Flavonoid Intake and Plasma Sex Steroid Hormones, Prolactin, and Sex Hormone-Binding Globulin in Premenopausal Women.

Abstract:
BACKGROUND
Flavonoids potentially exert anti-cancer effects, as suggested by their chemical structures and supported by animal studies. In observational studies, however, the association between flavonoids and breast cancer, and potential underlying mechanisms, remain unclear.

OBJECTIVE
To examine the relationship between flavonoid intake and sex hormone levels using timed blood samples in follicular and luteal phases in the Nurses' Health Study II among premenopausal women.

METHODS
Plasma concentrations of estrogens, androgens, progesterone, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), prolactin, and sex hormone-binding globulin (SHBG) were measured in samples collected between 1996 and 1999. Average flavonoid were calculated from semiquantitative food frequency questionnaires collected in 1995 and 1999. We used generalized linear models to calculate geometric mean hormone concentrations across categories of the intake of flavonoids and the subclasses.

RESULTS
Total flavonoid intake generally was not associated with the hormones of interest. The only significant association was with DHEAS (p-trend = 0.02), which was 11.1% (95% confidence interval (CI): -18.6%, -3.0%) lower comparing the highest vs. lowest quartile of flavonoid intake. In subclass analyses, the highest (vs. lowest) quartile of flavan-3-ol intake was associated with significantly lower DHEAS concentrations (-11.3% with 95% CI: -18.3%, -3.7%, p-trend = 0.01), and anthocyanin intake was associated with a significant inverse trend for DHEA (-18.0% with 95% CI: -27.9%, -6.7%, p-trend = 0.003).

CONCLUSION
Flavonoid intake in this population had limited impact on most plasma sex hormones in premenopausal women. Anthocyanins and flavan-3-ols were associated with lower levels of DHEA and DHEAS.

Wu|You|Y|0000-0001-9672-6129
Hankinson|Susan E|SE|
Smith-Warner|Stephanie A|SA|
Wang|Molin|M|
Eliassen|A Heather|AH|

flavonoid
premenopausal women
sex hormones
biomarker
circulating hormones


Manipulating Immune Tolerance with Micro-RNA Regulated Gene Therapy.

Abstract: The success of in vivo gene therapy greatly depends on the ability to control the immune response toward the therapeutic transgene. Over the last decade several vector-based and pharmacological approaches have been explored to control the immune-mediated clearance of transgene-expressing cells after viral delivery. One important outcome from these studies is the concept that expression of a transgene in tolerance-promoting organs, such as the liver and tolerogenic antigen-presenting cells, can help safeguard transgene-expressing cells from immune-mediated clearance. Gene therapists are now manipulating vectors to target naturally occurring tolerogenic properties of the body by: (i) incorporating tissue/cell specific promoters for targeted expression, (ii) using viral-capsid engineering to alter tropism and avoid pre-existing immunity, and (iii) regulating cell and activation dependent expression by including micro-RNA (miR) targets into expression cassettes. The combination of these three layers of vector regulation greatly enhances the targeting of tolerogenic cells and limits off-target expression of the transgene, which can lead to the induction of transgene-specific pathogenic effector T cells. In this review, we discuss the application of using miR transgene regulation to generate tolerogenic responses and speculate on possible mechanisms used by the liver to induce the transgene-specific regulatory T cells.

Goudy|Kevin Scott|KS|
Annoni|Andrea|A|
Naldini|Luigi|L|
Roncarolo|Maria-Grazia|MG|

tolerance
micro-RNA
gene therapy
transgene
liver
Treg
hepatocytes
regulatory cells


Sperm telomere length in motile sperm selection techniques: A qFISH approach.

Abstract: Several studies have associated telomere shortening with alterations in reproductive function. The objective of the present study was to determine telomere length (TL) in spermatozoa selected by either density-gradient centrifugation (DGC) or swim-up. The analysis of TL was performed using quantitative fluorescent in situ hybridisation (qFISH) using PNA probes in combination with a chromatin decompaction protocol in sperm cells. Results of TL were 24.64 ± 5.00 Kb and 24.95 ± 4.60 Kb before and after DGC, respectively, and 19.59 ± 8.02 Kb and 20.22 ± 5.18 Kb before and after swim-up respectively. Sperm selected by DGC or swim-up did not show any significant differences in TL as compared to nonselected sperm (p > .05). Negative correlations between TL and sperm motility (r = -.308; p = .049) and concentration (r = -.353; p = .028) were found. Furthermore, exposure of sperm to increasing concentrations of hydrogen peroxide during incubation resulted in a reduction in TL. These data indicate that oxidative stress may be one of the main factors involved in the reduction of TL in sperm. Preliminary clinical results from patients included in this study indicate that TL was shorter in spermatozoa from couples who never achieved a pregnancy compared to couples who did achieve at least one natural pregnancy (p < .05); however, the clinical utility of this biomarker still needs to be confirmed in further studies.

D017404:In Situ Hybridization, Fluorescence


Panel docking of small-molecule libraries - Prospects to improve efficiency of lead compound discovery.

Abstract: Computational docking as a means to prioritise small molecules in drug discovery projects remains a highly popular in silico screening approach. Contemporary docking approaches without experimental parametrisation can reliably differentiate active and inactive chemotypes in a protein binding site, but the absence of a correlation between the score of a predicted binding pose and the biological activity of the molecule presents a clear limitation. Several novel or improved computational approaches have been developed in the recent past to aid in screening and profiling of small-molecule ligands for drug discovery, but also more broadly in developing conceptual relationships between different protein targets by chemical probing. Among those new methodologies is a strategy known as inverse virtual screening, which involves the docking of a compound into different protein structures. In the present article, we review the different computational screening methodologies that employ docking of atomic models, and, by means of a case study, present an approach that expands the inverse virtual screening concept. By computationally screening a reasonably sized library of 1235 compounds against a panel of 48 mostly human kinases, we have been able to identify five groups of putative lead compounds with substantial diversity when compared to each other. One representative of each of the five groups was synthesised, and tested in kinase inhibition assays, yielding two compounds with micro-molar inhibition in five human kinases. This highly economic and cost-effective methodology holds great promise for drug discovery projects, especially in cases where a group of target proteins share high structural similarity in their binding sites.

Sarnpitak|Pakornwit|P|
Mujumdar|Prashant|P|
Taylor|Paul|P|
Cross|Megan|M|
Coster|Mark J|MJ|
Gorse|Alain-Dominique|AD|
Krasavin|Mikhail|M|
Hofmann|Andreas|A|

D055808:Drug Discovery
D006801:Humans
D062105:Molecular Docking Simulation
D011485:Protein Binding
D047428:Protein Kinase Inhibitors
D054852:Small Molecule Libraries

Drug discovery
Molecular docking
Protein kinase inhibitors


Empirical Modeling of Zn/ZnO Nanoparticles Decorated/Conjugated with Fotolon (Chlorine e6) Based Photodynamic Therapy towards Liver Cancer Treatment.

Abstract: The current study is based on Zn/ZnO nanoparticles photodynamic therapy (PDT) mediated effects on healthy liver cells and cancerous cells. The synthesis of Zn/ZnO nanoparticles was accomplished using chemical and hydrothermal methods. The characterization of the synthesized nanoparticles was carried out using manifold techniques (e.g., transmission electron microscopy (TEM), X-ray diffraction (XRD), and energy dispersive X-ray spectroscopy (EDS)). In order to study the biotoxicity of the grown nanoparticles, they were applied individually and in conjunction with the third generation photosensitiser Fotolon (Chlorine e6) in the in vivo model of the normal liver of the Wister rat, and in the in vitro cancerous liver (HepG2) model both in the dark and under a variety of laser exposures (630 nm, Ultraviolet (UV) light). The localization of ZnO nanoparticles was observed by applying fluorescence spectroscopy on a 1 cm² selected area of normal liver, whereas the in vitro cytotoxicity and reactive oxygen species (ROS) detection were carried out by calculating the loss in the cell viability of the hepatocellular model by applying a neutral red assay (NRA). Furthermore, a statistical analysis is carried out and it is ensured that the p value is less than 0.05. Thus, the current study has highlighted the potential for applying Zn/ZnO nanoparticles in photodynamic therapy that would lead to wider medical applications to improve the efficiency of cancer treatment and its biological aspect study.

Iqbal|Seemab|S|0000-0002-9976-4726
Fakhar-E-Alam|Muhammad|M|
Atif|M|M|
Ahmed|Nasar|N|
-Ul-Ahmad|Aqrab|A|
Amin|N|N|
Alghamdi|Raed Ahmed|RA|
Hanif|Atif|A|
Farooq|W Aslam|WA|

ZnO nanoparticles
photodynamic therapy
hepatocellular model
bio toxicity
photosensitizer


All-Atom Structural Models of the Transmembrane Domains of Insulin and Type 1 Insulin-Like Growth Factor Receptors.

Abstract: The receptor tyrosine kinase superfamily comprises many cell-surface receptors including the insulin receptor (IR) and type 1 insulin-like growth factor receptor (IGF1R) that are constitutively homodimeric transmembrane glycoproteins. Therefore, these receptors require ligand-triggered domain rearrangements rather than receptor dimerization for activation. Specifically, binding of peptide ligands to receptor ectodomains transduces signals across the transmembrane domains for trans-autophosphorylation in cytoplasmic kinase domains. The molecular details of these processes are poorly understood in part due to the absence of structures of full-length receptors. Using MD simulations and enhanced conformational sampling algorithms, we present all-atom structural models of peptides containing 51 residues from the transmembrane and juxtamembrane regions of IR and IGF1R. In our models, the transmembrane regions of both receptors adopt helical conformations with kinks at Pro961 (IR) and Pro941 (IGF1R), but the C-terminal residues corresponding to the juxtamembrane region of each receptor adopt unfolded and flexible conformations in IR as opposed to a helix in IGF1R. We also observe that the N-terminal residues in IR form a kinked-helix sitting at the membrane-solvent interface, while homologous residues in IGF1R are unfolded and flexible. These conformational differences result in a larger tilt-angle of the membrane-embedded helix in IGF1R in comparison to IR to compensate for interactions with water molecules at the membrane-solvent interfaces. Our metastable/stable states for the transmembrane domain of IR, observed in a lipid bilayer, are consistent with a known NMR structure of this domain determined in detergent micelles, and similar states in IGF1R are consistent with a previously reported model of the dimerized transmembrane domains of IGF1R. Our all-atom structural models suggest potentially unique structural organization of kinase domains in each receptor.

transmembrane domains
insulin-like growth factor receptor
insulin receptor
cell signaling
diabetes
molecular dynamics simulations


Functional Molecular Network Analysis Enables Prediction of Response to Vedolizumab Therapy in Anti-TNF Refractory IBD Patients.

Abstract:
Background
We applied for the first time 2 label-free technologies, physiological intermolecular modulation spectroscopy (PIMS) and nematic protein organization technic (NPOT) in anti-tumor necrosis factor (TNF) refractory inflammatory bowel disease (IBD) patients to identify clinical responders to vedolizumab therapy and elucidate their underlying functional molecular network.

Methods
PIMS analysis was performed in peripheral blood taken prior to the first vedolizumab application in 20 IBD patients (Crohn disease n = 13; ulcerative colitis n = 7) refractory to at least 1 previous anti-TNF agent therapy. Peripheral blood taken from clinical responders and nonresponders at week 14 of vedolizumab therapy were additionally subjected to NPOT analysis. Response to therapy was assessed by respective clinical disease activity scores (partial Mayo Score and Harvey-Bradshaw Index).

