclerosis are less clear. We recently showed that weight loss induced by 10,12 CLA in an atherosclerosis-susceptible mouse model with characteristics similar to human metabolic syndrome is accompanied by accumulation of alternatively activated macrophages within subcutaneous adipose tissue. The objective of this study was to evaluate whether 10,12 CLA-mediated weight loss was associated with an atheroprotective phenotype. Male low-density lipoprotein receptor deficient (Ldlr-/-) mice were made obese with 12 weeks of a high-fat, high-sucrose diet feeding (HFHS: 36% fat, 36% sucrose, 0.15% added cholesterol), then either continued on the HFHS diet with or without caloric restriction (CR), or switched to a diet with 1% of the lard replaced by either 9,11 CLA or 10,12 CLA for 8 weeks. Atherosclerosis and lipid levels were quantified at sacrifice. Weight loss in mice following 10,12 CLA supplementation or CR as a weight-matched control group had improved cholesterol and triglyceride levels, yet only the 10,12 CLA-treated mice had improved en face and aortic sinus atherosclerosis. 10,12 CLA-supplemented mice had increased lesion macrophage content, with enrichment of surrounding perivascular adipose tissue (PVAT) alternative macrophages, which may contribute to the anti-atherosclerotic effect of 10,12 CLA.

Kanter|Jenny E|JE|
Goodspeed|Leela|L|
Wang|Shari|S|
Kramer|Farah|F|
Wietecha|Tomasz|T|
Gomes-Kjerulf|Diego|D|
Subramanian|Savitha|S|
O'Brien|Kevin D|KD|
den Hartigh|Laura J|LJ|

perivascular adipose tissue
alternatively activated macrophages
type 2 cytokines


Efficacy of Trimetazidine in Limiting Periprocedural Myocardial Injury in Patients Undergoing Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis.

Abstract: We systematically searched the literature to assess the efficacy of trimetazidine in reducing periprocedural myocardial injury and improving postoperative left ventricular ejection fraction (LVEF) in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). An electronic search was conducted based on the PubMed, Ovid, Scopus, Springer, CENTRAL, and Google Scholar databases; 14 randomized controlled trials (RCTs) were included. Our meta-analysis showed a significant reduction in cardiac troponin I (cTnI) levels with trimetazidine compared with controls (P < .00001) but not in serum creatine kinase-myocardial band levels (P = .49). There were significantly reduced odds of ischemic ST-T segment changes with trimetazidine (P = .0.03) but lack of significant difference in the incidence of anginal attacks between the 2 groups (P = .10). Results also suggest significantly higher LVEF with trimetazidine compared with controls (P < .00001). Meta-regression analysis indicated no influence of duration of trimetazidine therapy on cTnI levels. The administration of preprocedure trimetazidine may have a role in reducing periprocedural myocardial injury in patients with CAD undergoing PCI. Evidence also suggests that postoperative trimetazidine may improve LVEF in the short term. Lack of high-quality trials and the heterogeneity of studies limit the ability of our analysis to draw strong conclusions. Further well-designed RCTs are required to supplement current evidence.

Wang|Chang|C| Chen|Weiwei|W| Yu|Ming|M| Yang|Ping|P|0000-0002-6494-2377

D016032:Randomized Controlled Trials as Topic

myocardial injury
percutaneous coronary intervention
coronary artery disease
cardiac troponin
complications


Calling Consults: A Workshop to Teach Trainees Using Both Didactic and Small Group-based Learning.

Abstract: Background: Safe patient care includes effective communication. The Accreditation Council for Graduate Medical Education common program requirements include core requirements for trainees to act in a consultative manner and communicate effectively. However, trainees do not commonly receive formal education on this topic. Objective: We created a 1-hour workshop to teach residents and fellows how to effectively call consults, including how to formulate a cogent and comprehensive consult question. Methods: The workshop, delivered over a 1-hour noon conference, included a didactic portion and interactive small-group case-based learning. We used pre- and postworkshop surveys to assess learners' prior training, knowledge, and comfort levels in calling consults. Subspecialists answered a separate survey about the quality of consults received from trainees before and 30 days after the workshop. Results: Seventy-three trainees attended the workshop (41.2% of total trainees invited). After the workshop, the percentage of learners who identified as very or somewhat comfortable with calling consults increased from 82% to 91%. Before the workshop, 87% of trainees could identify key elements in a consult, which increased to 100% after the workshop. There was not a statistically significant improvement in subspecialists' ratings of the overall quality of consults they received 30 days after the workshop. Conclusion: Training learners on the key components and etiquette of calling consults is crucial for the development of effective communication among providers. This training is generally lacking from undergraduate medical education; thus, it is important to provide education in calling consults during residency and fellowship.

Lee-Miller|Cathy|C| Navarre|Brittany|B| Lorimer|Dean|D| Price|Harper|H| Newbern|Dorothee|D| Librizzi|Jamie|J| Bhavaraju|Vasudha|V|

calling consults
workshop
residents and fellows
curriculum


Computational-Driven Epitope Verification and Affinity Maturation of TLR4-Targeting Antibodies.

Abstract: Toll-like receptor (TLR) signaling plays a critical role in the induction and progression of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematous, experimental autoimmune encephalitis, type 1 diabetes mellitus and neurodegenerative diseases. Deciphering antigen recognition by antibodies provides insights and defines the mechanism of action into the progression of immune responses. Multiple strategies, including phage display and hybridoma technologies, have been used to enhance the affinity of antibodies for their respective epitopes. Here, we investigate the TLR4 antibody-binding epitope by computational-driven approach. We demonstrate that three important residues, i.e., Y328, N329, and K349 of TLR4 antibody binding epitope identified upon in silico mutagenesis, affect not only the interaction and binding affinity of antibody but also influence the structural integrity of TLR4. Furthermore, we predict a novel epitope at the TLR4-MD2 interface which can be targeted and explored for therapeutic antibodies and small molecules. This technique provides an in-depth insight into antibody-antigen interactions at the resolution and will be beneficial for the development of new monoclonal antibodies. Computational techniques, if coupled with experimental methods, will shorten the duration of rational design and development of antibody therapeutics.

D000595:Amino Acid Sequence
D000911:Antibodies, Monoclonal
D001172:Arthritis, Rheumatoid
D061505:Cell Surface Display Techniques
D004660:Encephalitis
D018604:Epitope Mapping
D000939:Epitopes
D050031:Hashimoto Disease
D006801:Humans
D019636:Neurodegenerative Diseases
D011485:Protein Binding
D051197:Toll-Like Receptor 4

epitope
antibody
toll-like receptor
molecular dynamics
mutation


The neutrophil-to-lymphocyte ratio and mean platelet volume can be associated with severity of valvular involvement in patients with acute rheumatic carditis.

Abstract:
OBJECTIVE
The aim of the study was to investigate the association between the severity of acute rheumatic carditis (ARC) and the neutrophil-lymphocyte ratio (NLR) and mean platelet volume (MPV).

METHODS
Paediatric patients diagnosed with ARC between 2010 and 2016 and age- and gender-matched controls were retrospectively analysed. At the time of diagnosis, we reviewed the demographic features obtained: echocardiographic data, complete blood count reports, acute-phase reactants, including C-reactive protein, and erythrocyte sedimentation rate values. The patient group was further divided into two subgroups according to the degree of valvular regurgitation, which included those with severe and those with mild-to-moderate valvular regurgitation.

