Skeletal muscle function is compromised in many illnesses, including chronic infections. The Pseudomonas aeruginosa quorum sensing (QS) signal, 2-amino acetophenone (2-AA), is produced during acute and chronic infections and excreted in human tissues, including the lungs of cystic fibrosis patients. We have shown that 2-AA facilitates pathogen persistence, likely via its ability to promote the formation of bacterial persister cells, and that it acts as an interkingdom immunomodulatory signal that epigenetically reprograms innate immune functions. Moreover, 2-AA compromises muscle contractility and impacts the expression of genes involved in reactive oxygen species (ROS) homeostasis in skeletal muscle and in mitochondrial functions. Here, we elucidate the molecular mechanisms of 2-AA's impairment of skeletal muscle function and ROS homeostasis. Murine in vivo and differentiated C2C12 myotube cell studies showed that 2-AA promotes ROS generation in skeletal muscle via the modulation of xanthine oxidase (XO) activity, NAD(P)H oxidase2 (NOX2) protein level, and the activity of antioxidant enzymes. ROS accumulation triggers the activity of AMP-activated protein kinase (AMPK), likely upstream of the observed locations of induction of ubiquitin ligases Muscle RING Finger 1 (MuRF1) and Muscle Atrophy F-box (MAFbx), and induces autophagy-related proteins. The protein-level perturbation in skeletal muscle of silent mating type information regulation 2 homolog 1 (SIRT1), peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1), and uncoupling protein 3 (UCP3) is rescued by the antioxidant N-acetyl-l-cysteine (NAC). Together, these results unveil a novel form of action of a QS bacterial molecule and provide molecular insights into the 2-AA-mediated skeletal muscle dysfunction caused by P. aeruginosaIMPORTANCEPseudomonas aeruginosa, a bacterium that is resistant to treatment, causes serious acute, persistent, and relapsing infections in humans. There is increasing evidence that bacterial excreted small molecules play a critical role during infection. We have shown that a quorum sensing (QS)-regulated excreted small molecule, 2-AA, which is abundantly produced by P. aeruginosa, promotes persistent infections, dampens host inflammation, and triggers mitochondrial dysfunction in skeletal muscle. QS is a cell-to-cell communication system utilized by bacteria to promote collective behaviors. The significance of our study in identifying a mechanism that leads to skeletal muscle dysfunction, via the action of a QS molecule, is that it may open new avenues in the control of muscle loss as a result of infection and sepsis. Given that QS is a common characteristic of prokaryotes, it is possible that 2-AA-like molecules promoting similar effects may exist in other pathogens.

Larimichthys crocea is an endemic marine fish in East Asia that belongs to Sciaenidae in Perciformes. L. crocea has now been recognized as an "iconic" marine fish species in China because not only is it a popular food fish in China, it is a representative victim of overfishing and still provides high value fish products supported by the modern large-scale mariculture industry. Here, we report a chromosome-level reference genome of L. crocea generated by employing the PacBio single molecule sequencing technique (SMRT) and high-throughput chromosome conformation capture (Hi-C) technologies. The genome sequences were assembled into 1,591 contigs with a total length of 723.86 Mb and a contig N50 length of 2.83 Mb. After chromosome-level scaffolding, 24 scaffolds were constructed with a total length of 668.67 Mb (92.48% of the total length). Genome annotation identified 23,657 protein-coding genes and 7262 ncRNAs. This highly accurate, chromosome-level reference genome of L. crocea provides an essential genome resource to support the development of genome-scale selective breeding and restocking strategies of L. crocea.

The use of anion redox reactions is gaining interest for increasing rechargeable capacities in alkaline ion batteries. Although anion redox coupling of S2- and (S2)2- through dimerization of S-S in sulfides have been studied and reported, an anion redox process through electron hole formation has not been investigated to the best of our knowledge. Here, we report an O3-NaCr2/3Ti1/3S2 cathode that delivers a high reversible capacity of ~186 mAh g-1 (0.95 Na) based on the cation and anion redox process. Various charge compensation mechanisms of the sulfur anionic redox process in layered NaCr2/3Ti1/3S2, which occur through the formation of disulfide-like species, the precipitation of elemental sulfur, S-S dimerization, and especially through the formation of electron holes, are investigated. Direct structural evidence for formation of electron holes and (S2)n- species with shortened S-S distances is obtained. These results provide valuable information for the development of materials based on the anionic redox reaction.