Results
Clinical response to vedolizumab treatment was observed in 7 of 13 Crohn disease and 4 of 7 ulcerative colitis patients at week 14. Response to therapy was accurately predicted by PIMS blood analysis in 100% of ulcerative colitis and 77% of Crohn disease patients. Overall prediction of clinical response with PIMS blood analysis was achieved with a 89% positive predictive value and a 82% negative predictive value. NPOT analysis revealed the heightened expression of the proteins ITGB7, ITGAV, ITG3, PF4, and ASGH in the peripheral blood of vedolizumab responders compared to nonresponders.

Conclusions
PIMS analysis of the blood of anti-TNF refractory IBD patients was able to stratify responders to vedolizumab therapy with high accuracy and specificity. NPOT technology could decipher underling molecular networks in the blood of responders, enabling subsequent personalized therapeutic approaches in IBD.

Breidert|Matthias|M|
Eftekhari|Pierre|P|
Louis|François|F|
Rotoiu|Claudia|C|
Rath|Timo|T|
Neurath|Markus F|MF|
Atreya|Raja|R|

physiological intermolecular modification spectroscopy (PIMS)


Complete versus incomplete revascularization with drug-eluting stents for multi-vessel disease in stable, unstable angina or non-ST-segment elevation myocardial infarction: A meta-analysis.

Abstract:
OBJECTIVES
To determine whether drug-eluting stent (DES) coronary complete revascularization (CR) confers clinical benefit over incomplete revascularization (IR) in patients with multivessel coronary artery disease (MVD).

BACKGROUND
Clinical benefit of CR over IR in patients with MVD with angina (both stable and unstable) and non-ST-segment elevation myocardial infarction (NSTEMI) in DES has not been well studied.

METHODS
We conducted a systematic online literature search of PUBMED and EMBASE. Literatures that compared the clinical outcomes between CR and IR with exclusively or majority (>80%) using DES in patients without or included only small portion (<20%) of ST-segment elevation myocardial infarction or single-vessel coronary artery disease were included. Hazards ratio (HR) with 95% confidence interval (CI) was calculated with random-effects model.

RESULTS
No randomized clinical trials were identified. A total of 14 observational studies with total of 41 687 patients (CR 39.6% and IR 60.4%) were included in this meta-analysis. CR was associated with lower incident of all-cause mortality (HR 0.71, P = 0.001), major adverse events (HR 0.75, P < 0.001), cardiovascular mortality (HR 0.39, P < 0.001). Meta-regression analysis showed that CR significantly reduced the risk of all-cause mortality in advanced age, triple vessel disease and male sub-groups.

CONCLUSIONS
CR with DES conferred favorable outcomes compared to IR in MVD patients with stable, unstable angina or NTEMI. Further research to achieve higher CR in MVD patients may lead to improvement in prognosis in these cohorts.

D000072658:Non-ST Elevated Myocardial Infarction

revascularization
drug-eluting stents
multi-vessel coronary artery disease


Protein-Directed Synthesis of Bifunctional Adsorbent-Catalytic Hemin-Graphene Nanosheets for Highly Efficient Removal of Dye Pollutants via Synergistic Adsorption and Degradation.

Abstract: Herein, for the first time, we report a "green", one-pot reduction/decoration method for the synthesis of bifunctional adsorbent-catalytic hemin-graphene nanosheets by using a common available protein (bovine serum albumin, BSA) as both a reductant and a stabilizer. Our prepared nanosheets are highly stable and possess intrinsic peroxidase-like catalytic activity due to the decoration of BSA and hemin. Furthermore, benefiting from the combined advantages of graphene and BSA, these nanosheets are able to efficiently adsorb dye pollutants from aqueous solution. More importantly, due to their adsorption and catalytic ability, these adsorbent-catalytic nanosheets can be applied to highly efficient dye removal via synergistic adsorption and degradation. Specifically, our catalysts can easily bring organic dyes to their surface by adsorption, and then activate H2O2 to generate hydroxyl radicals, leading to the degradation of the dyes. Such catalytic mechanism of our as-prepared nanosheets was analogous to that of natural enzymes, in which the extremely high catalytic efficiency is largely dependent upon their ability to bring substrates in close proximity to the active sites of enzymes. Our finding may open new potential applications of hemin-graphene hybrid nanosheets in environmental chemistry, biotechnology, and medicine.

graphene
artificial enzyme
dye adsorption
dye degradation
nanohybrid


Changes in the fluid volume balance between intra- and extracellular water in a sample of Japanese adults aged 15-88 yr old: a cross-sectional study.

Abstract: The fluid volume balance between intracellular water (ICW) and extracellular water (ECW) gradually changes with age and various medical conditions. Comprehension of these physiological changes would aid in clinical decision-making related to body fluid assessments. A total of 1,992 individuals (753 men and 1,239 women) aged ≥15 yr included in this study had their body composition measurements performed at training gyms in 2014. We developed a regression formula to assess the association of age with the ratio of ECW to ICW in these subjects. The mean ages of male and female subjects were 51.2 ± 15.2 and 57.4 ± 15.2 yr, and their mean body mass indexes were 23.4 ± 3.3 and 21.1 ± 2.8 kg/m2, respectively. The total fluid volumes of male and female subjects were 39.6 ± 4.9 and 27.7 ± 3.0 liters, whereas the percent body fat mass per kilogram of body weight were 19 and 26%, respectively. The ECW-to-ICW ratio increased with age because of the steeper decrease in the ICW content than in the ECW content, especially after the age of 70 yr. The regression formulas used for calculating the age-adjusted ECW/ICW ratio were as follows: 0.5857 + 7.4334 × 10-6 × (age)2 in men and 0.6062 + 5.5775 × 10-6 × (age)2 in women. In conclusion, the fluid imbalance between ICW and ECW contents is driven by decreased cell volume associated with aging and muscle attenuation. Therefore, our proposed formula may serve as a useful assessment tool for the calculation of body fluid composition.

Ohashi|Yasushi|Y|0000-0003-1670-9498 Joki|Nobuhiko|N| Yamazaki|Keisuke|K| Kawamura|Takeshi|T| Tai|Reibin|R| Oguchi|Hideyo|H| Yuasa|Rena|R| Sakai|Ken|K|

D000293:Adolescent
D000328:Adult
D000367:Age Factors
D000368:Aged
D000369:Aged, 80 and over
D001823:Body Composition
D015992:Body Mass Index
D048429:Cell Size
D003430:Cross-Sectional Studies
D045604:Extracellular Fluid
D005260:Female
D018495:Fluid Shifts
D006801:Humans
D007424:Intracellular Fluid
D007564:Japan
D008297:Male
D008875:Middle Aged
D008954:Models, Biological
D012737:Sex Factors
D014882:Water-Electrolyte Balance
D055815:Young Adult

body composition
cell volume
extracellular fluid
fluid balance
intracellular fluid


Resilience and physical activity in people under home isolation due to COVID-19: A preliminary evaluation.

Abstract:
Background
The recent shelter-in-place order issued by the Spanish government (due to the outbreak of the COVID-19) forced the Spanish population to self-isolate at home. The psychological and social effects of this new situation are unknown. Therefore, this study aimed to examine the impact of such scenario on citizens' resilience, as well as the connections between resilience, physical activity (PA), gender, weight and body mass index (BMI) before and after confinement, and COVID-19-related information.

Methods
A total of 1795 people answered an online questionnaire conducted on March 21st, , 2020, seven days after the mandatory shelter-in-place health order was issued.

Results
Results showed that individuals who regularly engaged in Vigorous PA during the first week of confinement reported higher resilience in terms of higher locus of control, higher self-efficacy, and higher optimism. Moreover, inter-personal resilience differences were observed based on gender, age groups, BMI, weight, and people living with dependent persons or under health risk conditions.

Conclusion
To the best of our knowledge, these findings are the first quantitative evidence pointing towards a link between engagement in Vigorous PA and resilience within the COVID-19 restrictions in Spain. These findings may have important implications for general population during the course of this pandemic, or future ones.

Carriedo|Alejandro|A|
Cecchini|José A|JA|
Fernández-Río|Javier|J|
Méndez-Giménez|Antonio|A|

Confinement
Coronavirus
Psychological effects
Quarantine
Vigorous physical activity


N-terminal prohormone B-type natriuretic peptide and weaning outcome in postoperative patients with pulmonary complications.

Abstract:
OBJECTIVE
To evaluate the relationship between plasma N-terminal prohormone B-type natriuretic peptide (NT-proBNP) and weaning outcomes, and the ability of NT-proBNP level to predict weaning success, in cancer patients with pulmonary complications undergoing noncardiac major surgeries.

METHODS
Patients who were mechanically ventilated following postoperative respiratory failure were enrolled. NT-proBNP levels at the end of a 2-h spontaneous breathing trial were measured. Weaning was considered a success in patients who completed the trial and maintained spontaneous breathing following extubation for >48 h.

RESULTS
Out of 29 patients, 22 patients weaned successfully but weaning failed in 7 patients. Plasma NT-proBNP was significantly higher in the weaning failure group than in the weaning success group. For predicting weaning success, the optimal NT-proBNP threshold value at the end of the spontaneous breathing trial was <448 ng/l (receiver operating characteristic analysis; sensitivity 68.18%, specificity 85.71%, positive predictive value 93.7% and negative predictive value 46.2%).

CONCLUSION
Measuring NT-proBNP at the end of a spontaneous breathing trial may assist in predicting weaning success, as a noninvasive, quantitative and repeatable indicator of cardiac stress in patients with postsurgical respiratory failure.

Ma|Gang|G| Liao|Wei|W| Qiu|Junke|J| Su|Quanguan|Q| Fang|Yi|Y| Gu|Baochun|B|


Research on the optimization of air quality monitoring station layout based on spatial grid statistical analysis method.

Abstract: In recent years, with the significant increase in urban development, it has become necessary to optimize the current air monitoring stations to reflect the quality of air in the environment. Highlighting the spatial representation of some air monitoring stations using Beijing's regional air monitoring station data from 2012 to 2014, the monthly mean particulate matter concentration (PM10) in the region was calculated and through the IDW interpolation method and spatial grid statistical method using GIS, the spatial distribution of PM10 concentration in the whole region was deduced. The spatial distribution variation of districts in Beijing using the gridding model was performed, and through the 3-year spatial analysis, PM10 concentration data including the variation and spatial overlay (1.5 km × 1.5 km cell resolution grid), the spatial distribution result obtained showed that the total PM10 concentration frequency variation exceeded the standard. It is very important to optimize the layout of the existing air monitoring stations by combining the concentration distribution of air pollutants with the spatial region using GIS.

Li|Tianxin|T|
Zhou|Xing Chen|XC|
Ikhumhen|Harrison Odion|HO|
Difei|An|A|

D000393:Air Pollutants
D000397:Air Pollution
D000068476:Beijing
D004784:Environmental Monitoring
D052638:Particulate Matter

grid
Air monitoring station
IDW interpolation
regional statistics


Depletion of p42.3 gene inhibits proliferation and invasion in melanoma cells.

Abstract:
PURPOSE
The p42.3 gene is identified recently, and the upregulated expression has been characterized in a variety of human cancers and embryonic tissues but not yet in malignant melanoma. In this study, we explored the role of p42.3 gene in the development of melanoma.

