The concept of healthcare-associated infections (as opposed to hospital-acquired infections) in intraabdominal infections (IAIs) is scarcely supported by data in the literature. The aim of the present study was to analyse community-onset IAIs (non-postoperative/non-nosocomial) in patients admitted to intensive care units (ICUs), to investigate differences in resistance patterns linked to healthcare exposure and mortality-associated factors. A one-year prospective observational study (17 Spanish ICUs) was performed distributing cases as healthcare-associated infections (HCAI), community-acquired infections (CAI) and immunocompromised patients (ICP). Bacteria producing extended-spectrum β-lactamases (ESBL) and/or carbapenemase (CPE), high-level aminoglycoside- and/or methicillin- and/or vancomycin- resistance were considered antimicrobial resistant (AMR). Mortality-associated factors were identified by regression multivariate analysis. Of 345 patients included (18.8% HCAI, 6.1% ICP, 75.1% CAI), 51.6% presented generalized peritonitis; 32.5% were >75 years (55.4% among HCAI). Overall, 11.0% cases presented AMR (7.0% ESBL- and/or CPE), being significantly higher in HCAI (35.4%) vs. CAI (5.8%) (p<0.001) vs. ICP (0%) (p = 0.003). Overall 30-day mortality was 14.5%: 23.1% for HCAI and 11.6% for CAI (p = 0.016). Mortality (R2 = 0.262, p = 0.021) was positively associated with age >75 years (OR = 6.67, 95%CI = 2.56-17.36,p<0.001), Candida isolation (OR = 3.05, 95%CI = 1.18-7.87,p = 0.022), and SAPS II (per-point, OR = 1.08, 95%CI = 1.05-1.11, p<0.001) and negatively with biliary infections (OR = 0.06, 95%CI = 0.01-0.48,p = 0.008). In this study, the antimicrobial susceptibility pattern of bacteria isolated from patients with healthcare contact was shifted to resistance, suggesting the need for consideration of the healthcare category (not including hospital-acquired infections) for severe IAIs. 30-day mortality was positively related with age >75 years, severity and Candida isolation but not with AMR.

Although it is now recognized that women suffer from myofascial pain to a greater extent than men, and that the muscular fasciae can respond to hormonal stimuli, thanks to the expression of sex hormone receptors, how the fasciae can modify their structure under hormonal stimulation is not clear. In this work, an immunocytochemical analysis of collagen-I, collagen-III and fibrillin were carried out on fibroblasts isolated from human fascia lata after in vitro treatment with various levels of sex hormones β-estradiol and/or relaxin-1, according to the phases of a woman's period (follicular, periovulatory, luteal, post-menopausal phases and pregnancy). This study demonstrates for the first time that fascial cells can modulate the production of some components of the extracellular matrix according to hormone levels, when treated with β-estradiol: collagen-I falls from 6% of positivity in the follicular phase to 1.9 in the periovulatory phase. However, after the addition of relaxin-1 to the cell culture, the production of extracellular matrix decreased and remained at the same level (1.7% of collagen-I, at both follicular and periovulatory levels of hormones). These results confirm the antifibrotic function of relaxin-1, thanks to its ability to reduce matrix synthesis. They are also a first step in our understanding of how some hormonal dysfunctions in women can cause a dysregulation of extracellular matrix production in fasciae.

Crimean-Congo hemorrhagic fever (CCHF) is the most medically important tick-borne viral disease of humans and tuberculosis is the leading cause of death worldwide by a bacterial pathogen. These two diseases overlap geographically, however, concurrent infection of CCHF virus (CCHFV) with mycobacterial infection has not been assessed nor has the ability of virus to persist and cause long-term sequela in a primate model. In this study, we compared the disease progression of two diverse strains of CCHFV in the recently described cynomolgus macaque model. All animals demonstrated signs of clinical illness, viremia, significant changes in clinical chemistry and hematology values, and serum cytokine profiles consistent with CCHF in humans. The European and Asian CCHFV strains caused very similar disease profiles in monkeys, which demonstrates that medical countermeasures can be evaluated in this animal model against multiple CCHFV strains. We identified evidence of CCHFV persistence in the testes of three male monkeys that survived infection. Furthermore, the histopathology unexpectedly revealed that six additional animals had evidence of a latent mycobacterial infection with granulomatous lesions. Interestingly, CCHFV persisted within the granulomas of two animals. This study is the first to demonstrate the persistence of CCHFV in the testes and within the granulomas of non-human primates with concurrent latent tuberculosis. Our results have important public health implications in overlapping endemic regions for these emerging pathogens.