RESULTS
The number of cases with ARC and age- and gender-matched controls were 120 and 50, respectively. The mean age of the patients was 12.25 ± 2.89 (range: 7-18) years. NLR, MPV, anti-streptolysin-O, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), haemoglobin level, and white blood cell (WBC) and neutrophil count were significantly higher in patients with acute carditis compared with the controls (p < 0.001). NLR was found to have a significantly positive correlation with CRP (r = 0.177, p = 0.001), ESR (r = 0.81, p = 0.03) and WBC count ( r = 0.47, p = 0.001). Moreover, we found a positive correlation between NLR and severity of valvular regurgitation (r = 0.34, p < 0.001), and a negative correlation between MPV and severity of valvular regurgitation ( r = -0.38, p < 0.05) in our patients. In multiple linear regression analysis, severe valvular regurgitation was associated with NLR (0.51; 95% CI: 0.32-0.68; p = 0.006) and MPV ( -0.78; 95% CI: -0.72 to -0.98; p = 0.008).

CONCLUSIONS
NLR and MPV are novel inflammatory markers and simple, rapid and easily accessible prognostic parameters that can be associated with severity of valvular involvement in patients with ARC.

mean platelet volume
acute rheumatic carditis
neutrophil‐to‐lymphocyte ratio


PTEN downregulation induces apoptosis and cell cycle arrest in uterine cervical cancer cells.

Abstract: The tumor suppressors PTEN and p53 are often downregulated in various human cancer types, which has been associated with a poor prognosis. Recent evidence implies that PTEN downregulation may induce growth arrest of kidney cells and cancer cells. In the present study, the role of PTEN in the proliferation and survival of cervical cancer cells was investigated. It was found that PTEN silencing promoted apoptosis and cell-cycle arrest, accompanied by a significant decrease in the proportion of cells in the S1 phase of the cell cycle. Moreover, PTEN silencing in cervical cancer cells increased levels of p53, p27, p21, phospho-ERK and cleaved caspase-3, and decreased levels of cyclin A2 and cyclin D1. Furthermore, PTEN knockdown significantly impacted the viability of cervical cancer cells. P53 silencing did not affect the ability of PTEN knockdown to induce apoptosis in cervical cancer cells. Taken together, the present study results imply that PTEN silencing induces apoptosis and decreases proliferation in cervical cancer cells; hence, PTEN inhibition may represent a promising strategy for the treatment of cervical cancer.

Shin|Jin Woo|JW|
Kim|Se-Hee|SH|
Yoon|Jin Young|JY|


Clinical utility of anterior segment swept-source optical coherence tomography in glaucoma.

Abstract:
UNLABELLED
Optical coherence tomography (OCT), a noninvasive imaging modality that uses low-coherence light to obtain a high-resolution cross-section of biological structures, has evolved dramatically over the years. The Swept-source OCT (SS-OCT) makes use of a single detector with a rapidly tunable laser as a light source. The Casia SS-1000 OCT is a Fourier-domain, SS-OCT designed specifically for imaging the anterior segment. This system achieves high resolution imaging of 10΅m (Axial) and 30΅m (Transverse) and high speed scanning of 30,000 A-scans per second. With a substantial improvement in scan speed, the anterior chamber angles can be imaged 360 degrees in 128 cross sections (each with 512 A-scans) in about 2.4 seconds. We summarize the clinical applications of anterior segment SS-OCT in Glaucoma.

LITERATURE SEARCH
We searched PubMed and included Medline using the phrases anterior segment optical coherence tomography in ophthalmology, swept-source OCT, use of AS-OCT in glaucoma, use of swept-source AS-OCT in glaucoma, quantitative assessment of angle, filtering bleb in AS-OCT, comparison of AS-OCT with gonioscopy and comparison of AS-OCT with UBM. Search was made for articles dating 1990 to August 2015.

Angmo|Dewang|D|
Nongpiur|Monisha E|ME|
Sharma|Reetika|R|
Sidhu|Talvir|T|
Sihota|Ramanjit|R|
Dada|Tanuj|T|

Fourier-domain optical coherence tomography

frequency-domain optical coherence tomography

time-domain optical coherence tomography


Eculizumab in refractory catastrophic antiphospholipid syndrome: a case report and systematic review of the literature.

Abstract: Catastrophic antiphospholipid syndrome (CAPS) is a rare disorder, characterized by the development of multiple vascular thrombosis over a short period of time, in patients with persistently detectable antiphospholipid antibodies (aPLs). The vascular occlusions predominantly affect small vessels. The overall mortality is 36.9%, despite the recent progress in the therapeutic approach. It has been shown that aPLs are able to induce a hypercoagulability state through different mechanisms of action, including complement activation, which in turn plays a key role in the pathogenesis of some thrombotic microangiopathies. Consequently, complement inhibition may be proposed as a targeted intervention to effectively prevent the progression of the microthrombotic storm. The employment of the complement inhibitor eculizumab has been proposed in CAPS on the basis of occasional reports and expert opinion. We report the case of a 54-year-old woman with a CAPS refractory to conventional therapies, who was successfully treated with eculizumab. The administration of this anti-C5 monoclonal antibody aborted the acute progressive thrombotic events and prevented further clinical episodes of thrombosis in the following year. We also faced our case to a systematic literature review, by analyzing all reported cases of CAPS in which eculizumab was added to conventional therapy. Even if further investigation is needed, our results suggest that the inhibition of one mechanism of aPL-induced organ damage may be an add-on treatment for this condition.

Eculizumab
Catastrophic antiphospholipid syndrome
Complement
Thrombotic microangiopathy


The Challenge of Stratifying Obesity: Attempts in the Quebec Family Study.

Abstract: Background and aims: Obesity is a major health problem worldwide. Given the heterogeneous obesity phenotype, an optimal obesity stratification would improve clinical management. Since obesity has a strong genetic component, we aimed to develop a polygenic risk score (PRS) to stratify obesity according to the genetic background of the individuals. Methods: A total of 231 single nucleotide polymorphisms (SNP) significantly associated to body mass index (BMI) from 21 genome-wide association studies were genotyped or imputed in 881 subjects from the Quebec Family Study (QFS). The population was randomly split into discovery (80%; n = 704) and validation (20%; n = 177) samples with similar obesity (BMI ≥ 30) prevalence (27.8% and 28.2%, respectively). Family-based associations with obesity were tested for every SNP in the discovery sample and a weighed and continuous PRS231 was constructed. Generalized linear mixed effects models were used to test the association of PRS231 with obesity in the QFS discovery sample and validated in the QFS replication sample. Furthermore, the Fatty Acid Sensor (FAS) Study (n = 141; 27.7% obesity prevalence) was used as an independent sample to replicate the results. Results: The linear trend test demonstrated a significant association of PRS231 with obesity in the QFS discovery sample (ORtrend = 1.19 [95% CI, 1.14-1.24]; P = 2.0x10-16). We also found that the obesity prevalence was significantly greater in the higher PRS231 quintiles compared to the lowest quintile. Significant and consistent results were obtained in the QFS validation sample for both the linear trend test (ORtrend = 1.16 [95% CI, 1.07-1.26]; P = 6.7x10-4), and obesity prevalence across quintiles. These results were partially replicated in the FAS sample (ORtrend = 1.12 [95% CI, 1.02-1.24]; P = 2.2x10-2). PRS231 explained 7.5%, 3.2%, and 1.2% of BMI variance in QFS discovery, QFS validation, and FAS samples, respectively. Conclusions: These results revealed that genetic background in the form of a 231 BMI-associated PRS has a significant impact on obesity, but a limited potential to accurately stratify it. Further studies are encouraged on larger populations.

de Toro-Martín|Juan|J|
Guénard|Frédéric|F|
Bouchard|Claude|C|
Tremblay|Angelo|A|
Pérusse|Louis|L|
Vohl|Marie-Claude|MC|

obesity
genetics
polygenic risk score
body mass index
genome-wide association study


Antimicrobial Mechanism of pBD2 against Staphylococcus aureus.