METHODS
The expression of p42.3 was detected by immunohistochemistry staining of 261 cases of patient lesions, including nevi and melanoma, and its correlation with clinical pathological characteristics and prognosis was analyzed. Furthermore, a series of in vitro assays were used to investigate the biological function of p42.3 in melanoma cells.

RESULTS
Immunohistochemistry staining showed an elevated expression level of p42.3 in melanoma compared to nevi (P = 0.001). Statistical analysis indicated that this high level was well correlated with patients' clinical stage (P = 0.045), but not with gender, age, clinical type, mitotic rate, and overall survival (P > 0.05). Moreover, in vitro assays showed knockdown p42.3 gene expression could inhibit the biological profiling, including proliferation, migration, and invasion of melanoma cells, and also affect PI3K/Akt pathway, MAPK pathway, and β-catenin.

CONCLUSIONS
This study suggests that p42.3, acting like an oncogene, is involved in the malignant transformation process of melanoma and may serve as a biomarker for diagnostic and treatment purposes.

Liu|Hui|H| Zhu|Min|M| Li|Zhongwu|Z| Wang|Yan|Y| Xing|Rui|R| Lu|Youyong|Y| Xue|Weicheng|W|

p42.3 gene
Proliferation
Melanoma
Clinical stage
Migration and invasion


Idh2 deficiency accelerates renal dysfunction in aged mice.

Abstract: The free radical or oxidative stress theory of aging postulates that senescence is due to an accumulation of cellular oxidative damage, caused largely by reactive oxygen species (ROS) that are produced as by-products of normal metabolic processes in mitochondria. The oxidative stress may arise as a result of either increased ROS production or decreased ability to detoxify ROS. The availability of the mitochondrial NADPH pool is critical for the maintenance of the mitochondrial antioxidant system. The major enzyme responsible for generating mitochondrial NADPH is mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2). Depletion of IDH2 in mice (idh2-/-) shortens life span and accelerates the degeneration of multiple age-sensitive traits, such as hair grayness, skin pathology, and eye pathology. Among the various internal organs tested in this study, IDH2 depletion-induced acceleration of senescence was uniquely observed in the kidney. Renal function and structure were greatly deteriorated in 24-month-old idh2-/- mice compared with wild-type. In addition, disruption of redox status, which promotes oxidative damage and apoptosis, was more pronounced in idh2-/- mice. These data support a significant role for increased oxidative stress as a result of compromised mitochondrial antioxidant defenses in modulating life span in mice, and thus support the oxidative stress theory of aging.

Lee|Su Jeong|SJ|
Cha|Hanvit|H|
Lee|Seoyoon|S|
Kim|Hyunjin|H|
Ku|Hyeong Jun|HJ|
Kim|Sung Hwan|SH|
Park|Jung Hyun|JH|
Lee|Jin Hyup|JH|
Park|Kwon Moo|KM|
Park|Jeen-Woo|JW|

D000375:Aging
D000818:Animals
D007521:Isocitrate Dehydrogenase
D007674:Kidney Diseases
D008017:Life Expectancy
D008297:Male
D051379:Mice
D008810:Mice, Inbred C57BL
D018345:Mice, Knockout
D018384:Oxidative Stress
D017382:Reactive Oxygen Species
D015996:Survival Rate

Aging
Mitochondria
Redox status
Antioxidant enzyme
Knockout mice


Cardiotoxicity and myocardial infarction-associated DNA damage induced by thiamethoxam in vitro and in vivo: Protective role of Trigonella foenum-graecum seed-derived polysaccharide.

Abstract: The risk of pesticides on the human health and environment has drawn increasing attention. Today, new tools are developed to reduce pesticide adverse effects. This study aimed to evaluate the toxicity induced by, thiamethoxam (TMX), and the cytoprotective effect of a novel polysaccharide, named fenugreek seed water polysaccharide (FWEP) in vitro using H9c2 cardiomyoblastes and in vivo using Wistar rat model. Animals were assigned into four groups per eight rats each: group 1 served as a control group, group 2 received TMX, group 3, and group 4 received both FWEP and TMX tested at two doses (100 and 200 mg/kg, respectively). Regarding the in vitro study, our results demonstrated that TMX induced a decrease in H9c2 cell viability up to 70% with the highest concentration. In vivo, TMX injection induced marked heart damage noted by a significant increase in plasma lactate dehydrogenase, creatine phosphokinase, troponin-T, aspartate amino transferase activities, cholesterol, and triglyceride levels. Concomitant alterations in cardiac antioxidant defense system revealed depletion in the levels of glutathione and non-protein thiol and an increase in the activity of superoxide dismutase, catalase, and glutathione peroxidase. Similarly, a significant increase in heart lipid, malondialdehyde, advanced oxidation protein product and in protein carbonyls levels was also noted. In addition, heart tissues histo-architecture displayed major presence of apoptosis and necrosis as confirmed by DNA degradation. However, supplementation with FWEP alleviated heart oxidative damage and genotoxicity. In this manner, ABTS radical-scavenging activity, linoleic acid oxidation tests and heart genomic and DNA nicking assay had proved FWEP strong antioxidant potential. In conclusion, FWEP provided significant protection against TMX-induced heart injury, and could be a useful and efficient agent against cardiotoxicity and atherosclerosis.

D017392:Thiobarbituric Acid Reactive Substances

cardiotoxicity
thiamethoxam
polysaccharide
cytotoxicity
oxidative stress


Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia.

Abstract: Focal cortical dysplasia (FCD) is a major cause of the sporadic form of intractable focal epilepsies that require surgical treatment. It has recently been reported that brain somatic mutations in MTOR account for 15%-25% of FCD type II (FCDII), characterized by cortical dyslamination and dysmorphic neurons. However, the genetic etiologies of FCDII-affected individuals who lack the MTOR mutation remain unclear. Here, we performed deep hybrid capture and amplicon sequencing (read depth of 100×-20,012×) of five important mTOR pathway genes-PIK3CA, PIK3R2, AKT3, TSC1, and TSC2-by using paired brain and saliva samples from 40 FCDII individuals negative for MTOR mutations. We found that 5 of 40 individuals (12.5%) had brain somatic mutations in TSC1 (c.64C>T [p.Arg22Trp] and c.610C>T [p.Arg204Cys]) and TSC2 (c.4639G>A [p.Val1547Ile]), and these results were reproducible on two different sequencing platforms. All identified mutations induced hyperactivation of the mTOR pathway by disrupting the formation or function of the TSC1-TSC2 complex. Furthermore, in utero CRISPR-Cas9-mediated genome editing of Tsc1 or Tsc2 induced the development of spontaneous behavioral seizures, as well as cytomegalic neurons and cortical dyslamination. These results show that brain somatic mutations in TSC1 and TSC2 cause FCD and that in utero application of the CRISPR-Cas9 system is useful for generating neurodevelopmental disease models of somatic mutations in the brain.

Lim|Jae Seok|JS|
Gopalappa|Ramu|R|
Kim|Se Hoon|SH|
Ramakrishna|Suresh|S|
Lee|Minji|M|
Kim|Woo-Il|WI|
Kim|Junho|J|
Park|Sang Min|SM|
Lee|Junehawk|J|
Oh|Jung-Hwa|JH|
Kim|Heung Dong|HD|
Park|Chang-Hwan|CH|
Lee|Joon Soo|JS|
Kim|Sangwoo|S|
Kim|Dong Seok|DS|
Han|Jung Min|JM|
Kang|Hoon-Chul|HC|
Kim|Hyongbum Henry|HH|
Lee|Jeong Ho|JH|

D058534:Class I Phosphatidylinositol 3-Kinases

D065703:Malformations of Cortical Development, Group I

D000077004:Tuberous Sclerosis Complex 1 Protein

D000077005:Tuberous Sclerosis Complex 2 Protein

TSC1
TSC2
focal cortical dysplasia
brain somatic mutation
CRISPR-Cas9 genome editing
brain mosaicism
intractable epilepsy


Social ecology of resilience and Sumud of Palestinians.

Abstract: The aim of this article is to provide an overview of theoretical perspectives and practical research knowledge in relation to 'resilience', the resilience of Palestinians in particular and the related concept of 'Sumud'. 'Sumud' is a Palestinian idea that is interwoven with ideas of personal and collective resilience and steadfastness. It is also a socio-political concept and refers to ways of surviving in the context of occupation, chronic adversity, lack of resources and limited infrastructure. The concept of 'resilience' has deep roots, going back at least to the 10th century when Arabic scholars suggested strategies to cope with life adversity. In Europe, research into resilience extends back to the 1800s. The understanding of resilience has developed over four overlapping waves. These focus on individual traits, protective factors, ecological assets and (in the current wave) social ecological factors. The current wave of resilience research focuses on the contribution of cultural contextualisation and is an approach that is discussed in this article, which draws on Arabic and English language literature located through a search of multiple databases (CINAHL, British Nursing Index, ASSIA, MEDLINE, PsycINFO and EMBASE). Findings suggest that 'Sumud' is linked to the surrounding cultural context and can be thought of as an innovative, social ecological, approach to promoting resilience. We show that resilience is a prerequisite to 'Sumud', meaning that the individual has to be resilient in order to stay and not to leave their place, position or community. We close by pressing the case for studies which investigate resilience especially in underdeveloped countries such as Palestine (occupied Palestinian territories), and which reveal how resilience is embedded in pre-existing cultural contexts.

D000223:Adaptation, Psychological
D018912:Arabs
D000068337:Armed Conflicts
D003466:Cultural Characteristics
D006801:Humans
D008877:Middle East
D055500:Resilience, Psychological
D012931:Social Environment

social ecology
resilience
Sumud
cultural context
Palestine


The effects of stabilization exercises using a sling and stretching on the range of motion and cervical alignment of straight neck patients.

Abstract: [Purpose] The purpose of this study was to assess how stretching exercise training and sling exercise training for stabilization influences the cervical spine angles and cervical range of motion of straight neck patients. [Subjects and Methods] Twenty straight neck patients were selected as subjects and they were randomly divided into two groups, the stretching and sling stabilization exercise groups which 60 minutes of exercise three times a week for 6weeks. All the subjects in each of the two respective study groups received an X-ray and had their cervical range of motion measured, both before and after the exercise. [Results] When differences in the cervical spine angle between the pre- and the post-test were checked, it was found that only the stretching exercise group showed statistically significant decreases in the craniovertebral angle and the cranial rotation angle. When differences in the range of motion between pre- and post-test were checked, the sling stabilization exercise group showed a significant change in flexion, right rotation, left lateral bending, right lateral bending, and the stretching exercise group showed a significant change in left rotation, left lateral bending, and right lateral bending. [Conclusion] These results indicate that both types of exercises are effective at improving the cervical range of motion of straight neck patients, and that the stretching exercise was more effective than the sling stabilization exercise at improving cervical spine angles.

Straight neck
Stretching exercise
Sling exercise


The effect of foot position on erector spinae and gluteus maximus muscle activation during sit-to-stand performed by chronic stroke patients.