Technical guidelines for magnetic resonance imaging (MRI) of the small bowel (SB) in the setting of inflammatory bowel diseases (IBDs) were detailed in a 2017 consensus issued by European Society of Gastrointestinal and Abdominal Radiology (ESGAR) and European Society of Pediatric Radiology (ESPR); however, MRI for non-IBD conditions was not addressed. Hence, we performed a systematic review collecting researches on SB MRI for non-IBDs. The literatures were then divided into morphologic group and functional group. Information about the MRI techniques, gastrointestinal preparation, and details of cine-MRI protocols was extracted. We found that a 1.5 T MRI system, prone positioning, and MR enterography were frequently utilized in clinical practice. Gadolinium contrast sequences were routinely implemented, while diffusion-weighted imaging (DWI) was much less performed. The gastrointestinal preparation varied throughout the studies. No uniform protocols for cine imaging could be established. SB MRI examinations for non-IBDs are far from standardized, especially for functional studies. Recommendations for standard parameters in cine-MRI sequences are difficult to make due to lack of evidentiary support. MRI investigations in non-IBD conditions are needed and the standardization of non-IBD imaging in clinical practice is required.

Quantitatively assessing the impacts of drought on grassland has significant implications to understand the degradation mechanism and prevention degraded grassland. In this study, we analyzed the relationship between grassland drought and grassland Net Primary Productivity (NPP) based on the self-calibrated Palmer Drought Severity Index (scPDSI) from 1982 to 2008. The results showed that the global grassland scPDSI value had a slightly increasing trend with the rate of 0.0119 per year (R2 = 0.195), indicating that the global grassland drought lighter to some extent during study period. Moreover, the correlation coefficient between annual grassland NPP and scPDSI was from -0.83 to 0.92. The grassland NPP decreased under mild drought from 1992 to 1996. Additionally, the correlation coefficient between scPDSI and NPP for each grassland type was: Closed Shrublands > Non-woody grassland > Savannas > Open Shrublands > Woody Savannas, indicating that drought had difference influences on the different grassland types. Our results might provide the underlying insights needed to be guide for the effects of extreme weather events on grassland NPP.

The biochemical demands associated with tumor proliferation prompt neoplastic cells to augment the import of nutrients to sustain their survival and fuel cell growth, with a consequent metabolic remodeling. Fatty acids (FA) are crucial in this process, since they have a dual role as energetic coins and building blocks. Recently, our team has shown that FATP1 has a pivotal role in FA transfer between breast cancer cells (BCCs) and non-cancerous cells in the microenvironment. We aimed to investigate the role of FATP1 in BCCs and also to explore if FATP1 inhibition is a promising therapeutic strategy. In patients' data, we showed a higher expression of FATP1/SLC27A1 in TNBC, which correlated with a significant decreased overall survival (OS). In vitro, we verified that FA and estradiol stimulated FATP1/SLC27A1 expression in BCCs. Additionally, experiments with estradiol and PHTPP (ER-β antagonist) showed that estrogen receptor-β (ER-β) regulates FATP1/SLC27A1 expression, the uptake of FA and cell viability, in four BCC lines. Furthermore, the inhibition of FATP1 with arylpiperazine 5k (DS22420314) interfered with the uptake of FA and cell viability. Our study, unraveled FATP1 as a putative therapeutic target in breast cancer (BC).

When preparing a saccade, attentional resources are focused at the saccade target and its immediate vicinity. Here we show that this does not hold true when saccades are prepared toward a recently extinguished target. We obtained detailed maps of orientation sensitivity when participants prepared a saccade toward a target that either remained on the screen or disappeared before the eyes moved. We found that attention was mainly focused on the immediate surround of the visible target and spread to more peripheral locations as a function of the distance from the cue and the delay between the target's disappearance and the saccade. Interestingly, this spread was not accompanied with a spread of the saccade endpoint. These results suggest that presaccadic attention and saccade programming are two distinct processes that can be dissociated as a function of their interaction with the spatial configuration of the visual scene.