Abstract: Antimicrobial peptides (AMPs) show high antibacterial activity against pathogens, which makes them potential new therapeutics to prevent and cure diseases. Porcine beta defensin 2 (pBD2) is a newly discovered AMP and has shown antibacterial activity against different bacterial species including multi-resistant bacteria. In this study, the functional mechanism of pBD2 antibacterial activity against Staphylococcus aureus was investigated. After S. aureus cells were incubated with different concentrations of pBD2, the morphological changes in S. aureus and locations of pBD2 were detected by electron microscopy. The differentially expressed genes (DEGs) were also analyzed. The results showed that the bacterial membranes were broken, bulging, and perforated after treatment with pBD2; pBD2 was mainly located on the membranes, and some entered the cytoplasm. Furthermore, 31 DEGs were detected and confirmed by quantitative real-time PCR (qRT-PCR). The known functional DEGs were associated with transmembrane transport, transport of inheritable information, and other metabolic processes. Our data suggest that pBD2 might have multiple modes of action, and the main mechanism by which pBD2 kills S. aureus is the destruction of the membrane and interaction with DNA. The results imply that pBD2 is an effective bactericide for S. aureus, and deserves further study as a new therapeutic substance against S. aureus.

Zhang|Kun|K| Zhang|Heng|H| Gao|Chunyu|C| Chen|Ruibo|R| Li|Chunli|C|0000-0002-9071-161X

D060888:Real-Time Polymerase Chain Reaction

antimicrobial mechanism
antimicrobial peptides
morphological changes
electron microscopy
differentially expressed genes
quantitative real-time PCR


Effects of strength training on physical fitness and sport-specific performance in recreational, sub-elite, and elite rowers: A systematic review with meta-analysis.

Abstract:
The purpose of this systematic review with meta-analysis was to examine the effects of strength training (ST) on selected components of physical fitness (e.g., lower/upper limb maximal strength, muscular endurance, jump performance, cardiorespiratory endurance) and sport-specific performance in rowers. Only studies with an active control group were included if they examined the effects of ST on at least one proxy of physical fitness and/or sport-specific performance in rowers. Weighted and averaged standardized mean differences (SMD) were calculated using random-effects models. Subgroup analyses were computed to identify effects of ST type or expertise level on sport-specific performance. Our analyses revealed significant small effects of ST on lower limb maximal strength (SMD = 0.42, p = 0.05) and on sport-specific performance (SMD = 0.32, p = 0.05). Non-significant effects were found for upper limb maximal strength, upper/lower limb muscular endurance, jump performance, and cardiorespiratory endurance. Subgroup analyses for ST type and expertise level showed non-significant differences between the respective subgroups of rowers (p ≥ 0.32). Our systematic review with meta-analysis indicated that ST is an effective means for improving lower limb maximal strength and sport-specific performance in rowers. However, ST-induced effects are neither modulated by ST type nor rowers' expertise level.

ABBREVIATIONS
CON: control group; ICC: intraclass correlation coefficient; CRE: cardiorespiratory endurance; F: female; IG: intervention group; INT: intervention group; M: male; Sets: number of sets per exercise; SMD: standardized mean differences; SMDwm: weighted mean SMD; ST: strength training; RCT: randomized controlled trial; Reps: repetitions; RM: repetition maximum; TF: training frequency (times per week); TI: training intensity (eg., % of 1 repetition maximum); TP: training periods (weeks).

D054874:Athletic Performance
D000072599:Cardiorespiratory Fitness
D006801:Humans
D035002:Lower Extremity
D053580:Muscle Strength
D010809:Physical Fitness
D055070:Resistance Training
D034941:Upper Extremity
D000073678:Water Sports

Resistance training
athletic performance
oarsmen
on-water performance
plyometric training
race time


Syndecan-2 regulates melanin synthesis via protein kinase C βII-mediated tyrosinase activation.

Abstract: Syndecan-2, a transmembrane heparan sulfate proteoglycan that is highly expressed in melanoma cells, regulates melanoma cell functions (e.g. migration). Since melanoma is a malignant tumor of melanocytes, which largely function to synthesize melanin, we investigated the possible involvement of syndecan-2 in melanogenesis. Syndecan-2 expression was increased in human skin melanoma tissues compared with normal skin. In both mouse and human melanoma cells, siRNA-mediated knockdown of syndecan-2 was associated with reduced melanin synthesis, whereas overexpression of syndecan-2 increased melanin synthesis. Similar effects were also detected in human primary epidermal melanocytes. Syndecan-2 expression did not affect the expression of tyrosinase, a key enzyme in melanin synthesis, but instead enhanced the enzymatic activity of tyrosinase by increasing the membrane and melanosome localization of its regulator, protein kinase CβII. Furthermore, UVB caused increased syndecan-2 expression, and this up-regulation of syndecan-2 was required for UVB-induced melanin synthesis. Taken together, these data suggest that syndecan-2 regulates melanin synthesis and could be a potential therapeutic target for treating melanin-associated diseases.

Jung|Hyejung|H|
Chung|Heesung|H|
Chang|Sung Eun|SE|
Choi|Sora|S|
Han|Inn-Oc|IO|
Kang|Duk-Hee|DH|
Oh|Eok-Soo|ES|

syndecan-2
tyrosinase
melanogenesis
melanosome
protein kinase C β


Clinical imaging in dementia with Lewy bodies.

Abstract: Dementia with Lewy bodies (DLB) is a common neurodegenerative dementia in older people; however, the clinical features, particularly cognitive fluctuations and rapid eye movement sleep disorder, are often hard to elicit, leading to difficulty in making the diagnosis clinically. Here we examine the literature for the evidence behind imaging modalities that could assist in making the diagnosis. Dopamine transporter (DAT) imaging remains the best modality for differentiation from dementia of Alzheimer's type with high sensitivity and specificity reported based on pathological diagnoses. 123Iodine-metaiodobenzylguanidine myocardial scintigraphy (MIBG) however is rapidly becoming an alternative imaging modality for the diagnosis of DLB, though studies assessing its accuracy with postmortem verification are still awaited. However, there are suggestions that MIBG may be better in the differentiation of vascular parkinsonism from DLB than DAT scans but may have lower sensitivity for detecting DLB compared with the 80% sensitivity seen in DAT imaging. Structural MRI scans have long been used for the diagnosis of dementia; however, their utility in DLB is limited to revealing the presence of coexisting Alzheimer's disease. Fluorodeoxyglucose (FDG) PET is an alternative biomarker that can also differentiate Alzheimer's disease and DLB but lacks the evidence base of both DAT and MIBG scans.