Abstract: [Purpose] The aim of this study was to use surface electromyography (EMG) to investigate the effects of different foot positioning on bilateral erector spinae (ES) and gluteus maximus (GM) activation during sit-to-stand performed by individuals with stroke. [Subjects] Fifteen randomly selected participants with stroke were enrolled in this study. [Methods] All the participants were asked to perform sit-to-stand (STS) using three different strategies: (1) symmetric foot position, (2) unaffected foot placed behind the affected foot position (asymmetric-1), (3) affected foot placed behind the unaffected foot position (asymmetric-2). An EMG system was used to measure ES and GM muscle activities. The strategies were performed in a random order, and the mean values of five measurements were used in the analysis. One-way repeated measure ANOVA was used to determine the statistical significance of differences between the conditions. [Results] The affected ES muscle activity was significantly greater in asymmetric-2 (180.7±73.4) than in symmetrical foot placement (149.8±54.2). In addition, the affected ES, unaffected ES, and affected GM muscle activity were significantly greater in asymmetric-2 (180.7±73.4, 173.5±83.1, 98.3±90.3 respectively) than in asymmetric-1 foot placement (147.3±53.8, 151.2±76.5, 84.9±73.8 respectively). [Conclusion] Our results suggest that it may be more desirable for persons with stroke to place the affected foot behind the unaffected foot when performing STS to increase affected ES and GM muscle activation.

Nam|Inkyeong|I|
Shin|Jin|J|
Lee|Yoseb|Y|
Lee|Mi Young|MY|
Chung|Yijung|Y|


Health effects of feeding genetically modified (GM) crops to livestock animals: A review.

Abstract: A large share of genetically modified (GM) crops grown worldwide is processed into livestock feed. Feed safety of GM crops is primarily based on compositional equivalence with near-isogenic cultivars and experimental trials in rodents. However, feeding studies in target animals add to the evaluation of GM crops with respect to animal health. This review aimed to evaluate the possible health effects of feeding GM crops to livestock by reviewing scientific publications on experimental studies in ruminants, pigs, and poultry in which at least one of the following health parameters was investigated: body condition score, organ weight, haematology, serum biochemistry, histopathology, clinical examination, immune response, or gastrointestinal microbiota. In most experiments, either Bt (Bacillus thuringiensis) maize, Roundup Ready (RR) soybean, or both were fed to livestock animals. Significant differences (P<0.05) in health parameters were most often observed when animals were fed Bt maize, although most effects measured were unlikely to be of biological significance and were within normal biological ranges. Health effects of RR soybean were only observed in one experimental study with broilers. Based on this literature review, we conclude that there is no clear evidence that feed composed of first generation GM crops has adverse effects on animal health.

de Vos|Clazien J|CJ|
Swanenburg|Manon|M|

D000821:Animal Feed
D000818:Animals
D001413:Bacillus thuringiensis
D018556:Crops, Agricultural
D000069196:Gastrointestinal Microbiome
D058751:Livestock
D030821:Plants, Genetically Modified
D013025:Soybeans
D003313:Zea mays

Ruminants
Pigs
Poultry
Health parameters
Genetically modified (GM) feed


Effect of nitrogen and cold working on structural and mechanical behavior of Ni-free nitrogen containing austenitic stainless steels for biomedical applications.

Abstract: This investigation deals with the evaluation of structural and mechanical behavior of deformed (10% and 20% cold work) and annealed (at 1050°C for 15 min followed by water quenching) Ni-free high nitrogen austenitic stainless steels (HNSs). The microstructure was observed by optical micrograph and the mechanical properties were determined by macrohardness and tensile tests. Both stress strain behavior and work hardening behavior were evaluated. HNSs have smaller grain size as compared to low nitrogen steels and no formation of martensite was observed after 20% cold working. Further, it was found that hardness; yield strength and ultimate tensile strength of the steels linearly increases and elongation decreased with nitrogen content and degree of cold working. The strength coefficient was observed to be higher for the high nitrogen steels; it decreased to some extent with degree of cold working. The work hardening exponent was also observed to decrease with degree of cold working. Influence of nitrogen on mechanical properties was mainly related to its effect on solid solution strengthening. X-ray diffraction analysis of annealed as well as deformed alloys further confirmed no evidence for formation of martensite or any other secondary phases. SEM fractography of the annealed and deformed samples after tensile tests indicates predominantly ductile fracture in all specimens.

Talha|Mohd|M|
Behera|C K|CK|
Sinha|O P|OP|


Design and topology optimization of air conditioning suspension bracket for metro.

Abstract: During the operation of subway vehicles, the vibration of air conditioning units is mainly transmitted to the vehicle body through the suspension support, which seriously affects the stability and comfort of the vehicle during operation. Therefore, the design and optimization of the suspension support of air conditioning units has become a hot topic in the research of the dynamic characteristics of subway vehicles. In this paper, the rigid and flexible coupling dynamic model of metro is firstly calculated to simulate the stress of the suspension point of air conditioning of the vehicle body when the vehicle is running. The initial structure design of the suspension support is carried out, and the stress of the air conditioning suspension point is taken as the load input to analyze the stiffness and strength of the initial structure of the suspension support. Then, the fatigue life is taken as the topology constraint, and the variable density method (SIMP) is used to optimize the topology of the suspension bracket. Finally, the optimized suspension support is validated. The results show that after topological optimization, the maximum displacement and maximum stress of the suspension support under vertical, horizontal, and vertical loads are reduced by 80%, 93%, and 99%, respectively, compared with the original structure model, and the maximum stress under vertical loads is reduced by 50%.

suspension support
variable density method (SIMP)
Metro vehicles
topology optimization/fatigue life


Widespread JNK-dependent alternative splicing induces a positive feedback loop through CELF2-mediated regulation of MKK7 during T-cell activation.

Abstract: Alternative splicing is prevalent among genes encoding signaling molecules; however, the functional consequence of differential isoform expression remains largely unknown. Here we demonstrate that, in response to T-cell activation, the Jun kinase (JNK) kinase MAP kinase kinase 7 (MKK7) is alternatively spliced to favor an isoform that lacks exon 2. This isoform restores a JNK-docking site within MKK7 that is disrupted in the larger isoform. Consistently, we show that skipping of MKK7 exon 2 enhances JNK pathway activity, as indicated by c-Jun phosphorylation and up-regulation of TNF-α. Moreover, this splicing event is itself dependent on JNK signaling. Thus, MKK7 alternative splicing represents a positive feedback loop through which JNK promotes its own signaling. We further show that repression of MKK7 exon 2 is dependent on the presence of flanking sequences and the JNK-induced expression of the RNA-binding protein CELF2, which binds to these regulatory elements. Finally, we found that ∼25% of T-cell receptor-mediated alternative splicing events are dependent on JNK signaling. Strikingly, these JNK-dependent events are also significantly enriched for responsiveness to CELF2. Together, our data demonstrate a widespread role for the JNK-CELF2 axis in controlling splicing during T-cell activation, including a specific role in propagating JNK signaling.

Martinez|Nicole M|NM|
Agosto|Laura|L|
Qiu|Jinsong|J|
Mallory|Michael J|MJ|
Gazzara|Matthew R|MR|
Barash|Yoseph|Y|
Fu|Xiang-Dong|XD|
Lynch|Kristen W|KW|

D048031:JNK Mitogen-Activated Protein Kinases


Elucidation of the structure of retroviral proteases: a reminiscence.

Abstract: Determinations of only a very few protein structures had consequences comparable to the impact exerted by the structure of the protease encoded by HIV-1, published just over 25 years ago. The structure of this relatively small protein and its cousins from other retroviruses provided a clear target for a spectacularly successful structure-assisted drug design effort that offered new hope for controlling the then-escalating AIDS epidemic. This reminiscence is limited primarily to work conducted at the National Cancer Institute, and is not meant to be a comprehensive history of the field, but is rather an attempt to provide a very personal account of how the structures of this most thoroughly studied crystallographic target were determined.

Jaskolski|Mariusz|M|
Miller|Maria|M|
Mohana Rao|J K|JK|
Gustchina|Alla|A|
Wlodawer|Alexander|A|

D054547:National Cancer Institute (U.S.)

protease
drug design
HIV
crystal structures
inhibitors


Honey bee Apis mellifera larvae gut microbial and immune, detoxication responses towards flumethrin stress.

Abstract: Mites are considered the worst enemy of honey bees, resulting in economic losses in agricultural production. In apiculture, flumethrin is frequently used to control mites. It causes residues of flumethrin in colonies which may threaten honey bees, especially for larvae. Still, the impact of flumethrin-induced dysbiosis on honey bees larval health has not been fully elucidated, and any impact of microbiota for decomposing flumethrin in honey bees is also poorly understood. In this study, 2-day-old larvae were fed with different flumethrin-sucrose solutions (0, 0.5, 5, 50 mg/kg) and the dose increased daily (1.5, 2, 2.5 and 3 μL) until capped, thereafter the expression level of two immune genes (hymenoptaecin, defensin1) and two detoxication-related genes (GST, catalase) were measured. Meanwhile, the effect of flumethrin on honey bee larvae (Apis mellifera) gut microbes was also explored via 16S rRNA Illumina deep sequencing. We found that flumethrin at 5 mg/kg triggered the over expression of immune-related genes in larvae, while the larval detoxification-related genes were up-regulated when the concentrations reached 50 mg/kg. Moreover, the abundance and diversity of microbes in flumethrin-treated groups (over 0.5 mg/kg) were significantly lower than control group, but it increased with flumethrin concentrations among the flumethrin-treated groups. Our results revealed that microbes served as a barrier in the honey bee gut and were able to protect honey bee larvae to a certain extent, and reduce the stress of flumethrin on honey bee larvae. In addition, as the concentration of flumethrin increases, honey bee larvae activate their immune system then detoxification system to defend against the potential threat of flumethrin. This is the first report on the impact of flumethrin on gut microbiota in honey bees larvae. The findings revealed new fundamental insights regarding immune and detoxification of host-associated microbiota.

Yu|Longtao|L| Yang|Heyan|H| Cheng|Fuping|F| Wu|Zhihao|Z| Huang|Qiang|Q| He|Xujiang|X| Yan|Weiyu|W| Zhang|Lizhen|L| Wu|Xiaobo|X|

Honey bees
Larvae
Flumethrin
Immune genes
Gut microbiota
Detoxification genes


Human error identification for laparoscopic surgery: Development of a motion economy perspective.

Abstract: This study postulates that traditional human error identification techniques fail to consider motion economy principles and, accordingly, their applicability in operating theatres may be limited. This study addresses this gap in the literature with a dual aim. First, it identifies the principles of motion economy that suit the operative environment and second, it develops a new error mode taxonomy for human error identification techniques which recognises motion economy deficiencies affecting the performance of surgeons and predisposing them to errors. A total of 30 principles of motion economy were developed and categorised into five areas. A hierarchical task analysis was used to break down main tasks of a urological laparoscopic surgery (hand-assisted laparoscopic nephrectomy) to their elements and the new taxonomy was used to identify errors and their root causes resulting from violation of motion economy principles. The approach was prospectively tested in 12 observed laparoscopic surgeries performed by 5 experienced surgeons. A total of 86 errors were identified and linked to the motion economy deficiencies. Results indicate the developed methodology is promising. Our methodology allows error prevention in surgery and the developed set of motion economy principles could be useful for training surgeons on motion economy principles.

Al-Hakim|Latif|L| Sevdalis|Nick|N| Maiping|Tanaphon|T| Watanachote|Damrongpan|D| Sengupta|Shomik|S| Dissaranan|Charuspong|C|

Laparoscopic surgery
Motion economy
Human error identification technique


Human airway trypsin-like protease, a serine protease involved in respiratory diseases.