Most known thioredoxin-type proteins (Trx) participate in redox pathways, using two highly conserved cysteine residues to catalyze thiol-disulfide exchange reactions. Here we demonstrate that the so far unexplored Trx2 from African trypanosomes (Trypanosoma brucei) lacks protein disulfide reductase activity but functions as an effective temperature-activated and redox-regulated chaperone. Immunofluorescence microscopy and fractionated cell lysis revealed that Trx2 is located in the mitochondrion of the parasite. RNA-interference and gene knock-out approaches showed that depletion of Trx2 impairs growth of both mammalian bloodstream and insect stage procyclic parasites. Procyclic cells lacking Trx2 stop proliferation under standard culture conditions at 27°C and are unable to survive prolonged exposure to 37°C, indicating that Trx2 plays a vital role that becomes augmented under heat stress. Moreover, we found that Trx2 contributes to the in vivo infectivity of T. brucei. Remarkably, a Trx2 version, in which all five cysteines were replaced by serine residues, complements for the wildtype protein in conditional knock-out cells and confers parasite infectivity in the mouse model. Characterization of the recombinant protein revealed that Trx2 can coordinate an iron sulfur cluster and is highly sensitive towards spontaneous oxidation. Moreover, we discovered that both wildtype and mutant Trx2 protect other proteins against thermal aggregation and preserve their ability to refold upon return to non-stress conditions. Activation of the chaperone function of Trx2 appears to be triggered by temperature-mediated structural changes and inhibited by oxidative disulfide bond formation. Our studies indicate that Trx2 acts as a novel chaperone in the unique single mitochondrion of T. brucei and reveal a new perspective regarding the physiological function of thioredoxin-type proteins in trypanosomes.

The distribution of type I and II chalcone isomerases (CHIs) in plants is highly family specific. We have previously reported that ancient land plants, such as the liverworts and Selaginella moellendorffii, harbor type II CHIs. To better understand the function and evolution of CHI-fold proteins, transcriptomic data obtained from 52 pteridophyte species were subjected to sequence alignment and phylogenetic analysis. The residues determining type I/II CHI identity in the pteridophyte CHIs were identical to those of type I CHIs. The enzymatic characterization of a sample of 24 CHIs, representing all the key pteridophyte lineages, demonstrated that 19 of them were type I enzymes and that five exhibited some type II activity due to an amino acid mutation. Two pteridophyte chalcone synthases (CHSs) were also characterized, and a type IV CHI (CHIL) was demonstrated to interact physically with CHSs and CHI, and to increase CHS activity by decreasing derailment products, thus enhancing flavonoid production. These findings suggest that the emergence of type I CHIs may have coincided with the divergence of the pteridophytes. This study deepens our understanding of the molecular mechanism of CHIL as an enhancer in the flavonoid biosynthesis pathway.

Plants regulate responses towards herbivory through fine-tuning of defence-related hormone production, expression of defence genes, and production of secondary metabolites. Jasmonic acid (JA) plays a key role in plant-herbivorous arthropod interactions. To understand how pepper (Capsicum annuum) responds to herbivory, leaf transcriptomes and metabolomes of two genotypes different in their susceptibility to spider mites were studied. Mites induced both JA and salicylic acid (SA) signalling. However, mite infestation and exogenous JA resulted in distinct transcriptome profiles. Compared with JA, mites induced fewer differentially expressed genes involved in metabolic processes (except for genes involved in the phenylpropanoid pathway) and lipid metabolic processes. Furthermore, pathogen-related defence responses including WRKY transcription factors were more strongly induced upon mite infestation, probably as a result of induced SA signalling. Untargeted analysis of secondary metabolites confirmed that JA treatment induced larger changes in metabolism than spider mite infestation, resulting in higher terpenoid and flavonoid production. The more resistant genotype exhibited a larger increase in endogenous JA and volatile and non-volatile secondary metabolites upon infestation, which could explain its stronger defence. Reasoning that in JA-SA antagonizing crosstalk, SA defences are prioritized over JA defences, we hypothesize that lack of SA-mediated repression of JA-induced defences could result in gain of resistance towards spider mites in pepper.