Life-history implications of the allometric scaling of growth.

Abstract: Several phenomenological descriptions, such as the von Bertalanffy growth model, have been widely used to describe size-at-age and individual growth across a diverse range of organisms. However, for modelling life histories, as opposed to just growth, biologically and mechanistically meaningful growth models, based on allocation decisions, have become increasingly important. This is because fitness is determined by survival and reproduction, which are not addressed directly in phenomenological growth models. To elucidate these considerations, we take as a starting point the biphasic growth model by Quince et al. (2008a, J. Theor. Biol. 254:197) which has the advantage that the underlying allometric scaling of net energy intake can be freely chosen. First, we reformulate this model such that individual size is given in meaningful units of length and weight, facilitating the model׳s interpretation and application. Second, we show that even though different allometric scaling relationships can produce practically identical growth trajectories, the accompanying reproductive investments are highly dependent on the chosen allometric exponent. Third, we demonstrate how this dependence has dramatic consequences for evolutionary predictions, in particular with regard to the age and size at maturation. These findings have considerable practical relevance, because empirically observed allometric exponents are often uncertain and systematically differ from those assumed in current standard growth models.

Boukal|David S|DS|
Dieckmann|Ulf|U|
Enberg|Katja|K|
Heino|Mikko|M|
Jørgensen|Christian|C|

Size-at-age
Fitness
Reproductive investment
Allometric exponent
Maturation


A comparison of QuantStudio™ 3D Digital PCR and ARMS-PCR for measuring plasma EGFR T790M mutations of NSCLC patients.

Abstract:
Background
The AURA3 clinical trial has shown that advanced non-small cell lung cancer (NSCLC) patients with EGFR T790M mutations in circulating tumor DNA (ctDNA) could benefit from osimertinib.

Purpose
The aim of this study was to assess the usefulness of QuantStudio™ 3D Digital PCR System platform for the detection of plasma EGFR T790M mutations in NSCLC patients, and compare the performances of 3D Digital PCR and ARMS-PCR.

Patients and methods
A total of 119 Chinese patients were enrolled in this study. Mutant allele frequency of plasma EGFR T790M was detected by 3D Digital PCR, then 25 selected samples were verified by ARMS-PCR and four of them were verified by next generation sequencing (NGS).

Results
In total, 52.94% (69/119) had EGFR T790M mutations detected by 3D Digital PCR. In 69 positive samples, the median mutant allele frequency (AF) was 1.09% and three cases presented low concentration (AF <0.1%). Limited by the amount of plasma DNA, 17 samples (AF <2.5%) and eight samples (T790M-) were selected for verification by ARMS-PCR. Four of those samples were verified by NGS as a third verification method. Among the selected 17 positive cases, ten samples presented mutant allele frequency <0.5%, and seven samples presented intermediate mutant allele frequency (0.5% AF 2.5%). However, only three samples (3/17) were identified as positive by ARMS-PCR, namely, P6 (AF =1.09%), P7 (AF =2.09%), and P8 (AF =2.21%). It is worth mentioning that sample P9 (AF =2.05%, analyzed by 3D Digital PCR) was identified as T790M- by ARMS-PCR. Four samples were identified as T790M+ by both NGS and 3D Digital PCR, and typically three samples (3/4) presented at a low ratio (AF <0.5%).

Conclusion
Our study demonstrated that 3D Digital PCR is a novel method with high sensitivity and specificity to detect EGFR T790M mutation in plasma.

Feng|Qin|Q| Gai|Fei|F| Sang|Yaxiong|Y| Zhang|Jie|J| Wang|Ping|P| Wang|Yue|Y| Liu|Bing|B| Lin|Dongmei|D| Yu|Yang|Y| Fang|Jian|J|

3D Digital PCR
osimertinib
allele frequency
EGFR TKIs
erlotinib
gefitinib
icotinib
resistance


Post-extraction pain in the adjacent tooth after surgical extraction of the mandibular third molar.

Abstract:
Background
After tooth extraction, pain due to dry socket and pain in the adjacent tooth are common. The aim of this study was to retrospectively analyze pain in the adjacent tooth after surgical extraction of the mandibular third molar.

Methods
Postoperative pain due to dry socket, pain in the adjacent tooth, and pain from other causes were present. Group A included patents with dry socket alone; group B included patients with pain in the adjacent tooth alone; and group C included patients with both. The duration of symptoms was recorded. In addition, the prognosis of pain was divided into the complete improvement, improvement, maintenance, deterioration, and complete deterioration groups.

Results
A total of 312 mandibular third molars were extracted from 13, 60, and 10 patients in groups A, B, and C, respectively. The mean duration of symptoms was 5 days in group A and B and 15.2 days in group C. There were statistically significant differences in the duration of symptoms between groups A and C and groups B and C.

Conclusion
Pain in the adjacent tooth after third molar extraction can be caused by inflammatory reactions and pressure on this tooth. The pain caused by pressure on the periodontal ligament and alveolar bone results from the cytokines released by osteoclasts, which are responsible for bone destruction. However, pain from periodontal ligament damage caused by excessive pressure may be misunderstood as pulpal pain. Unconscious parafunctional habits, such as clenching and bruxism, could also be associated with post-extraction pain.

Third Molar
Postoperative Pain
Weight-Bearing


Early environment and long-term outcomes of preterm infants.

Abstract: Prematurity is associated with an increased risk of long-term health and neurodevelopmental problems. Key perinatal and neonatal factors that affect these outcomes have long been studied. However, more recently, there has been an appreciation of the importance of environmental factors in long-term outcomes of preterm babies, particularly in light of the rapid maturation of the brain during these babies' early days of life. Breastmilk and breastfeeding is the gold standard for infant feeding, including preterm babies. The benefits are well established in regard to protection from serious complications like necrotising enterocolitis. Although theoretically plausible, the benefits for neurodevelopment are less clear. Noise, pain and the environment of the neonatal intensive care can also affect infant neurodevelopment. It is established that noise and pain have deleterious effects. However, the benefits of single-room vs open-bay neonatal units remain under debate. Developmental care practices, of which there are many, are increasingly embraced worldwide. There are benefits both for the parents and the baby, however, the evidence is difficult to pool due to the heterogeneity of studies and study populations. Finally, it is important to remember the importance of the role of parents in shaping long-term neurodevelopment of the high-risk preterm newborn. Increasingly, positive parenting and parents' mental health are shown to have long lasting advantages for preterm infants. A deeper understanding of early environmental factors is key to developing future interventions to optimise outcomes of preterm newborns.

Prematurity
Developmental care
Parenting
Neurodevelopmental outcomes


The Influence of Chronic Pain and Catastrophizing on Patient Outcomes in an Athletic Therapy Setting.

Abstract:
CONTEXT
Chronic pain is a challenge for Athletic Trainers and Athletic Therapists working in a clinical or university setting. The fear avoidance model, including catastrophizing, is well established in other health professions but is not established in Athletic Training and Athletic Therapy and may affect rehabilitation outcomes.

OBJECTIVE
To measure the influence of catastrophizing on rehabilitation outcomes of patients being treated in an Athletic Therapy setting.

DESIGN
Prospective single group pre-post design.

SETTING
Student Athletic Therapy clinic.

PATIENTS
A total of 92 patients were evaluated at initial assessment, and 49 were evaluated at follow-up.