In chemotaxis, cells are modulating their migration patterns in response to concentration gradients of a guiding substance. Immune cells are believed to use such chemotactic sensing for remotely detecting and homing in on pathogens. Considering that immune cells may encounter a multitude of targets with vastly different migration properties, ranging from immobile to highly mobile, it is not clear which strategies of chemotactic pursuit are simultaneously efficient and versatile. We tackle this problem theoretically and define a tunable response function that maps temporal or spatial concentration gradients to migration behavior. The seven free parameters of this response function are optimized numerically with the objective of maximizing search efficiency against a wide spectrum of target cell properties. Finally, we reverse-engineer the best-performing parameter sets to uncover strategies of chemotactic pursuit that are efficient under different biologically realistic boundary conditions. Although strategies based on the temporal or spatial sensing of chemotactic gradients are significantly more efficient than unguided migration, such 'blind search' turns out to work surprisingly well, in particular if the immune cells are fast and directionally persistent. The resulting simulated data can be used for the design of chemotaxis experiments and for the development of algorithms that automatically detect and quantify goal oriented behavior in measured immune cell trajectories.

Embryonic stem cell (ESC) derived tissue is a promising tool to be used in different clinical, preclinical and also scientific settings, for example as in vivo biological pacemaker, preclinical drug safety screening tool or ultimately as part of a cell replacement therapy. However, before ESC derived tissue can be used routinely for these purposes in humans, further studies are needed. In this context, the aims of the present study were to examine the effect of antiarrhythmic drugs on human ESC (hESC) und human induced pluripotent stem cell (hiPSC) derived cardiomyocytes by analyzing the beat rate variability (BRV), which can be considered as the in vitro equivalent of the heart rate variability (HRV) in vivo. Short-term recordings of extracellular field potentials of spontaneously beating cardiomyocytes derived from hESCs and hiPSCs were made using Microelectrode Arrays (MEA). The effect of Flecainide, Ivabradine and Metoprolol was tested. The offline analysis of the BRV was mainly focused on time domain methods. Additionally a non-linear analysis method was used. The evaluation of the Poincaré-Plots of the measurements without pharmacological intervention revealed that the vast majority of the scatter plots have a similar, ellipsoid shape. Flecainide and Ivabradine influenced BRV parameters significantly, whereas Metoprolol did not alter the BRV markedly. We detected remarkable similarities between the BRV of hESC and hiPSC derived cardiomyocytes in vitro and the HRV in vivo. The effect of antiarrhythmic drugs on spontaneously beating cardiomyocytes derived from hESC and hiPSC was generally consistent with clinical experiences and also with our previous study based on murine ESC derived cardiomyocytes. In conclusion, our study points out the great potential of hESC and hiPSC derived tissue to be used routinely for many different applications in medicine and science.

This population-based cross-sectional study investigated the association between menstrual cycle irregularity and tinnitus in premenopausal Korean women. We used data from the 5th Korea National Health and Nutrition Examination Survey (2010-2012). A total of 4633 premenopausal women were included. Hierarchical multivariable logistic regression analysis was performed. Individuals with tinnitus accounted for 21.6%. Women with tinnitus or menstrual irregularity had significantly higher rates of stress, depressive mood, and suicidal ideation than those without. The proportion of individuals with irregular menstrual cycles with duration of longer than 3 months increased as the severity of tinnitus increased (P = 0.01). After adjusting for confounding variables, the odds of tinnitus increased in individuals with irregular menstrual cycles compared to those with regular menstrual cycles. The odds ratios (ORs) of tinnitus tended to increase as the duration of menstrual irregularity became longer (1.37, 95% confidence interval: 1.06-1.78 for duration of up to 3 months; 1.71, 1.03-2.85 for duration of longer than 3 months, P for trend = 0.002). Our study found a positive association between menstrual cycle irregularity and tinnitus. Menstrual cycle irregularity may be a related factor of tinnitus in women with childbearing age.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons resulting in severe neurological symptoms. Previous findings of our lab suggested that the axonal guidance tyrosine-kinase receptor EphA4 is an ALS disease-modifying gene. Reduction of EphA4 from developmental stages onwards rescued a motor neuron phenotype in zebrafish, and heterozygous deletion before birth in the SOD1G93A mouse model of ALS resulted in improved survival. Here, we aimed to gain more insights in the cell-specific role of decreasing EphA4 expression in addition to timing and amount of EphA4 reduction. To evaluate the therapeutic potential of lowering EphA4 later in life, we ubiquitously reduced EphA4 levels to 50% in SOD1G93A mice at 60 days of age, which did not modify disease parameters. Even further lowering EphA4 levels ubiquitously or in neurons, did not improve disease onset or survival. These findings suggest that lowering EphA4 as target in ALS may suffer from a complex therapeutic time window. In addition, the complexity of the Eph-ephrin signalling system may also possibly limit the therapeutic potential of such an approach in ALS. We suggest here that a specific EphA4 knockdown in adulthood may have a limited therapeutic potential for ALS.