Air pollution has been a serious public health issue over the past few decades particularly in developing countries. Air pollution exposure during pregnancy poses potential threat to offspring as the deleterious substances might pass through placenta to alter foetal development. A growing number of studies have demonstrated that long non-coding RNAs (lncRNAs) participate in the development of many diseases, including congenital defects. Here, we used RNA sequencing to identify differentially expressed lncRNAs in air pollution-exposed rat embryos compared with control group. Our data suggested that 554 lncRNAs (216 up-regulated and 338 down-regulated) were significantly differentially expressed in the air pollution-exposed embryos. Moreover, potential cellular functions of these deregulated lncRNAs were predicted via KEGG signal pathway/GO enrichment analyses, which suggested the possible involvements of neurological process, sensory perception of smell and the G-protein signalling pathway. Furthermore, potential functional network of deregulated lncRNAs and their correlated mRNAs in the development of congenital spinal abnormality was established. Our data suggested that lncRNAs may play a vital role in the pathophysiology of air pollution-exposed congenital spinal malformation.

Gene silencing exists in eukaryotic organisms as a conserved regulation of the gene expression mechanism. In general, small RNAs (sRNAs) are produced within the eukaryotic cells and incorporated into an RNA-induced silencing complex (RISC) within cells. However, exogenous sRNAs, once delivered into cells, can also silence target genes via the same RISC. Here, we explored this concept by targeting the Cellulose synthase A3 (CesA3) gene of Hyaloperonospora arabidopsidis (Hpa), the downy mildew pathogen of Arabidopsis thaliana. Hpa spore suspensions were mixed with sense or antisense sRNAs and inoculated onto susceptible Arabidopsis seedlings. While sense sRNAs had no obvious effect on Hpa pathogenicity, antisense sRNAs inhibited spore germination and hence infection. Such inhibition of infection was not race-specific, but dependent on the length and capping of sRNAs. Inhibition of infection by double stranded sRNA was more efficient than that observed with antisense sRNA. Thus, exogenous sRNA targeting conserved CesA3 could suppress Hpa infection in Arabidopsis, indicating the potential of this simple and efficient sRNA-based approach for deciphering gene functions in obligate biotrophic pathogens as well as for R-gene independent control of diseases in plants.

Diabetic neuropathy (DN) is one of the most common complications of diabetes that occurs in more than 67% of individuals with diabetes. Genetic polymorphisms may play an important role in DN development. However, until now, the association between genetic polymorphisms and DN risk has remained unknown. We performed a systematic review, meta-analysis, and trial sequential analysis (TSA) of the association between all genetic polymorphisms and DN risk.

Peripheral blood mononuclear cells (PBMCs) play important roles in the pathogenesis of IgA nephropathy (IgAN). Our study aimed to provide a deep understanding of IgAN and focused on the dysregulation of hsa-miR-590-3p and its target gene HMGB2 in PBMCs. Three gene expression profile datasets (GSE14795, GSE73953 and GSE25590) were downloaded from the GEO database. The DEGs (differentially expressed genes)-miRNA network that was associated with IgAN was constructed by Cytoscape, and HMGB2 and hsa-miR-590-3p were selected for further exploration. The dual-luciferase reporter system was utilized to verify their interaction. Then, the expression levels of HMGB2 and hsa-miR-590-3p in PBMCs were detected by qPCR in another cohort, and the correlation of their expression levels with the clinical pathological manifestations and serum Gd-IgA1(galactose-deficient IgA1) levels was also investigated. HMGB2 was identified as the target gene of hsa-miR-590-3p. Furtherly, the elderly patients had higher HMGB2 expression levels than the expression levels of the younger patients. As the serum creatinine, serum BUN levels increased, the expression of HMGB2 decreased; Besides, the HMGB2 expression was positively correlated with serum complement 3(C3) levels, and it also had a negative correlation with the diastolic blood pressure, but not reach statistical significance. What is more, both hsa-miR-590-3p and HMGB2 expression had a slight correlation tendency with serum Gd-IgA1 levels in the whole population. In conclusion, HMGB2, the target gene of hsa-miR-590-3p, was identified to correlate with the severity of IgAN, and this provides more clues for the pathogenesis of IgAN.

New or enlarging T2-hyperintense white matter lesions (WML) are associated with clinical disease progression in multiple sclerosis (MS). The prognostic value of WML shrinking is unclear. Assuming that waning of acute inflammation and repair processes would be the main drivers of WML shrinking, we aimed to assess the prognostic value of WML shrinking in early MS.

Biotin-thiamine-responsive basal ganglia disease (BTBGD) is an autosomal recessive neurometabolic disorder mostly presented in children. The disorder is described as having subacute encephalopathy with confusion, dystonia, and dysarthria triggered by febrile illness that leads to neuroregression and death if untreated. Using biotin and thiamine at an early stage of the disease can lead to significant improvement.