Abstract: More than 2% of all human genes are coding for a complex system of more than 700 proteases and protease inhibitors. Among them, serine proteases play extraordinary, diverse functions in different physiological and pathological processes. The human airway trypsin-like protease (HAT), also referred to as TMPRSS11D and serine 11D, belongs to the emerging family of cell surface proteolytic enzymes, the type II transmembrane serine proteases (TTSPs). Through the cleavage of its four major identified substrates, HAT triggers specific responses, notably in epithelial cells, within the pericellular and extracellular environment, including notably inflammatory cytokine production, inflammatory cell recruitment, or anticoagulant processes. This review summarizes the potential role of this recently described protease in mediating cell surface proteolytic events, to highlight the structural features, proteolytic activity, and regulation, including the expression profile of HAT, and discuss its possible roles in respiratory physiology and disease.

Menou|Awen|A|
Duitman|JanWillem|J|
Flajolet|Pauline|P|
Sallenave|Jean-Michel|JM|
Mailleux|Arnaud André|AA|
Crestani|Bruno|B|

urokinase-type plasminogen activator receptor


Radiation-associated meningioma in the elderly: development of meningioma with olfactory neuroblastoma recurrence 10 years after irradiation.

Abstract: The pathogenesis of meningiomas is not established [1,2]. However, intracranial irradiation in childhood is a risk factor for the development of meningiomas later in life [2-6]. Children treated with irradiation for tinea capitis of the scalp showed an almost ten-fold increase in development of meningiomas relative to age-matched controls [2,3]. In a study of almost 18,000 children who survived for at least five years after receiving external beam radiation, 2.3% developed meningiomas within 17 years of follow-up [5]. Notably, meningioma formation after radiation therapy (RT) occurs almost exclusively in patients irradiated as children or young adults. Development of a radiation-associated meningioma (RAM) in patients who received RT in the sixth or seventh decade is very rare. For example, in studies including a total of 58 adults receiving RT, only two cases of RAM occurred in patients 50 years old or older [8,9].

Johnson|Mahlon D|MD|
Piech|Kenneth|K|
Emandian|Seyed|S|

meningioma
olfactory neuroblastoma
radiation


Erectile dysfunction cannot be used in primary screening of pre-diabetes.

Abstract: We hypothesized that erectile dysfunction is associated with impaired fasting glucose and impaired glucose tolerance and could be used in primary screening of pre-diabetes. Although erectile dysfunction is known to be closely associated with diabetes, we demonstrate that it is not associated with pre-diabetes in 926 apparently healthy men.

Ettala|Otto O|OO|
Korhonen|Päivi E|PE|
Syvänen|Kari T|KT|
Kaipia|Antti J|AJ|
Vahlberg|Tero J|TJ|
Aarnio|Pertti T|PT|
Boström|Peter J|PJ|

D000368:Aged
D001786:Blood Glucose
D003430:Cross-Sectional Studies
D042241:Early Diagnosis
D007172:Erectile Dysfunction
D018149:Glucose Intolerance
D005951:Glucose Tolerance Test
D006801:Humans
D008297:Male
D008403:Mass Screening
D008875:Middle Aged
D011236:Prediabetic State

International Index of Erectile Function shot form


Feasting in fresh water: impacts of food concentration on freshwater tolerance and the evolution of food × salinity response during the expansion from saline into fresh water habitats.

Abstract: Saline to freshwater invasions have become increasingly common in recent years. A key hypothesis is that rates of freshwater invasions have been amplified in recent years by increased food concentration, yet this hypothesis has remained unexplored. We examined whether elevated food concentration could enhance freshwater tolerance, and whether this effect evolves following saline to freshwater invasions. We examined physiological response to salinity and food concentration in a 2 × 2 factorial design, using ancestral brackish and freshwater invading populations of the copepod Eurytemora affinis. We found that high food concentration significantly increases low-salinity tolerance. This effect was reduced in the freshwater population, indicating evolution following the freshwater invasion. Thus, ample food could enable freshwater invasions, allowing subsequent evolution of low-salinity tolerance even under food-poor conditions. We also compared effects of food concentration on freshwater survival between two brackish populations from the native range. Impacts of food concentration on freshwater survival differed between the brackish populations, suggesting variation in functional properties affecting their propensity to invade freshwater habitats. The key implication is that high food concentration could profoundly extend range expansions of brackishwater species into freshwater habitats, potentially allowing for condition-specific competition between saline invaders and resident freshwater species.

Lee|Carol Eunmi|CE|
Moss|Wynne E|WE|
Olson|Nora|N|
Chau|Kevin Fongching|KF|
Chang|Yu-Mei|YM|
Johnson|Kelsey E|KE|

freshwater colonization
natural selection
osmoregulation
phenotypic plasticity
range limits
reaction norm
starvation resistance


Neuroimaging in Frontotemporal Dementia: Heterogeneity and Relationships with Underlying Neuropathology.

Abstract: Frontotemporal dementia encompasses a group of clinical syndromes defined pathologically by degeneration of the frontal and temporal lobes. Historically, these syndromes have been challenging to diagnose, with an average of about three years between the time of symptom onset and the initial evaluation and diagnosis. Research in the field of neuroimaging has revealed numerous biomarkers of the various frontotemporal dementia syndromes, which has provided clinicians with a method of narrowing the differential diagnosis and improving diagnostic accuracy. As such, neuroimaging is considered a core investigative tool in the evaluation of neurodegenerative disorders. Furthermore, patterns of neurodegeneration correlate with the underlying neuropathological substrates of the frontotemporal dementia syndromes, which can aid clinicians in determining the underlying etiology and improve prognostication. This review explores the advancements in neuroimaging and discusses the phenotypic and pathologic features of behavioral variant frontotemporal dementia, semantic variant primary progressive aphasia, and nonfluent variant primary progressive aphasia, as seen on structural magnetic resonance imaging and positron emission tomography.

Behavioral variant frontotemporal dementia

Semantic variant primary progressive aphasia

Nonfluent agrammatic variant primary progressive aphasia


Public Trust in Physicians-Health Care Commodification as a Possible Deteriorating Factor: Cross-sectional Analysis of 23 Countries.

Abstract: Trust in physicians has declined, and surveys of public opinion show a poor level of public trust in physicians. Commodification of health care has been speculated as a plausible driving force. We used cross-national data of 23 countries from the International Social Survey Programme 2011 to quantify health care commodification and study its role in the trust that patients generally place in physicians. A modified health care index was used to quantify health care commodification. There were 34 968 respondents. A question about the level of general trust in physicians and a 4-item "general trust in physicians" scale were used as our major and minor outcomes. The results were that compared with those in the reference countries, the respondents in the health care-commodified countries were approximately half as likely to trust physicians (odds ratio: 0.47, 95% confidence interval [CI]: 0.31-0.72) and scored 1.13 (95% CI: 1.89-0.37) less on the general trust scale. However, trust in physicians in the health care-decommodified countries did not differ from that in the reference countries. In conclusion, health care commodification may play a meaningful role in the deterioration of public trust in physicians.

Huang|Ellery Chih-Han|EC|
Pu|Christy|C|
Chou|Yiing-Jenq|YJ|
Huang|Nicole|N|

trust
commodification
health care commodification
health care commercialization
multilevel
patient trust
surveys and questionnaires


Physicochemical properties of anti Vibrio harveyi egg yolk antibody (IgY) and its immunological influence in Indian white shrimp Fenneropenaeus indicus.

Abstract: Edible antibodies specific to host pathogens is an attractive approach to establish protective immunity, especially against gastrointestinal pathogens both in humans and animals. The edible antibody of anti-Vibrio harveyi IgY (anti-V. h IgY) was produced by antigen mixed with immunoadjuvant Asparagus racemosus and Glycine max. Hens were immunized and eggs were collected five weeks after the immunization. Anti-V. harveyi IgY stability in different digestive enzymes such as trypsin and chymotrypsin were evaluated to determine its ability to withstand in the gastrointestinal tract of F. indicus. Specific binding activity and concentration (average 9.5% of total IgY content) of the anti-V. h IgY were determined by the ELISA using V. harveyi antigen. Further the anti-V. h IgY diets including V.h wo, V.h A, V.h G and control diets were fed to F. indicus for 60 days. After 30 and 60 of feeding, group of shrimps were challenged with virulent V. harveyi. After the respective days of feeding, haematological and immunological changes were studied. The parameters including total haemocyte count (THC), coagulase activity, oxyhaemocyanin level, prophenoloxidase, intracellular superoxide anion production, lysozyme, phagocytosis and bacterial agglutinin had significantly (P ≤ .001) increased in the experimental groups in comparission with the control diet fed shrimps. The anti-V. h IgY coated diets helped to reduce the Vibrio load and boosted the immune system in F. indicus's against V. harveyi challenge. The research work shows the potential applications of egg yolk antibodies as anti-bacterial prophylactic uses for infectious diseases and suggests an edible antibody concept as an alternative to conventional antibiotics.

Kumaran|Thankamani|T| Thirumalaikumar|Eswaramoorthy|E| Lelin|Chinnadurai|C| Palanikumar|Pandi|P| Michaelbabu|Mariavincent|M| Citarasu|Thavasimuthu|T|

Vibrio harveyi
Fenneropenaeus indicus
Immunoadjuvants
Edible antibody (IgY)
Gallus gallus domesticus


Comparative Proteomic Analysis of Tumor Mesenchymal-Like Stem Cells Derived from High Grade versus Low Grade Gliomas.

Abstract:
OBJECTIVE
Gliomas are the most common primary brain tumors, and have been ranked as the fourth leading cause of cancer death. Tumor mesenchymal-like stem cells (tMSCs) contribute to the aggressive behavior of glial tumors by providing a favorable microenvironment for the malignant cells. The aim of our study was to identify differential proteome of tMSCs derived from low vs. high grade glioma tumors.

MATERIALS AND METHODS
Patients with newly diagnosed low and high grade gliomas were included in this case control study. tMSCs were isolated from tumors using enzymatic digestion validated by flow cytometer analysis after sub-culturing. Differential proteomic analysis of tMSCs derived from low and high grade tumors was performed by two-dimensional gel electrophoresis and mass spectrometry. Protein spots with more than two fold differences and P values below 0.05 were considered as differentially expressed ones.

RESULTS
In tMSCs isolated from low and high grade gliomas, different isoforms of mesenchymal-related proteins vimentin and transgelin were differentially expressed. Overexpressed proteins in tMSCs isolated from low grade gliomas were mitochondrial manganese-containing superoxide dismutase (Mn-SOD), 40S ribosomal protein SA, and GTP-binding nuclear protein, while in tMSCs isolated from high grade gliomas, cathepsin B, endoplasmin, ezrin, peroxiredoxin1, and pyruvate kinase (PK) were found to be significantly overexpressed.

CONCLUSION
For the first time, we analyzed the differential proteomic profiles of tMSCs isolated from glioma tumors with different grades. It was found that molecules related to mesenchymal cells (vimentin and transglin), in addition to those related to tumor aggressiveness with potential secretory behavior (e.g. cathepsin B) were among differentially expressed proteins.

Taghipour|Mousa|M| Omidvar|Aydine|A| Razmkhah|Mahboobeh|M| Ghaderi|Abbas|A| Mojtahedi|Zahra|Z|

Proteomics
Glioma
Pyruvate Kinase
Mesenchymal Stem Cells


Nanomedicine: Bioavailability, Biotransformation and Biokinetics.