The age-associated imbalances between proliferation and apoptosis lead to impaired spermatogenesis and infertility. The age-associated decline in vitamin D3 levels has been reported and suggested the anti-aging potential of vitamin D3. However, the age-associated decline levels of vitamin D3 has not been studied in relation to the testicular activity. Thus, we investigated the effect of vitamin D3 on the expression of testicular proliferation markers, apoptotic markers, antioxidants system and oxidative stress in a D-gal-induced aged rat model. The present study investigated the levels of vitamin D3 and AGE in serum and testes along with the expression of the AGE-receptor (AGER) in the testis. Vitamin D3 treatment significantly increases cell proliferation and decreases apoptosis in a D-gal-induced aged rat testis. Furthermore, vitamin D3 significantly decreases oxidative stress in aged rat testis by improving the antioxidant defense systems. The expression of AGER was down-regulated by vitamin D3 treatment in aged testis. The circulating and intra-testicular AGE was higher in aged groups, however, only circulating vitamin D3 levels decreased in aged groups. The immunolocalization of VDR showed increased immunostaining in the testis by vitamin D3 treatment. Thus, it can be concluded that vitamin D3 delays testicular senescence by regulating proliferation and apoptosis.

We characterized the vaginal ecosystem during common infections of the female genital tract, as vulvovaginal candidiasis (VVC, n = 18) and Chlamydia trachomatis infection (CT, n = 20), recruiting healthy (HC, n = 21) and bacterial vaginosis-affected (BV, n = 20) women as references of eubiosis and dysbiosis. The profiles of the vaginal microbiome and metabolome were studied in 79 reproductive-aged women, by means of next generation sequencing and proton based-nuclear magnetic resonance spectroscopy. Lactobacillus genus was profoundly depleted in all the genital infections herein considered, and species-level analysis revealed that healthy vaginal microbiome was dominated by L. crispatus. In the shift from HC to CT, VVC, and BV, L. crispatus was progressively replaced by L. iners. CT infection and VVC, as well as BV condition, were mainly characterised by anaerobe genera, e.g. Gardnerella, Prevotella, Megasphaera, Roseburia and Atopobium. The changes in the bacterial communities occurring during the genital infections resulted in significant alterations in the vaginal metabolites composition, being the decrease of lactate a common marker of all the pathological conditions. In conclusion, according to the taxonomic and metabolomics analysis, we found that each of the four conditions is characterized by a peculiar vaginal microbiome/metabolome fingerprint.

Terpene trilactones (TTLs) are the main secondary metabolites of Ginkgo biloba. As one of the rate-limiting enzymes in the mevalonic acid (MVA) pathway of TTL biosynthesis, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) catalyzes the 3-hydroxy-3-methylglutaryl coenzyme A to form MVA. In this study, two cDNA sequences of HMGR genes, namely, GbHMGR2 and GbHMGR3, were cloned from G. biloba. The protein sequences of GbHMGR2 and GbHMGR3, which contain several functional domains, were analyzed. Regulatory elements related to light, hormone, and stress response were detected in the promoter regions of GbHMGR2 and GbHMGR3. The catalytic activity of these genes was verified by a functional complement experiment in yeast. Quantitative real-time PCR (qRT-PCR) showed the distinct expression patterns of the two genes in different organs. The TTL contents in the organs were detected by high-performance liquid chromatography- evaporative light scattering detector. GbHMGR2 and GbHMGR3 were responded to cold, dark, methyl jasmonate (MJ), abscisic acid (ABA), salicylic acid (SA), and ethephon (Eth) treatments. The TTL contents were also regulated by cold, dark, MJ, ABA, SA, and Eth treatment. In conclusion, GbHMGR2 and GbHMGR3 may participate in the MVA pathway of TTL biosynthesis.