Light intensity plays an important role in the regulation of growth, behavior, reproduction, and welfare of avian species. Light intensity preference behavior has been suggested to be involved in welfare of birds. This study aims to investigate the effects of different light intensity and dual light intensity choice (DLIC) lighting program on plasma corticosterone (CORT), and tryptophan hydroxylase 2 (TPH2, the rate-limiting enzyme of serotonin biosynthesis) and tyrosine hydroxylase (TH, the rate-limiting enzyme of dopamine biosynthesis) gene expression in the brainstem of male chickens. Day old broilers were housed in two commercial houses, and placed in 24 pens. All the treatment groups were provided with 23 h light (L) /1 h dark (D) and 30 lx (lx) light intensity during the first week and then 18L:6D (10 lx) from day 7 to 14. Blood and brain were sampled at 14 days of age (10 lx) before the onset of light treatments. On day 15, four treatments (2, 10, 20, and 100 lx), and DLIC treatment (2/20 lx) were initiated. Samples were collected on days 15, 16, 17, 30 and 41. TPH2 expression in the dorsal raphe nucleus (DRN) and caudal raphe nucleus (CRN) of brainstem, and TPH2 and TH expression in ventral tegmental areas (VTN) of the midbrain were determined by qPCR. Results showed that bright light and DLIC lighting program temporarily attenuated plasma CORT, suggesting the short-term stress attenuating effect of bright light and DLIC lighting program. Differential TPH2 expression in the DRN and CRN observed in the DLIC birds indicate a significant effect of DLIC lighting program on the serotonergic activity in the avian brainstem. At the 41 days of age, the significant downregulation of TPH2 and TH expression occurred in the VTA of DLIC treated birds compared to the other group of birds. Taken together, temporal and spatial regulation of TPH2 and TH expression by DLIC lighting program indicate that compensatory regulation of serotonergic and dopaminergic activities might be involved in the light intensity preference behavior of birds, suggesting a possible beneficial effect of the DLIC lighting program on broiler welfare.

The impact of aging on cerebrovascular function and tissue oxygenation during graded hypoxemia is incompletely known. This study compared the age effect on these variables during cyclic hypoxemia-reoxygenation.

The development of awake intraoperative brain-mapping procedures for resection of brain tumors is of growing interest in neuroscience, because it enables direct testing of brain tissue, previously only possible in non-human primates. In a recent study performed in this setting specific effects can be induced by direct electrical stimulation on different sectors of premotor cortex during the execution of a hand manipulation task. Specifically, direct electrical stimulation applied on a dorsal sector of precentral cortex led to an increase in motor unit recruitment in hand muscles during execution of a hand manipulation task (Recruitment sector). The opposite effect was elicited when electrical stimulation was delivered more ventrally on the precentral cortex (Suppression sector). We studied whether the different effects on motor behavior induced by direct electrical stimulation applied on the two sites of the precentral cortex underlie differences in their functional connectivity with other brain areas, measured using resting state fMRI. Using healthy adults scanned as part of the Human Connectome Project, we computed the functional connectivity of each sector used as seeds. The functional connectivity patterns of the two intraoperative seeds was similar but cross-comparison revealed that the left and right Recruitment sectors had stronger functional connections with the hand region of the sensorimotor cortex, while the right Suppression region displayed stronger functional connectivity with a bilateral set of parieto-frontal areas crucial for the integration of perceptual and cognitive hand-related sensorimotor processes required for goal-related hand actions. Our results suggest that analyzing data obtained in the intraoperative setting with resting state functional magnetic resonance imaging in healthy brains can yield useful insight into the roles of different premotor sectors directly involved in hand-object interaction.

Lactate is now recognized as an important intermediate in brain metabolism, but its role is still under investigation. In this work we mapped the distribution of lactate and bicarbonate produced from intravenously injected 13C-pyruvate over the whole brain using a new imaging method, hyperpolarized 13C MRI (N = 14, ages 23 to 77). Segmenting the 13C-lactate images into brain atlas regions revealed a pattern of lactate that was preserved across individuals. Higher lactate signal was observed in cortical grey matter compared to white matter and was highest in the precuneus, cuneus and lingual gyrus. Bicarbonate signal, indicating flux of [1-13C]pyruvate into the TCA cycle, also displayed consistent spatial distribution. One-way ANOVA to test for significant differences in lactate among atlas regions gave F = 87.6 and p < 10-6. This report of a "lactate topography" in the human brain and its consistent pattern is evidence of region-specific lactate biology that is preserved across individuals.