INTERVENTION
All participants completed self-reported function questionnaires to assess level of injury and then received individualized treatments for a variety of musculoskeletal injuries. All measures were completed at initial assessment and at follow-up approximately 6 weeks later.

MAIN OUTCOME MEASURES
The authors measured function using a variety of patient self-reported functional questionnaires: the Disability of the Arm, Shoulder, and Hand; Lower Extremity Functional Scale; the Neck Disability Index; and the Oswestry Disability Index depending on injury site. Catastrophizing was measured using the Pain Catastrophizing Scale.

RESULTS
Function significantly improved from the initial assessment to the follow-up (P > .001). Patients with acute pain experienced a significantly greater improvement in function between the initial assessment and follow-up compared with participants with chronic pain (P = .050). Those with high catastrophizing presented with lower levels of function at initial assessment (66.8%) and follow-up (72.1%) compared with those with low catastrophizing (80.8% and 87.0%, respectively).

CONCLUSION
Similar to other studies in other professions, the function of patients with chronic pain does not improve as much compared with patients recovering from acute pain in an Athletic Therapy setting. It is important to measure patient-reported outcomes to evaluate patient rehabilitation progress. Rehabilitating patients with chronic pain is a challenge, and pain catastrophizing should be evaluated at the initial assessment since catastrophizing is associated with worse function.

pain
patient-reported outcomes
clinical interventions
psychology


Remote just-in-time telementored trauma ultrasound: a double-factorial randomized controlled trial examining fluid detection and remote knobology control through an ultrasound graphic user interface display.

Abstract:
BACKGROUND
Remote-telementored ultrasound involves novice examiners being remotely guided by experts using informatic-technologies. However, requiring a novice to perform ultrasound is a cognitively demanding task exacerbated by unfamiliarity with ultrasound-machine controls. We incorporated a randomized evaluation of using remote control of the ultrasound functionality (knobology) within a study in which the images generated by distant naive examiners were viewed on an ultrasound graphic user interface (GUI) display viewed on laptop computers by mentors in different cities.

METHODS
Fire-fighters in Edmonton (101) were remotely mentored from Calgary (n = 65), Nanaimo (n = 19), and Memphis (n = 17) to examine an ultrasound phantom randomized to contain free fluid or not. Remote mentors (2 surgeons, 1 internist, and 1 ED physician) were randomly assigned to use GUI knobology control during mentoring (GUIK+/GUIK-).

RESULTS
Remote-telementored ultrasound was feasible in all cases. Overall accuracy for fluid detection was 97% (confidence interval = 91 to 99%) with 3 false negatives (FNs). Positive/negative likelihood ratios were infinity/0.0625. One FN occurred with the GUIK+ and 2 without (GUIK-). There were no statistical test performance differences in either group (GUIK+ and GUIK-).

CONCLUSIONS
Ultrasound-naive 1st responders can be remotely mentored with high accuracy, although providing basic remote control of the knobology did not affect outcomes.

Kirkpatrick|Andrew W|AW|
McKee|Ian|I|
McKee|Jessica L|JL|
Ma|Irene|I|
McBeth|Paul B|PB|
Roberts|Derek J|DJ|
Wurster|Charles L|CL|
Parfitt|Robbie|R|
Ball|Chad G|CG|
Oberg|Scott|S|
Sevcik|William|W|
Hamilton|Douglas R|DR|

Ultrasound
Remote education
Resuscitation
Telemedicine
Telesonography


Molecular characterization and secreted production of basidiomycetous cell-bound β-glycosidases applicable to production of galactooligosaccharides.

Abstract: Cell-bound β-glycosidases of basidiomycetous yeasts show promise as biocatalysts in galactooligosaccharide (GOS) production. Using degenerated primers designed from Hamamotoa singularis (Hs) bglA gene, we newly identified three genes that encode cell-bound β-glycosidase from Sirobasidium magnum (Sm), Rhodotorula minuta (Rm), and Sterigmatomyces elviae (Se). These three genes, also named bglA, encoded family 1 glycosyl hydrolases with molecular masses of 67‒77 kDa. The BglA enzymes were approximately 44% identical to the Hs-BglA enzyme and possessed a unique domain at the N-terminus comprising 110 or 210 amino acids. The Sm-, Rm-, and Se-BglA enzymes as well as the Hs-BglA enzyme were successfully produced by recombinant Aspergillus oryzae, and all enzymes were entirely secreted to the supernatants. Furthermore, addition of some nonionic detergents (e.g. 0.4% [v/v] Triton-X) increased the production, especially of the Hs- or Se-BglA enzyme. Out of the BglA enzymes, the Se-BglA enzyme showed remarkable thermostability (∼70°C). Additionally, the Sm- and Se-BglA enzymes had better GOS yields, so there was less residual lactose than in others. Accordingly, the basidiomycetous BglA enzymes produced by recombinant A. oryzae would be applicable to GOS production, and the Se-BglA enzyme appeared to be the most promising enzyme for industrial uses.

Ishikawa|Eiji|E|0000-0002-4179-9010 Ikeda|Masakazu|M| Sotoya|Hidetsugu|H| Anbe|Minako|M| Matsumoto|Hoshitaka|H| Kiwaki|Mayumi|M| Hatano|Hiroshi|H|

thermostability
GOS isomer
enzyme preparation
glycoside hydrolase family 1
soluble protein


Sleep following traumatic brain injury (TBI): experiences and influencing factors.

Abstract: Objective: This study aimed to 1) describe and explore the experiences of sleep following a moderate or severe traumatic brain injury (TBI) in community-dwelling adults, 2) elicit factors that positively or negatively impact the sleep experience, and 3) understand sleep-related education provided to survivors.Design: Qualitative description.Methods: Face-to-face interviews with 16 individuals using a semi-structured interview guide. Transcripts were systematically coded and common themes were identified. The final sample consisted of primarily Caucasian men with average age of 32.4 years (SD = 9.9), and average of 2.6 years (SD = .89) years post injury.Results: Community-dwelling survivors of TBI experienced poor sleep quality and quantity post-injury and described a variety of approaches to manage their sleep. Survivors described coping with sleep changes and using sleep as a coping mechanism for TBI. Additionally, survivors' responses indicated perceived lack of resources and preference for receiving education from knowledgeable, familiar clinicians during face-to-face encounters.Conclusions: This study provides a description of reported sleep experiences following TBI and adds new knowledge regarding sleep management strategies and preferences for resources. The findings suggest a need for education regarding sleep for rehabilitation professionals and long-term sleep support after discharge from rehabilitation.

sleep
Traumatic brain injury
qualitative
health education


The use of inulin and wheat bran only during the starter period or during the entire rearing life of broilers: effects on growth performance, small intestinal maturation, and cecal microbial colonization until slaughter age.