Abstract:
BACKGROUND
Nanomedicine is increasingly used to treat various ailments. Biocompatibility of nanomedicine is primarily governed by its properties such as bioavailability, biotransformation and biokinetics. One of the major advantages of nanomedicine is enhanced bioavailability of drugs. Biotransformation of nanomedicine is important to understand the pharmacological effects of nanomedicine. Biokinetics includes both pharmacokinetics and toxicokinetics of nanomedicine. Physicochemical parameters of nanomaterials have extensive influence on bioavailability, biotransformation and biokinetics of nanomedicine.

METHODS
We carried out a structured peer-reviewed research literature survey and analysis using bibliographic databases.

RESULTS
Eighty papers were included in the review. Papers dealing with bioavailability, biotransformation and biokinetics of nanomedicine are found and reviewed. Bioavailability and biotransformation along with biokinetics are three major factors that determine the biological fate of nanomedicine. Extensive research work has been done for drugs of micron size but studies on nanomedicine are scarce. Therefore, more emphasis in this review is given on the bioavailability and biotransformation of nanomedicine along with biokinetics.

CONCLUSION
Bioavailability results based on various nanomedicine are summarized in the present work. Biotransformation of nanodrugs as well as nanoformulations is also the focus of this article. Both in vitro and in vivo biotransformation studies on nanodrugs and its excipients are necessary to know the effect of metabolites formed. Biokinetics of nanomedicine is captured in details that are complimentary to bioavailability and biotransformation. Nanomedicine has the potential to be developed as a personalized medicine once its physicochemical properties and its effect on biological system are well understood.

Ravindran|Selvan|S|
Tambe|Amlesh J|AJ|
Suthar|Jitendra K|JK|
Chahar|Digamber S|DS|
Fernandes|Joyleen M|JM|
Desai|Vedika|V|

Nanomedicine
bioavailability
biotransformation
biokinetics
drug discovery
metabolism.


Bioavailability of quercetin in humans and the influence of food matrix comparing quercetin capsules and different apple sources.

Abstract: The objective of the four-way cross-over pilot study was the investigation of quercetin bioavailability after ingestion of apple quercetin incorporated in different matrices and quercetin dihydrate capsule. Six healthy volunteers were given a standard diet supplemented with 71μmol quercetin equivalents from vacuum impregnated apple chips, apple peel extract capsules and apple peel. Quercetin dihydrate capsules were used as control. The vacuum impregnated apple chips were enriched with a quercetin rich apple peel extract. The ingestion of vacuum impregnated apple chips, apple peel extract capsules and apple peel resulted in similar plasma quercetin and plasma total flavonol concentrations compared to the quercetin dihydrate capsule. With regard to the bioavailabilities of all quercetin treatments, a reduced release from vacuum impregnated apple chips can be excluded. The apple peel matrix which is rich in indigestible dietary fibers impacted the profile of the plasma flavonol time curve similar to poor soluble quercetin dihydrate. Finally, the quercetin bioavailability of vacuum impregnated apple chips (AUC0-1440min: 104±24μmol·min∙L-1) as functional food was similar to the supplementation with apple peel extract capsules (AUC0-1440min: 87±27μmol∙min∙L-1).

Petersen|Beate|B|
Egert|Sarah|S|
Bosy-Westphal|Anja|A|
Müller|Manfred J|MJ|
Wolffram|Siegfried|S|
Hubbermann|Eva M|EM|
Rimbach|Gerald|G|
Schwarz|Karin|K|

Bioavailability
Food matrix
Supplementation
Apple products
Quercetin sources


D-Dimer Combined With CRP Can Improve the Differential Value of Bacterial Meningitis and Tuberculous Meningitis.

Abstract:
OBJECTIVE
To explore the diagnostic value of the coagulation marker D-dimer and its combination with the traditional marker C-reactive protein (CRP) in distinguishing bacterial meningitis (BM) from tuberculous meningitis (TM).

METHODS
We performed a retrospective study on specimens from 173 patients with meningitis who were hospitalized at the First Affiliated Hospital of Guangxi Medical University, Guangxi, China, from 2012 through 2020. The patient records were divided into the BM group and the TM group, and hematological parameters D-dimer and CRP were evaluated for the 2 groups.

RESULTS
The levels of D-dimer and CRP in the BM group were significantly higher than those levels in the TM group (P ˂.001 for each), and the sensitivity and specificity of the combined detection of the 2 markers was 86.3% to 100%; the area under the receiver operating characteristic (ROC) curve reached 0.983 (95% confidence interval [CI], 0.966-0.999).

CONCLUSION
D-dimer testing has high specificity in distinguishing between BM and TM; CRP testing also has high sensitivity. The combined diagnosis of the 2 biomarkers helps to distinguish TM from BM.

Lu|Liuyi|L| Qi|Yunwei|Y| Chen|Huaping|H| Hu|Zuojian|Z| Yang|Sitao|S| Qin|Simeng|S| Zhang|Linyan|L| Chen|Mingxing|M| Qin|Xue|X|

D-dimer
CRP
bacterial meningitis
tuberculous meningitis
biomarkers
joint diagnosis


The impact of behavioral interventions on co-infection dynamics: An exploration of the effects of home isolation.

Abstract: Behavioral epidemiology, the field aiming to determine the impact of individual behavior on the spread of an epidemic, has gained increased recognition during the last few decades. Behavioral changes due to the development of symptoms have been studied in mono-infections. However, in reality, multiple infections are circulating within the same time period and behavioral changes resulting from contraction of one of the diseases affect the dynamics of the other. The present study aims at assessing the effect of home isolation on the joint dynamics of two infectious diseases, including co-infection, assuming that the two diseases do not confer cross-immunity. We use an age- and time- structured co-infection model based on partial differential equations. Social contact matrices, describing different mixing patterns of symptomatic and asymptomatic individuals are incorporated into the calculation of the age- and time-specific marginal forces of infection. Two scenarios are simulated, assuming that one of the diseases has more severe symptoms than the other. In the first scenario, people stay only at home when having symptoms of the most severe disease. In the second scenario, twice as many people stay at home when having symptoms of the most severe disease than when having symptoms of the other disease. The results show that the impact of home isolation on the joint dynamics of two infectious diseases depends on the epidemiological parameters and properties of the diseases (e.g., basic reproduction number, symptom severity). In case both diseases have a low to moderate basic reproduction number, and there is no home isolation for the less severe disease, the final size of the less severe disease increases with the proportion of symptomatic cases of the most severe disease staying at home, after an initial decrease. This counterintuitive result could be explained by a shift in the peak time of infection of the disease with the most severe symptoms, resulting in a smaller number of people with less contacts at the peak time of the other infection. When twice as many people stay at home when having symptoms of the most severe disease than when having symptoms of the other disease, increasing the proportion staying at home always reduces the final size of both diseases, and the number of co-infections. In conclusion, when providing advise if people should stay at home in the context of two or more co-circulating diseases, one has to take into account epidemiological parameters and symptom severity.

Hendrickx|Diana M|DM|
Abrams|Steven|S|
Hens|Niel|N|

Behavioral epidemiology
Co-infection model
Partial differential equations
Reproduction numbers


Patients' self-perceived burden, caregivers' burden and quality of life for amyotrophic lateral sclerosis patients: a cross-sectional study.

Abstract:
AIMS AND OBJECTIVES
This study surveys the quality of life of amyotrophic lateral sclerosis patients and the factors associated with amyotrophic lateral sclerosis patients' self-perceived burden and their caregivers' burden.

BACKGROUND
Burdens of patients with amyotrophic lateral sclerosis and their caregivers in Chinese population are largely unknown.

DESIGN
A cross-sectional study was conducted among 81 pairs of amyotrophic lateral sclerosis patients and their caregivers.

METHODS
Amyotrophic lateral sclerosis patients' self-perceived burden and caregivers' burden were assessed by the Self-Perceived Burden Scale and Zarit-Burden Interview, respectively. Quality of life of amyotrophic lateral sclerosis patients was measured using the World Health Organization Quality of Life-Bref. The amyotrophic lateral sclerosis Functional Rating Scale-Revised questionnaire was used to estimate patients' physical function.

RESULTS
Both patients and caregivers reported a mild to moderate burden. The World Health Organization quality of life-Bref scores were decreased in respondents with lower amyotrophic lateral sclerosis Functional Rating Scale-Revised, higher Self-Perceived Burden Scale and higher Zarit-Burden Interview scores. Self-Perceived Burden Scale scores were associated with patients' knowledge of amyotrophic lateral sclerosis, respiratory function and female sex. Zarit-Burden Interview scores were associated with caregivers' age, patients' motor function and out-of-pocket payment.

CONCLUSION
With increase in amyotrophic lateral sclerosis patients' self-perceived burden and caregivers' burden, quality of life of amyotrophic lateral sclerosis patients decreased. Female patients, who had known more about the disease, and those with severe respiratory dysfunction were subject to higher self-perceived burden. Older caregivers and caregivers of patients with severe motor dysfunction and more out-of-pocket payment experienced more care burdens.

RELEVANCE TO CLINICAL PRACTICE
Our study suggests that paying more attention to female amyotrophic lateral sclerosis patients might benefit patients in China or other South-East Asian countries under the Confucian concept of ethics. There is an urgent demand to expand medical insurance coverage to cover amyotrophic lateral sclerosis in China and other developing countries. Long and adequate supports are needed for relieving caregiver's burden. To improve the quality of life of patients, relieving the patients' SBP and caregivers' burden is likely to be not only required, but also essential.

Geng|Dan|D| Ou|RuWei|R| Miao|XiaoHui|X| Zhao|LiHong|L| Wei|QianQian|Q| Chen|XuePing|X| Liang|Yan|Y| Shang|HuiFang|H| Yang|Rong|R|

D007722:Health Knowledge, Attitudes, Practice

self-perceived burden
quality of life
amyotrophic lateral sclerosis
medical insurance
caregiver burden
nursing
psychosocial care


The Role of MDR1 (C3435T) Gene Polymorphism in Patients with Chronic Obstructive Pulmonary Disease Associated with Type 2 Diabetes Mellitus.

Abstract: Chronic obstructive pulmonary disease is a multifactorial disease characterized by gene-gene interaction as well as environmental effects. The incidence of type 2 diabetes mellitus is proved to be higher in the presence of chronic obstructive pulmonary disease than in the case of its absence. We aimed to study the genotypes of MDR1 (C3435T) gene polymorphism and its relationship with clinical, instrumental, and laboratory parameters in chronic obstructive pulmonary disease associated with type 2 diabetes mellitus. All the patients were divided into two groups. The first group included 53 patients with chronic obstructive pulmonary disease, and the second group included 49 patients with chronic obstructive pulmonary disease with comorbid type 2 diabetes mellitus. The COPD assessment test (CAT), 6-minute walk test, BODE integral index, spirometry, and bioimpedansometry were used for examination. Lipid spectrum, carbohydrate metabolism, endothelial functional status, leptin, adiponectin, and serum levels were also determined by means of enzyme immunoassay. Our study results showed no significant difference between the genotypes of the control group of healthy individuals and patients with chronic obstructive pulmonary disease and comorbid type 2 diabetes mellitus. Though, a certain association of this gene polymorphism with clinical findings by CAT-test, specific parameters of carbohydrate (fasting glucose) and lipid metabolism (total cholesterol and low-density cholesterol lipoproteins), endothelial functional state (nitrate/nitrite level) with the minor allele T available was found.