The Bph1 gene was the first reported brown planthopper (BPH, Nilaparvata lugens) resistance gene in Mudgo rice and was widely used as a commercial cultivar for controlling BPH infestations. However, rapid adaptations of BPH on the Mudgo rice resulted in its resistance breakdown and the emergence of virulent BPH populations. Thus, specific BPH populations and rice varieties can serve as good model systems for studying the roles of different bio-compounds and proteins in the insect-plant interactions. Although our understandings have been improved on the complexity of BPH and rice interactions, the underlying molecular mechanisms remain largely unknown. Here we analyzed the feeding performances and the transcriptomic responses of two BPH populations (Mugdo-BPH and TN1-BPH) during compatible (Mudog-BPH feeding on Mudgo rice) and incompatible (TN1-BPH feeding on Mudgo rice) interactions. The electrical penetration graph (EPG) results indicated that the BPH feeding and performances during the incompatible interaction are significantly affected in terms of decreased honeydew, loss of weight, decreased phloem sap ingestion (N4 waveform), but increased non-penetration (NP waveform) phase. Abundance of glucose and trehalose was reduced in BPH during the incompatible interaction. Transcriptomic surveys of insects in both interactions revealed that genes involved in cuticle formation, detoxification, metabolite transport, digestion, RNA processing, lipid or fatty acid metabolism, and proteolysis were significantly down-regulated during the incompatible interaction, whereas genes involved in insulin signaling were significantly upregulated. Knockdown of four genes, including the sugar transporter NlST45, the serine and arginine-rich protein NlSRp54, the cytochrome P450 gene NlCYP6AY1, and the cuticle protein NlCPR70 through RNA-interference revealed thess genes are important for BPH survival. Overall, the results of this study will be helpful for the future researches on BPH virulence shifts.

Epidemiological studies have shown an increased risk of cardiovascular events in migraineurs. The pathophysiological mechanisms of this observation remain largely unknown. Recent genetic and epidemiologic studies suggest, that atherosclerosis might be the overlapping pathophysiological mechanism in migraine and coronary heart disease. The aim of the present study was to evaluate if the increased cardiovascular risk in migraineurs is attributed to an increased coronary artery calcification. For this the coronary artery calcium score was assessed by computed tomography of the heart in 1.437 patients of which 337 were migraineurs. All patients had a similar cardiovascular risk profile, so that the risk for coronary calcifications could be considered similar between migraineurs and non-migraineurs. The results showed no significant differences in the amount of coronary calcifications in patients with or without migraine. This suggests that a more pronounced coronary artery calcification, as a surrogate marker of coronary atherosclerosis, does not underlie the increased cardiovascular risk in migraineurs. A distinct common pathophysiological mechanism in migraine and coronary heart disease such as endothelial dysfunction or vasospasm should be discussed instead. However, it has to be considered, that the coronary artery calcification score does not indicate the total risk of atherosclerotic changes in the coronary arteries.

Late embryogenesis abundant (LEA) proteins are widely known to be present in higher plants and are believed to play important functional roles in embryonic development and abiotic stress responses. However, there is a current lack of systematic analyses on the LEA protein gene family in tea plant. In this study, a total of 48 LEA genes were identified using Hidden Markov Model profiles in C. sinensis, and were classified into seven distinct groups based on their conserved domains and phylogenetic relationships. Genes in the CsLEA_2 group were found to be the most abundant. Gene expression analyses revealed that all the identified CsLEA genes were expressed in at least one tissue, and most had higher expression levels in the root or seed relative to other tested tissues. Nearly all the CsLEA genes were found to be involved in seed development, and thirty-nine might play an important role in tea seed maturation concurrent with dehydration. However, only sixteen CsLEA genes were involved in seed desiccation, and furthermore, most were suppressed. Additionally, forty-six CsLEA genes could be induced by at least one of the tested stress treatments, and they were especially sensitive to high temperature stress. Furthermore, it was found that eleven CsLEA genes were involved in tea plant in response to all tested abiotic stresses. Overall, this study provides new insights into the formation of CsLEA gene family members and improves our understanding on the potential roles of these genes in normal development processes and abiotic stress responses in tea plant, particularly during seed development and desiccation. These results are beneficial for future functional studies of CsLEA genes that will help preserve the recalcitrant tea seeds for a long time and genetically improve tea plant.