Abstract: Inulin and wheat bran were added to broiler diets during the starter period or during the entire rearing period to investigate whether the effects of using these ingredients remained until slaughter age. Diets containing no inulin and no wheat bran (CON), 2% inulin (IN), 10% wheat bran (WB), or 2% inulin + 10% wheat bran (IN+WB) were provided until day 11. Thereafter, each dietary treatment was further divided into a continued diet with supplementation or a control diet, resulting in 7 groups (CON, IN/IN, IN/CON, WB/WB, WB/CON, IN+WB/IN+WB, or IN+WB/CON). On day 40, 12 chickens per group were euthanized. The IN/IN group increased the cecal molar ratio of butyrate but had a lower relative abundance of Lactobacillus (P < 0.05). Additionally, the cecal molar ratio of propionate was higher in the IN/CON group compared to the IN/IN group (P = 0.034). The WB/CON group had the best results on BW and feed conversion ratio (FCR) (P < 0.05). Only the cecal molar ratio of iso-butyrate was higher in the WB/WB group (P = 0.013). Moreover, compared to the CON group, both WB/WB and WB/CON groups reduced the relative abundances of Bifidobacterium and Escherichia coli, and only the WB/WB group reduced the relative abundance of Enterobacteriaceae (P < 0.05). Both IN+WB/IN+WB and IN+WB/CON groups increased BW until day 21 and lowered the relative abundance of Bifidobacterium (P < 0.05). The IN+WB/IN+WB group increased the cecal molar ratio of butyrate but reduced the molar ratio of propionate with a higher relative abundance of Enterobacteriaceae (P < 0.05). In conclusion, the lack of positive effects induced by inulin might be explained by the dose being too high. The beneficial effects on BW, FCR, and microbiota induced by wheat bran during the starter period were lasting when supplementation was stopped, suggesting that wheat bran could be a favorable ingredient during the starter period.

Li|Bing|B| Schroyen|Martine|M| Leblois|Julie|J| Beckers|Yves|Y| Bindelle|Jérôme|J| Everaert|Nadia|N|

D000824:Animal Nutritional Physiological Phenomena

inulin
wheat bran
broiler chicken
cecal microbiota
short chain fatty acid


Diminished substrate-mediated cardiac mitochondrial respiration and elevated autophagy in adult male offspring of gestational diabetic rats.

Abstract: Heart diseases are common in the offspring of diabetic mother (ODM). Defects in mitochondrial metabolism and autophagy may, in part, be responsible for the adverse structural and functional alterations in the heart. The principal objective of this study was to investigate cardiac mitochondrial respiration and autophagy in male and female offspring of diabetic pregnancy at two different developmental stages of life, weaning and adult. Male and female offspring of rats with streptozotocin-induced gestational diabetes were used for the study and compared with offspring of control (non-diabetic) mother (OCM) rats. High-resolution respirometry was used to measure substrate-mediated respiration in mitochondria isolated from ventricular tissues of ODM and OCM. Expression of proteins associated with autophagy and oxidative stress was examined by western blot analysis. Mitochondrial complex I and complex II respiration was significantly reduced in adult male ODM while it was unaltered or less affected in weaning male, adult and weaning female ODM. Elevated autophagy was observed in adult male but not in adult female ODM. Expression of oxidative stress markers was observed to be similar in all the groups. Altered cardiac mitochondrial respiration and autophagy were observed in adult male ODM compared to OCM, while the male and female offspring at weaning stage were less affected. The results of the study show that maternal hyperglycemia affects mitochondrial respiration and autophagy in the ODM heart, which may potentially be responsible for the cardiovascular complications observed in adult life.

Raji|Sasikala Rajendran|SR|
Nandini|Ravikumar Jayakumari|RJ|
Ashok|Sivasailam|S|
Anand|Chellappan Reghuvaran|CR|
Vivek|Velayudhan Pillai|VP|
Jayakumar|Karunakaran|K|
Harikrishnan|Vijayakumar Sreelatha|VS|
Manjunatha|Shankarappa|S|
Gopala|Srinivas|S|0000-0001-5885-6256

mitochondrial respiration
autophagy
offspring
gestational diabetes
heart


Adiposity, CVD risk factors and testosterone: Variation by partnering status and residence with children in US men.

Abstract: Background and objectives: In many settings, partnered, invested fathers have lower testosterone than single men or fathers who are not involved in caregiving. Reduced testosterone has been identified as a risk factor for multiple chronic diseases, and men's health also commonly varies by life history status. There have been few tests of whether variation in testosterone based on partnering and parenting has implications for men's health. Methodology: We analysed data from a US population-representative sample (NHANES) of young-to-middle aged US men (n = 875; mean age: 29.8 years ± 6.0 [SD]). We tested for life history status differences in testosterone, adiposity levels and biomarkers of cardiovascular disease (CVD)-risk (HDL cholesterol; triglycerides; white blood cell count [WBC]). Results: Partnered men residing with children (RC) had lower testosterone and elevated abdominal adiposity compared to never married men not residing with children. While they did not significantly differ for WBC or triglycerides, partnered RC men also had comparatively lower HDL. Partnered RC males' lower testosterone accounted for their relatively elevated adiposity, but testosterone, adiposity, and health-related covariates did not explain their relatively reduced HDL. Conclusions and implications: Our results linking life history status-based differences in testosterone and adiposity, alongside our complementary HDL findings, indicate that testosterone-related psychobiology might have implications for partnered RC men's CVD risk in the US and other similar societal settings. These types of socially contextualized observations of men's health and physiological function particularly merit incorporation in clinical discussions of fatherhood as a component of men's health.

Gettler|Lee T|LT|
Sarma|Mallika S|MS|
Gengo|Rieti G|RG|
Oka|Rahul C|RC|
McKenna|James J|JJ|

father
NHANES
cardiovascular disease
androgens
marriage
men’s health


Use of a small DNA virus model to investigate mechanisms of CpG dinucleotide-induced attenuation of virus replication.

Abstract: Suppression of the CpG dinucleotide is widespread in RNA viruses infecting vertebrates and plants, and in the genomes of retroviruses and small mammalian DNA viruses. The functional basis for CpG suppression in the latter was investigated through the construction of mutants of the parvovirus, minute virus of mice (MVM) with increased CpG or TpA dinucleotides in the VP gene. CpG-high mutants displayed extraordinary attenuation in A9 cells compared to wild-type MVM (>six logs), while TpA elevation showed no replication effect. Attenuation was independent of Toll-like receptor 9 and STING-mediated DNA recognition pathways and unrelated to effects on translation efficiency. While translation from codon-optimized VP RNA was enhanced in a cell-free assay, MVM containing this sequence was highly attenuated. Further mutational analysis indicated that this arose through its increased numbers of CpG dinucleotides (7→70) and separately from its increased G+C content (42.3→57.4 %), which independently attenuated replication. CpG-high viruses showed impaired NS mRNA expression by qPCR and reduced NS and particularly VP protein expression detected by immunofluorescence and replication in A549 cells, effects reversed in zinc antiviral protein (ZAP) knockout cells, even though nuclear relocalization of VP remained defective. The demonstrated functional basis for CpG suppression in MVM and potentially other small DNA viruses and the observed intolerance of CpGs in coding sequences, even after codon optimization, has implications for the use of small DNA virus vectors in gene therapy and immunization.

Loew|Lisa|L| Goonawardane|Niluka|N| Ratcliff|Jeremy|J| Nguyen|Dung|D| Simmonds|Peter|P|

D000072283:A549 Cells
D001482:Base Composition
D003062:Codon
D015226:Dinucleoside Phosphates
D006801:Humans
D008915:Minute Virus of Mice
D009154:Mutation
D012367:RNA, Viral
D016601:RNA-Binding Proteins
D017361:Viral Nonstructural Proteins
D014764:Viral Proteins
D015678:Viral Structural Proteins
D014779:Virus Replication

CpG dinucleotide
parvovirus
minute virus of mice
TpA dinucleotide
zinc antiviral protein
codon optimization


Characterizing Tractability of Simple Well-Designed Pattern Trees with Projection.