D018435:ATP Binding Cassette Transporter, Subfamily B

D029424:Pulmonary Disease, Chronic Obstructive

Chronic obstructive pulmonary disease
diabetes mellitus
MDR1 gene


Preoperative Serum Leptin Level Is Associated with Preoperative Pain Threshold and Postoperative Analgesic Consumption in Patients Undergoing Cesarean Section.

Abstract:
OBJECTIVE
This study aimed to investigate the preoperative level of serum leptin in cesarean section (C-section) patients with and without acute labor pain and its association with postoperative analgesic consumption and preoperative pain threshold.

MATERIALS AND METHODS
Preoperative leptin levels, preoperative pain threshold, postoperative analgesic consumption in the first 24 h, and postoperative pain severity (visual analog scale (VAS) scores at 1, 2, 4, 6, 12, and 24 h postoperatively) in C-section patients with labor pain (emergency C-section; n = 21) and without labor pain (elective C-section; n = 25) were compared.

RESULTS
There were no signiﬁcant differences between the groups regarding the demographic characteristics. Leptin levels, postoperative VAS scores, and analgesic consumption were significantly higher in the group with labor pain, while the preoperative pain threshold was lower. Serum leptin levels correlated negatively with pain threshold and positively with postoperative analgesic consumption. Multiple linear regression analyses in our study revealed that the preoperative leptin levels and having an emergency C-section independently affected the postoperative analgesic consumption and preoperative pain threshold, whereas their combined effects on these parameters were statistically not significant.

CONCLUSION
Preoperative levels of serum leptin were higher in C-section patients with labor pain than in those without labor pain, and increased serum leptin levels were associated with decreased preoperative pain threshold and increased postoperative analgesic consumption in our study population. Postoperative analgesic requirements may vary among patients, and their requirements might be predicted using preoperative indicators. Serum levels of leptin might be one such indicator and this warrants further studies with larger sample sizes.

Seringec Akkececi|Nurten|N|
Oksuz|Gozen|G|
Urfalioğlu|Aykut|A|
Gunesacar|Ramazan|R|
Bakacak|Murat|M|
Arslan|Mahmut|M|
Kelleci|Bekir Mehmet|BM|

Leptin
Pain threshold
Postoperative analgesic consumption
Labor pain
Visual analog scale


Brexpiprazole as an adjunctive treatment in young adults with major depressive disorder who are in a school or work environment.

Abstract:
BACKGROUND
Major depressive disorder (MDD) is a common, debilitating disorder with substantial socioeconomic burden. Many patients with MDD experience symptoms that impair functioning and productivity, often negatively affecting work or educational pursuits. This Phase 3b open-label study evaluated adjunctive brexpiprazole in young adults with MDD, who were in work or study.

METHODS
Young patients (18-35 years) with MDD (inadequate responders to 1-3 antidepressant treatments [ADT] for their current episode) received brexpiprazole 1-3mg/day (target dose, 2mg/day) adjunctive to the same stable dose of ADT for 12 weeks.

RESULTS
Depressive symptoms improved during treatment with adjunctive brexpiprazole (primary endpoint, least squares [LS] mean change from baseline in Montgomery-Åsberg Depression Rating Scale [MADRS] total score, -18.1 [p<0.0001]). Reductions from baseline in Sheehan Disability Scale Score (SDS; LS mean change -11.2 [p<0.0001]) and Work Limitations Questionnaire (WLQ; p<0.0001) indicated improvements in the effects of patients' symptoms on functioning (work/school, social life, and home responsibilities). Changes from baseline in additional measures supported improvements in patient functioning and depression symptoms. The most common adverse events were headache (21.3%), weight increase (17.0%), and somnolence (17.0%); reported rates of akathisia were low (6.4%). Clinically relevant increases in weight (≥7%) occurred in 10.5% of patients.

LIMITATIONS
Open-label design; absence of comparator.

CONCLUSIONS
Brexpiprazole may represent an effective therapy for adjunctive treatment strategy of young adults with MDD who are working or studying. The observed improvements in work/school functioning in patients with MDD, whose depression was treated with ADT+brexpiprazole, suggests potential to reduce socioeconomic burden.

Weisler|Richard H|RH|
Ota|Ai|A|
Tsuneyoshi|Kana|K|
Perry|Pamela|P|
Weiller|Emmanuelle|E|
Baker|Ross A|RA|
Sheehan|David V|DV|

D011569:Psychiatric Status Rating Scales

Brexpiprazole
Young adults
Major depressive disorder
Work
Functioning


Neuroprotective effects of leptin on cerebral ischemia through JAK2/STAT3/PGC-1-mediated mitochondrial function modulation.

Abstract: Neuroprotective effects of leptin have been shown in mouse model of cerebral ischemia/reperfusion injury and primary cortical neuronal culture with oxygen-glucose deprivation (OGD), while the underlying mechanisms are less understood. In the present study, we investigated whether leptin modulated mitochondrial function through JAK2/STAT3 in vivo mouse model of transient middle cerebral artery occlusion (MCAO) and in OGD-challenged primary neuronal cultures. JAK2/STAT3; mitochondrial biogenesis markers (PGC-1α); and apoptosis-associated proteins (caspase-3, BCL-2, BCL-XL, and cytochrome c) were detected by western blotting and reverse transcription-polymerase chain reaction at 1 h before and after ischemia/reperfusion. P-STAT3 and PGC-1α in neurons and astrocytes were detected. Moreover, mitochondrial morphology of the ischemic ipsilateral penumbra is examined using transmission electron microscopy. Primary cerebral cortical neurons were evaluated for viability, mitochondrial membrane potential (MMP), and apoptosis to assess whether dose-dependent neuroprotective effects of leptin during OGD were mitigated by the JAK2/STAT3 inhibitor AG490. Leptin activated JAK2/STAT3 signaling in neurons and astrocytes distributed in the ischemic ipsilateral penumbra, with peak p-STAT3 levels observed at 1 h after reperfusion. Leptin increased PGC-1α, BCL-2, and BCL-XL protein levels, cell viability, and MMP and decreased apoptosis both in vitro and in vivo; these effects were reversed by AG490 treatment. Our findings suggest that leptin-mediated neuroprotective effects in tMCAO may peak at 1 h to induce the transcription of its target gene PGC-1α, stabilization of MMP, inhibition of mitochondrial permeability transition pore opening, release of cytochrome c, and apoptosis.

Zhang|Wenfang|W| Jin|Yinchuan|Y| Wang|Dong|D| Cui|Jingjing|J|

D020244:Infarction, Middle Cerebral Artery

Leptin
PGC-1α
Mitochondrial membrane potential (MMP)
Brain
Signaling pathway


Impact of T161, Y318 and S363 alanine mutations on regulation of the human delta-opioid receptor (hDOPr) induced by peptidic and alkaloid agonists.

Abstract: Previously, we showed a differential regulation of the human delta-opioid receptor (hDOPr) by etorphine and [D-Pen2, D-Pen5] enkephalin (DPDPE). To understand the molecular basis of such differences, we introduced 3 alanine mutations at the residues T161. Y318 and S363. Both wild type (WT) and hDOPr mutants were expressed in HEK cells containing endogenous arrestins or CFP-tagged arrestin 3, then desensitization, internalization, recycling and phosphorylation were studied. In a context of endogenous arrestin expression, a major difference in DOPr desensitization was observed between agonists that was modified with the T161A mutation upon etorphine and with the S363A substitution upon DPDPE exposure. While both agonists induced a major receptor internalization, T161A and S363A impaired DOPr sequestration only for etorphine. However, similar level of S363 phosphorylation was measured between agonists. When CFP-tagged arrestin 3 was over-expressed, a similar profile of desensitization was measured for both agonists. In this context, all the 3 alanine mutations decreased etorphine-induced receptor desensitization. Using FRET, we showed similar interactions between WT hDOPr and arrestin 3 under DPDPE and etorphine stimulation which were delayed by both the Y318A and the S363A substitutions for etorphine. Finally, hDOPr recycling was qualitatively evaluated by microscopy and showed neither arrestin 3/hDOPr colocalization nor major impact of alanine mutations except for the S363A which impaired internalization and recycling for etorphine. The T161, Y318 and S363 residues of hDOPr could underlie the differential regulation promoted by DPDPE and etorphine.

Camacho|Elise|E| Marie|Nicolas|N| Dupas|Quentin|Q| Martel|Caroline|C| Nowoczyn|Marie|M| Elie|Nicolas|N| Rochais|Christophe|C| Töth|Geza|G| Allouche|Stéphane|S|

Arrestin
Desensitization
Internalization
Phosphorylation
Biased agonism
Opioid receptor regulation


Implication of Acute Kidney Injury in Heart Failure.

Abstract: Patients with acute or chronic decompensated heart failure (ADHF) present with various degrees of heart and kidney dysfunction characterizing cardiorenal syndrome (CRS). CRS can be generally defined as a pathophysiologic disorder of the heart and kidneys whereby acute or chronic dysfunction of 1 organ may induce acute or chronic dysfunction of the other. ADHF is a challenge in the management of heart failure. This review provides an overview the pathophysiology of type 1 CRS together with new approaches to treatment in patients with heart failure with worsening renal function or acute kidney disease.

Ronco|Claudio|C|
Bellasi|Antonio|A|
Di Lullo|Luca|L|

D058186:Acute Kidney Injury
D059347:Cardio-Renal Syndrome
D019468:Disease Management
D018450:Disease Progression
D006333:Heart Failure
D006801:Humans

Acute decompensated heart failure (ADHF)


Effectiveness of ESPITO analgesia in enhancing recovery in patients undergoing open radical cystectomy when compared to a contemporaneous cohort receiving standard analgesia: an observational study.

Abstract:
OBJECTIVES
Bowel dysfunction is a major complication following open surgery for invasive cancer of the bladder that results in significant discomfort; complications and can prolong the length of stay. The incidence of postoperative ileus following open radical cystectomy has been reported as 23-40%. The median length of hospital stay after this surgery in the United Kingdom is 11 days. Standard analgesic techniques include wound infusion analgesia combined with systemic morphine or thoracic epidural analgsia. Combined erector spinae plane and intrathecal opioid analgesia is a novel technique that has been reported to be an effective method of providing perioperative analgesia thereby enhancing recovery after open radical cystectomy.

METHODS
We performed a prospective study on the effectiveness of the novel analgesic technique (combined erector spinae plane and intrathecal opioid analgesia) in reducing the incidence of postoperative ileus, thereby facilitating early discharge following open radical cystectomy when compared to a contemporaneous control group receiving standard analgesia. Twenty-five patients received the novel analgesia while 31 patients received standard analgesia as a part of enhanced recovery programme. Standard analgesia arm included 14 patients who recived thoracic epidural analgesia (14/31, 45%) and 17 patients who received combined wound infusion analgesia and patient controlled analgesia with morphine (17/31, 55%). Primary outcome was the incidence of postoperative ileus. Secondary outcomes included length of hospital stay, tramadol consumption and time to bowel opening.

RESULTS
Combined erector spinae plane and intrathecal opioid analgesia was associated with a reduced incidence of postoperative ileus (16 [4/25] vs. 65% [20/31], p<0.001), reduced time to first open bowel (4.4 ± 2.3 vs. 6.6 ± 2.3, p<0.001) and reduced median (IQR) length of hospital stay (7[6, 12] vs. 10[8, 15], p=0.007). There was no significant difference in rescue analgesia (intravenous tramadol) consumption. Complete avoidance of systemic morphine played a key role in improved outcomes.