V565 is an engineered TNFα-neutralising single domain antibody formulated into enteric coated mini-tablets to enable release in the intestine after oral administration as a possible oral treatment for inflammatory bowel disease (IBD). Following oral administration, ileal recovery of V565 was investigated in four patients with terminal ileostomy. Intestinal and systemic pharmacokinetics were measured in six patients with Crohn's disease and evidence of target engagement assessed in five patients with ulcerative colitis. Following oral administration, V565 was detected at micromolar concentrations in ileal fluid from the ileostomy patients and in stools of the Crohn's patients. In four of the five ulcerative colitis patients, biopsies taken after 7d dosing demonstrated V565 in the lamina propria with co-immunostaining on CD3+ T-lymphocytes and CD14+ macrophages. Phosphorylation of signalling proteins in biopsies taken after 7d oral dosing was decreased by approximately 50%. In conclusion, enteric coating of V565 mini-tablets provided protection in the stomach with gradual release in intestinal regions affected by IBD. Immunostaining revealed V565 tissue penetration and association with inflammatory cells, while decreased phosphoproteins after 7d oral dosing was consistent with V565-TNFα engagement and neutralising activity. Overall these results are encouraging for the clinical utility of V565 in the treatment of IBD.

X-ray reflectometry (XRR), a surface-sensitive technique widely used for characterizing surfaces, buried interfaces, thin films, and multilayers, enables determination of the electron density distribution perpendicular to a well-defined surface specularly reflecting X-rays. However, the electron density distribution parallel to the surface cannot be determined from an X-ray reflectivity curve. The electron density correlation in the lateral direction is usually probed by measuring the grazing-incidence small-angle X-ray scattering (GISAXS). GISAXS measurement, however, typically requires using a collimated X-ray point beam to distinguish the GISAXS from the specularly reflected X-rays, and so the sample must be scanned in the lateral direction with the point beam to investigate variations in the surface and interface morphology for a region larger than the size of the beam. In this paper, we report a new approach based on X-ray grating interferometry: an X-ray sheet beam is used instead of an X-ray point beam. A method using this approach can simultaneously provide one-dimensional real-space images of X-ray reflectivity, surface curvature, and 'dark-field' contrast with a field-of-view of more than a few millimetres. As a demonstration, a sample having a 400 nm line and space SiO2 pattern with a depth of 10 nm on its surface was used, and the dark-field contrast due to the unresolved line and space structure, creating GISAXS in the lateral direction, was successfully observed. Quantitative analysis of these contrasts provided the real-space distribution of the structural parameters for a simple model of the grating structure. Our study paves the way to a new approach to structure analysis, providing a quantitative way to investigate real-space variations in surface and interface morphology through wavefront analysis.

Global crop production is facing the challenge of a high projected demand, while the yields of major crops are not increasing at sufficient speeds. Crop breeding is an important way to boost crop productivity, however its improvement rate is partially hindered by the long crop generation cycles. If end-season crop traits such as yield can be predicted through early-season phenotypic measurements, crop selection can potentially be made before a full crop generation cycle finishes. This study explored the possibility of predicting soybean end-season traits through the color and texture features of early-season canopy images. Six thousand three hundred and eighty-three images were captured at V4/V5 growth stage over 6039 soybean plots growing at four locations. One hundred and forty color features and 315 gray-level co-occurrence matrix-based texture features were derived from each image. Another two variables were also introduced to account for location and timing differences between the images. Five regression and five classification techniques were explored. Best results were obtained using all 457 predictor variables, with Cubist as the regression technique and Random Forests as the classification technique. Yield (RMSE = 9.82, R2 = 0.68), Maturity (RMSE = 3.70, R2 = 0.76) and Seed Size (RMSE = 1.63, R2 = 0.53) were identified as potential soybean traits that might be early predictable.