Abstract: We study the complexity of evaluating well-designed pattern trees, a query language extending conjunctive queries with the possibility to define parts of the query to be optional. This possibility of optional parts is important for obtaining meaningful results over incomplete data sources as it is common in semantic web settings. Recently, a structural characterization of the classes of well-designed pattern trees that can be evaluated in polynomial time was shown. However, projection-a central feature of many query languages-was not considered in this study. We work towards closing this gap by giving a characterization of all tractable classes of simple well-designed pattern trees with projection (under some common complexity theoretic assumptions). Since well-designed pattern trees correspond to the fragment of well-designed {AND, OPTIONAL}-SPARQL queries this gives a complete description of the tractable classes of queries with projections in this fragment that can be characterized by the underlying graph structures of the queries. For non-simple pattern trees the tractability criteria for simple pattern trees do not capture all tractable classes. We thus extend the characterization for the non-simple case in order to capture some additional tractable cases.

Well-designed pattern trees
Characterizing tractable classes
FPT
Query evaluation
SPARQL


Igf3 activates β-catenin signaling to stimulate spermatogonial differentiation in zebrafish.

Abstract: Follicle-stimulating hormone (Fsh) is a major regulator of spermatogenesis, targeting somatic cell functions in the testes. We reported previously that zebrafish Fsh promoted the differentiation of type A undifferentiated spermatogonia (Aund) by stimulating the production of factors that advance germ cell differentiation, such as androgens, insulin-like peptide 3 (Insl3) and insulin-like growth factor 3 (Igf3). In addition, Fsh also modulated the transcript levels of several other genes, including some belonging to the Wnt signaling pathway. Here, we evaluated if and how Fsh utilizes part of the canonical Wnt pathway to regulate the development of spermatogonia. We quantified the proliferation activity and relative section areas occupied by Aund and type A differentiating (Adiff) spermatogonia and we analyzed the expression of selected genes in response to recombinant proteins and pharmacological inhibitors. We found that from the three downstream mediators of Fsh activity we examined, Igf3, but not 11-ketotestosterone or Insl3, modulated the transcript levels of two β-catenin sensitive genes (cyclinD1 and axin2). Using a zebrafish β-catenin signaling reporter line, we showed that Igf3 activated β-catenin signaling in type A spermatogonia and that this activation did not depend on the release of Wnt ligands. Pharmacological inhibition of the β-catenin or of the phosphoinositide 3-kinase (PI3K) pathways revealed that Igf3 activated β-catenin signaling in a manner involving PI3K to promote the differentiation of Aund to Adiff spermatogonia. This mechanism represents an intriguing example for a pituitary hormone like Fsh using Igf signaling to recruit the evolutionary conserved, local β-catenin signaling pathway to regulate spermatogenesis.

Safian|Diego|D|
Bogerd|Jan|J|
Schulz|Rüdiger W|RW|

β-catenin
differentiation
spermatogonia
proliferation
Igf signaling


Initial diagnosis and management of chronic obstructive pulmonary disease in Australia: views from the coal face.

Abstract:
BACKGROUND
Early diagnosis and management can mitigate the long-term morbidity and mortality of chronic obstructive pulmonary disease (COPD).

AIMS
To gain insights into the initial diagnostic process and early management of COPD by Australian general practitioners (GP).

METHODS
A random sample of Australian GP was invited to complete a postal survey, which assessed familiarity with and use of contemporary practice guidelines, diagnostic criteria and management preferences for COPD.

RESULTS
A total of 233 GP completed the survey. While most GP based a COPD diagnosis on smoking history (94.4%), symptoms (91.0%) and spirometry (88.8%), only 39.9% of respondents recorded a formal diagnosis of COPD after the patient's first symptomatic presentation. Tiotropium was the preferred treatment in 77.3% of GP for the initial management of COPD, while only 27.5% routinely recommended pulmonary rehabilitation. GP routinely recorded patients' smoking status and offered smoking cessation advice, but the timing of this advice varied. Less than half of the respondents routinely used COPD management guidelines or tools and resources provided by the Australian Lung Foundation.

CONCLUSION
There is scope for major improvement in GP familiarity with and use of COPD management guidelines and readily available tools and resources. Some systematic issues were highlighted in the Australian primary care setting, such as a reactive and relatively passive and delayed approach to diagnosis, potentially delayed smoking cessation advice and underutilisation of pulmonary rehabilitation. There is an urgent need to devise strategies for improving patient outcomes in COPD using resources that are readily available.

D029424:Pulmonary Disease, Chronic Obstructive

diagnosis
chronic obstructive
pulmonary disease
disease management
general practice
guideline adherence


In situ analysis of male meiosis in C. elegans.

Abstract: We describe a routine method to locate cells of appropriate meiotic stages in the gonad of Caenorhabditis elegans males prior to 3D reconstruction of meiotic spindles by electron tomography. For this, serial semi-thick (300nm) sections of whole worms are pre-screened and recorded at low magnification by transmission electron microscopy. Cells of interest are identified in aligned image stacks showing the entire proximal region of male gonads at low magnification. Tilt series of selected cells are then recorded at higher magnification to reconstruct meiotic spindles of selected cells in 3D. Our approach allows a routine staging of spermatocytes without the use of anesthetics or the application of physical immobilization of worms. We also describe a modification of a previously published protocol (Muller-Reichert, Srayko, Hyman, O'Toole, & McDonald, 2007) by using polyvinylpyrrolidone (PVP) instead of bovine serum albumin (BSA) as a "filler" for specimen loading in high-pressure freezing.

Fabig|Gunar|G| Schwarz|Anna|A| Striese|Cynthia|C| Laue|Michael|M| Müller-Reichert|Thomas|T|

Male meiosis
C. elegans
3D reconstruction
Spindles
Electron tomography
Electron microscopy
Microtubules
X-chromosome


Effect of supporting 3D-garment on gait postural stability in children with bilateral spastic cerebral palsy.

Abstract:
BACKGROUND
Children with cerebral palsy show dysfunctional postural control which interferes with their functional performance and daily-life activities.

OBJECTIVE
The aim of the study was to identify the effect of a 3D supporting garment on trunk postural control and interjoint coordination during gait in children with bilateral cerebral palsy.

METHODS
We analyzed tridimensional trunk motion, trunk-thigh and interjoint coordination in 15 4-10 year-old children with bilateral spastic cerebral palsy (GMFCS I or II) and 16 4-10 year-old typically developing children while walking with or without a supporting garment.

RESULTS
We found significantly changes in the coordination between trunk and lower limbs in children with cerebral palsy. Step velocity and cadence both increased significantly in children with cerebral palsy but in controls, the cadence remained unaltered. Interjoint coordination between hip-knee and knee-ankle was altered during the stance phase only in the subgroup of children with cerebral palsy without any limitations in ankle joint passive range of motion.

CONCLUSION
3D supporting garments improve trunk-thigh and lower limb interjoint coordination in walking in children with bilateral cerebral palsy.

Degelaen|Marc|M|
De Borre|Ludo|L|
Buyl|Ronald|R|
Kerckhofs|Eric|E|
De Meirleir|Linda|L|
Dan|Bernard|B|

cerebral palsy
postural control
3D supporting garment
interjoint coordination


Azoospermia and reciprocal translocations: should whole-exome sequencing be recommended?