CONCLUSIONS
ESPITO was successful in reducing postoperative ileus and length of hospital stay after open radical cystectomy when compared to standard analgesia within an enhanced recovery programme.

Niraj|G|G|
Tariq|Zubair|Z|
Ratnayake|Ashani|A|
Jackson|Benjamin L|BL|
Ahson|Mehar|M|
Kamel|Yehia|Y|
Kaushik|Vipul|V|

D016058:Analgesia, Patient-Controlled
D000701:Analgesics, Opioid
D015653:Cystectomy
D006801:Humans
D059408:Pain Management
D011446:Prospective Studies

radical cystectomy
wound infusion analgesia
thoracic epidural analgesia
erector spinae plane analgesia


Reduce, Reuse, Recycle for Food Waste: A Second Life for Fresh-Cut Leafy Salad Crops in Animal Diets.

Abstract: The world's population is growing rapidly, which means that the environmental impact of food production needs to be reduced and that food should be considered as something precious and not wasted. Moreover, an urgent challenge facing the planet is the competition between the food produced for humans and the feed for animals. There are various solutions such as the use of plant/vegetable by-products (PBPs) and former foodstuffs, which are the co/by-products of processing industries, or the food losses generated by the food production chain for human consumption. This paper reviews the by-co-products derived from the transformation of fresh-cut leafy salad crops. A preliminary nutritional evaluation of these materials is thus proposed. Based on their composition and nutritional features, in some cases similar to fresh forage and grasses, this biomass seems to be a suitable feedstuff for selected farm animals, such as ruminants. In conclusion, although the present data are not exhaustive and further studies are needed to weigh up the possible advantages and disadvantages of these materials, fresh-cut leafy salad crops represent a potential unconventional feed ingredient that could help in exploiting the circular economy in livestock production, thereby improving sustainability.

food waste
fresh-cut leafy salad crops
former foodstuffs
ruminants
animal nutrition
vegetable by products


Asynchronous stochastic Boolean networks as gene network models.

Abstract: Logical models have widely been used to gain insights into the biological behavior of gene regulatory networks (GRNs). Most logical models assume a synchronous update of the genes' states in a GRN. However, this may not be appropriate, because each gene may require a different period of time for changing its state. In this article, asynchronous stochastic Boolean networks (ASBNs) are proposed for investigating various asynchronous state-updating strategies in a GRN. As in stochastic computation, ASBNs use randomly permutated stochastic sequences to encode probability. Investigated by several stochasticity models, a GRN is considered to be subject to noise and external perturbation. Hence, both stochasticity and asynchronicity are considered in the state evolution of a GRN. As a case study, ASBNs are utilized to investigate the dynamic behavior of a T helper network. It is shown that ASBNs are efficient in evaluating the steady-state distributions (SSDs) of the network with random gene perturbation. The SSDs found by using ASBNs show the robustness of the attractors of the T helper network, when various stochasticity and asynchronicity models are considered to investigate its dynamic behavior.

D003198:Computer Simulation
D053263:Gene Regulatory Networks
D008957:Models, Genetic
D011336:Probability
D013269:Stochastic Processes
D018417:Th1 Cells

stochastic Boolean networks
stochasticity
gene regulatory networks
asynchronous state update


Effects of Lifestyle Changes on the Mental Health of Healthcare Workers with Different Sense of Coherence Levels in the Era of COVID-19 Pandemic.

Abstract: Sense of coherence (SOC) is a psychological factor that contributes to mental health maintenance under stressful environment. Likewise, level of SOC might affect mental health among healthcare workers during the COVID-19 pandemic differently. In this study, we investigated the relationships between lifestyle changes and mental health (General Health Questionnaire-12: GHQ-12) among different level of SOC (weak, moderate, or strong by SOC-13). The data of 898 healthcare workers from cross-sectional survey dataset were extracted and analyzed. As results, based on GHQ-12 score, 86.1% of 244 participants with weak SOC, 60.1% of 606 participants with moderate SOC, and 31.3% of 48 participants with strong SOC had poor mental health. Both SOC levels and lifestyle changes (except alcohol consumption) had significant main effects on the GHQ-12 score. Analysis on the association between lifestyle changes and mental health status stratified by SOC level reveled that among participants with weak SOC, those who increased their leisure and activity time had reduced odds of poor mental health than those who made no changes (OR: 0.08, CI: 0.01 to 0.64). Healthcare workers with weak SOC were at risk of poor mental health during the COVID-19 pandemic, and lifestyle changes may improve their mental health.

lifestyle
mental health
healthcare worker
sense of coherence
COVID-19


Correlation of the plasma levels of soluble RAGE and endogenous secretory RAGE with oxidative stress in pre-diabetic patients.

Abstract:
BACKGROUND
Soluble RAGE (sRAGE), endogenous secretory RAGE (esRAGE) and oxidative stress played important roles in the pathogenesis of diabetes and its complications. The changes in sRAGE and esRAGE during pre-diabetes were indefinite.

METHODS
Patients were divided into NGT, pre-diabetes (pre-DM), and newly diagnosed diabetes mellitus (DM) groups according to blood glucose levels. The levels of sRAGE, esRAGE, 8-isoprostaglandin F2α (8-iso-PGF2α), superoxide dismutase (SOD) activity, total antioxidant capacity (TAOC), malondialdehyde (MDA), and other related indicators were then assessed.

RESULTS
sRAGE and esRAGE in the pre-DM and DM groups were significantly lower than in the NGT group (p<0.05). In the pre-DM group, sRAGE was positively correlated with esRAGE (r=0.382, P=0.007), and negatively correlated with homeostasis model assessment-estimated insulin resistance (HOMA-IR), MDA, and 8-iso-PGF2α (r=-0.314, -0.313, and -0.34, P=0.028, 0.028, and 0.016, respectively). The concentration of esRAGE was positively correlated with sRAGE and TAOC (r=0.382 and 0.598, and P=0.007, <0.001), and negatively correlated with MDA (r=-0.397, P=0.005).

CONCLUSIONS
Changes in sRAGE, esRAGE, and oxidative stress occurred in pre-diabetic patients. sRAGE and esRAGE might play an essential role in the balance between oxidative stress and antioxidant defense.

THE SIGNIFICANT FINDINGS OF THE STUDY
Changes in sRAGE, esRAGE, and oxidative stress occurred in pre-diabetic patients. THIS STUDY ADDS: sRAGE, esRAGE, and oxidative stress are altered early during pre-diabetes. sRAGE and esRAGE may have played different roles in the balance between oxidative stress and the antioxidant defense.

D000067759:Receptor for Advanced Glycation End Products

Oxidative stress
Pre-diabetes
sRAGE
esRAGE
Diabetes


Probabilistic generation of random networks taking into account information on motifs occurrence.

Abstract: Because of the huge number of graphs possible even with a small number of nodes, inference on network structure is known to be a challenging problem. Generating large random directed graphs with prescribed probabilities of occurrences of some meaningful patterns (motifs) is also difficult. We show how to generate such random graphs according to a formal probabilistic representation, using fast Markov chain Monte Carlo methods to sample them. As an illustration, we generate realistic graphs with several hundred nodes mimicking a gene transcription interaction network in Escherichia coli.

D004926:Escherichia coli
D053263:Gene Regulatory Networks
D008957:Models, Genetic
D014158:Transcription, Genetic

biological network
graphical model
network motif
prior information


The Sodium Channel β4 Auxiliary Subunit Selectively Controls Long-Term Depression in Core Nucleus Accumbens Medium Spiny Neurons.

Abstract: Voltage-gated sodium channels are essential for generating the initial rapid depolarization of neuronal membrane potential during action potentials (APs) that enable cell-to-cell communication, the propagation of signals throughout the brain, and the induction of synaptic plasticity. Although all brain neurons express one or several variants coding for the core pore-forming sodium channel α subunit, the expression of the β (β1-4) auxiliary subunits varies greatly. Of particular interest is the β4 subunit, encoded by the Scn4b gene, that is highly expressed in dorsal and ventral (i.e., nucleus accumbens - NAc) striata compared to other brain regions, and that endows sodium channels with unique gating properties. However, its role on neuronal activity, synaptic plasticity, and behaviors related to drugs of abuse remains poorly understood. Combining whole-cell patch-clamp recordings with two-photon calcium imaging in Scn4b knockout (KO) and knockdown mice, we found that Scn4b altered the properties of APs in core accumbens medium spiny neurons (MSNs). These alterations are associated with a reduction of the probability of MSNs to evoke spike-timing-dependent long-term depression (tLTD) and a reduced ability of backpropagating APs to evoke dendritic calcium transients. In contrast, long-term potentiation (tLTP) remained unaffected. Interestingly, we also showed that amphetamine-induced locomotor activity was significantly reduced in male Scn4b KO mice compared to wild-type controls. Taken together, these data indicate that the Scn4b subunit selectively controls tLTD by modulating dendritic calcium transients evoked by backpropagating APs.

Ji|Xincai|X|
Saha|Sucharita|S|
Gao|Guangping|G|
Lasek|Amy W|AW|
Homanics|Gregg E|GE|
Guildford|Melissa|M|
Tapper|Andrew R|AR|
Martin|Gilles E|GE|

sodium channel
long-term depression
nucleus accumbens
Scn4b
calcium imaging
dendrites
knockout mice
spike-timing-dependent plasticity


Maternal vitamin D deficiency causes smaller muscle fibers and altered transcript levels of genes involved in protein degradation, myogenesis, and cytoskeleton organization in the newborn rat.

Abstract:
SCOPE
Epidemiologic data reveal associations between low serum concentrations of 25-hydroxyvitamin D (25(OH)D) and higher risk of falls and muscle weakness. Fetal stage is critical for the development of skeletal muscle, but little information is available on the impact of maternal vitamin D deficiency on muscles of offspring.

METHODS AND RESULTS
To investigate the morphology and transcriptome of gastrocnemius muscle in newborns in response to maternal vitamin D deficiency, 14 female rats were fed either a vitamin D₃ deficient (0 IU/kg) or a vitamin D₃ adequate diet (1000 IU/kg) 8 weeks prior to conception, during pregnancy, and lactation. Analysis of cholecalciferol, 25(OH)D₃ and 1,25-dihydroxyvitamin D₃ show that dams fed the vitamin D deficient diet and their newborns suffered from a relevant vitamin D deficiency. Muscle cells of vitamin D deficient newborns were smaller than those of vitamin D adequate newborns (p < 0.05). Muscle transcriptome of the newborns revealed 426 probe sets as differentially expressed (259 upregulated, 167 downregulated) in response to vitamin D deficiency (fold change ≥1.5, p < 0.05). The effected genes are involved in protein catabolism, cell differentiation and proliferation, muscle cell development, and cytoskeleton organization.

CONCLUSION
Maternal vitamin D deficiency has a major impact on morphology and gene expression profile of skeletal muscle in newborns.

Max|Daniela|D|
Brandsch|Corinna|C|
Schumann|Sarah|S|
Kühne|Hagen|H|
Frommhagen|Matthias|M|
Schutkowski|Alexandra|A|
Hirche|Frank|F|
Staege|Martin S|MS|
Stangl|Gabriele I|GI|

D039382:Maternal Nutritional Physiological Phenomena

Maternal vitamin D deficiency
Rat
Skeletal muscle
Offspring
Transcript profiling