Abstract:
BACKGROUND
Although chromosome rearrangements are responsible for spermatogenesis failure, their impact depends greatly on the chromosomes involved. At present, karyotyping and Y chromosome microdeletion screening are the first-line genetic tests for patients with non-obstructive azoospermia. Although it is generally acknowledged that X or Y chromosome rearrangements lead to meiotic arrest and thus rule out any chance of sperm retrieval after a testicular biopsy, we currently lack markers for the likelihood of testicular sperm extraction (TESE) in patients with other chromosome rearrangements.

RESULTS
We investigated the use of a single nucleotide polymorphism comparative genome hybridization array (SNP-CGH) and whole-exome sequencing (WES) for two patients with non-obstructive azoospermia and testicular meiotic arrest, a reciprocal translocation: t(X;21) and t(20;22), and an unsuccessful TESE. No additional gene defects were identified for the t(X;21) carrier - suggesting that t(X;21) alone damages spermatogenesis. In contrast, the highly consanguineous t(20;22) carrier had two deleterious homozygous variants in the TMPRSS9 gene; these might have contributed to testicular meiotic arrest. Genetic defect was confirmed with Sanger sequencing and immunohistochemical assessments on testicular tissue sections.

CONCLUSIONS
Firstly, TMPRSS9 gene defects might impact spermatogenesis. Secondly, as a function of the chromosome breakpoints for azoospermic patients with chromosome rearrangements, provision of the best possible genetic counselling means that genetic testing should not be limited to karyotyping. Given the risks associated with TESE, it is essential to perform WES - especially for consanguineous patients.

Ghieh|Farah|F| Barbotin|Anne-Laure|AL| Prasivoravong|Julie|J| Ferlicot|Sophie|S| Mandon-Pepin|Béatrice|B| Fortemps|Joanne|J| Garchon|Henri-Jean|HJ| Serazin|Valérie|V| Leroy|Clara|C| Marcelli|François|F| Vialard|François|F|

Translocation
Whole-exome sequencing
Non-obstructive azoospermia
Meiotic arrest
TMPRSS9


Magnetic γ'-Fe4 N/Fe3 C, χ-Fe5 C2 , and θ-Fe3 C by a Simple Route for Application as Electrochemical Catalysts.

Abstract: A new and simple method to fabricate magnetic Fe4 N/Fe3 C samples is reported. Meanwhile, pure phase iron carbides (θ-Fe3 C and χ-Fe5 C2 ) were obtained by controlling experimental conditions. The structures, magnetic properties, and morphology of the samples were investigated according to the generalized analysis of X-ray diffraction, X-ray photoelectron spectroscopy, as well as transmission electron microscopy and vibrating sample magnetometry. The magnetic properties measurement revealed the remarkable magnetic properties of the samples at 2 and 300 K. The application of the prepared samples as catalysts for oxygen evolution reaction was also investigated in alkaline solution. This simple and convenient route provides a new path to fabricate other metal nitrides and carbides.

Lei|Xiang|X| Ye|Zhantong|Z| Zhao|Nan|N| Lei|Feifei|F| Yang|Hua|H|

magnetic properties
oxygen evolution reaction
electrochemistry
high saturation magnetization
nanocrystals


Clinical and serological prognostic factors in childhood Guillain-Barré syndrome: A prospective cohort study in Bangladesh.

Abstract: Guillain-Barré syndrome (GBS) is the most common cause of acute flaccid paralysis in children. The objective of this study was to investigate the preceding infections, clinical, serological and electrophysiological characteristics and outcome of childhood GBS in Bangladesh. We included 174 patients with GBS aged <18 years from a prospective cohort in Bangladesh between 2010 and 2018. We performed multivariate logistic regression to determine the risk factors for poor outcome. Among 174 children with GBS, 74% (n = 129) were male. Around half of the patients (49%, n = 86) had severe muscle weakness, 65% (n = 113) were bedbound (GBS disability score 4) and 17% (n = 29) patients required mechanical ventilation at admission. Campylobacter jejuni serology and anti-GM1 IgG antibody were positive in 66% and 21% of the patients respectively. One hundred and forty-three (82%) patients did not receive standard treatment and half of them recovered fully or with minor deficits at 6-month. Twenty patients (11%) died throughout the study period. At 3-month of onset of weakness, complete recovery or recovery with minor deficit was significantly higher in demyelinating GBS patients compared to axonal GBS patients (86% vs 51%, P = .001). Cranial nerve palsy (OR = 4.00, 95%CI = 1.55-10.30, P = .004) and severe muscle weakness (OR = 0.16, 95%CI = 0.06-0.45, P = .001) were the important risk factors of poor outcome in children with GBS. Further large-scale studies are required for better understanding of factors associated with mortality and morbidity in childhood GBS.

Hasan|Imran|I|0000-0002-1282-3157 Papri|Nowshin|N| Hayat|Shoma|S| Jahan|Israt|I| Ara|Gulshan|G| Islam|Badrul|B| Islam|Zhahirul|Z|0000-0003-0935-8079

Guillain-Barré syndrome
Bangladesh
outcome
childhood GBS


The Spodoptera exigua (Lepidoptera: Noctuidae) ABCC2 Mediates Cry1Ac Cytotoxicity and, in Conjunction with Cadherin, Contributes to Enhance Cry1Ca Toxicity in Sf9 Cells.

Abstract: In insects, the mode of Cry1A toxins action has been studied in detail and many receptors that participate in the process are known. Recent evidence has revealed that an ABC transporter (ABCC2) is involved in conferring resistance to Cry1A toxins and that ABCC2 could be a receptor of Cry1A. However, it is not known whether Cry1Ca interacts with the same receptor proteins as Cry1A. In this study, we report the cloning of an ABC transporter gene, SeABCC2b, from the midgut of Spodoptera exigua (Hübner) larvae, and its expression in Sf9 cells for a functional analysis. The addition of Cry1Ca and Cry1Ac to Sf9 cell culture caused swelling in 28.5% and 93.9% of the SeABCC2-expressing cells, respectively. In contrast, only 7.4% and 1.3% of the controls cells swelled in the presence of Cry1Ca and Cry1Ac. Thus, SeABCC2b-expressing Sf9 cells had increased susceptibility to Cry1Ca and Cry1Ac. Similarly, S. exigua cadherin (SeCad1b) expressed in Sf9 cells caused 47.1% and 1.8% of the SeCad1b-expressing cells to swell to Cry1Ca and Cry1Ac exposure. Therefore, Sf9 cells expressing SeCad1b were more sensitive to Cry1Ca than Cry1Ac. Together, our data suggest that SeABCC2b from S. exigua mediates Cry1Ac cytotoxicity and, in conjunction with SeCad1b, contributes to enhance Cry1Ca toxicity in Sf9 cells.

Ren|Xiang-Liang|XL| Jiang|Wei-Li|WL| Ma|Ya-Jie|YJ| Hu|Hong-Yan|HY| Ma|Xiao-Yan|XY| Ma|Yan|Y| Li|Guo-Qing|GQ|

D000089762:Multidrug Resistance-Associated Protein 2

cytotoxicity
cadherin
Sf9 cell
SeABCC2
crystal toxin