Chemodynamic therapy (CDT) has recently emerged as a promising treatment for cancer due to the high specificity of CDT towards tumor microenvironment (TME). However, the low efficiency of reactive oxygen species (ROS) generation and the robust ROS defensive mechanisms in cancer cells remain critical hurdles for current CDT. Addressing both challenges in a single platform, we developed a novel redox and light-responsive (RLR) nanoparticle with a core-shell structure. Remarkably, our hierarchical RLR nanoparticle is composed of an ultrasmall Fe3O4 nanoparticle engineered framework of hollow carbon matrix core and a nanoflower-like MnO2 shell. Under the abundant overexpressed glutathione (GSH) and acidic nature in TME, the RLR nanoparticle was programmed to degrade and self-activate CDT-induced cancer-killing by accelerating ROS generation via overcoming the ROS defensive mechanisms based on the depletion of intracellular GSH, the sequential production of theranostic ion species (e.g., Mn2+ and Fe2+), a spatiotemporal controllable photothermal hyperthermia and a redox triggered chemotherapeutic drug release. Additionally, the carbon framework of RLR nanoparticle could collapse by leaching of iron ions. An excellent selective and near-complete tumor suppression based on the RLR nanoparticles through a strong synergy between CDT, PTT and anti-cancer drugs was demonstrated via in vitro and in vivo anti-tumoral assays.

Accumulating evidence has uncovered long non-coding RNAs (lncRNAs) as central regulators in the pathogenesis of diverse human cancers including colorectal cancer (CRC). The present study discovered that a novel lncRNA ITIH4 antisense RNA 1 (ITHI4-AS1) was frequently under-expressed in most normal human tissues, including colon tissues. Therefore, we aimed to investigate the role of ITHI4-AS1 in CRC. Interestingly, a significant overexpression of ITIH4-AS1 was observed in CRC cell lines relative to normal NCM460 cells. Also, we investigated the facilitating role of ITIH4-AS1 in CRC cell growth and metastasis both in vitro and in vivo. Additionally, we explained that ITIH4-AS1 upregulation in CRC was attributed to downregulation or even depletion of RE1 silencing transcription factor (REST), a presently identified transcriptional repressor for ITIH4-AS1. Meanwhile, the contribution of ITIH4-AS1 to CRC development was validated to rely on the activation of the JAK/STAT3 pathway. More importantly, we verified that FUS interacted with both ITIH4-AS1 and STAT3, and that ITIH4-AS1 evoked nuclear translocation of phosphorylated (p)-STAT3 in CRC through recruiting FUS. In summary, our findings unveiled for the first time that REST downregulation-enhanced ITIH4-AS1 exerts pro-tumor functions in CRC through FUS-dependent activation of the JAK/STAT3 pathway, implying that targeting ITIH4-AS1 may be a novel effective strategy for CRC therapy.

The responsible use of water, as well as its reuse and purification, has been a major problem for decades now. In this work, we study a method for adsorbing ions from aqueous solutions on charged interfaces using highly porous electrodes. This water purification process is based on the electric double layer concept, using the method known as capacitive deionization (CDI): If we pump salty solutions through the volume comprised between two porous electrodes while applying a potential difference to them, ions present in the solution are partially removed and trapped on the electrode surfaces. It has been well established that the use of carbon electrodes in combination with ion exchange membranes (membrane-CDI) improves the efficiency of the method above that achieved with bare activated carbon. Another approach that has been tested is based on coating the carbon with polyelectrolyte layers, converting them into "soft electrodes" (SEs). Here we investigate the improvement found when combining SEs with membranes, and it is shown that the amount of ions adsorbed and the ratio between ions removed and electrons transported reach superior values, also associated with a faster kinetics of the process. The method is applied to the partial desalination of up to 100 mM NaCl solutions, something hardly achievable with bare or membrane-covered electrodes. A theoretical model is presented for the ion transport in the presence of both the membrane and the polyelectrolyte coating.

Zearalenone (ZEN) is a mycotoxin that not only binds to estrogen receptors, but also interacts with steroidogenic enzymes and acts as an endocrine disruptor. The aim of this study was to verify the hypothesis that low doses, minimal anticipated biological effect level (MABEL), no-observed-adverse-effect level (NOAEL) and lowest-adverse-effect level (LOAEL), of ZEN administered orally for 42 days can induce changes in the peripheral blood concentrations of selected steroid hormones (estradiol, progesterone and testosterone) in pre-pubertal gilts. The experiment was performed on 60 clinically healthy gilts with average BW of 14.5 ± 2 kg, divided into three experimental groups and a control group. Group ZEN5 animals were orally administered ZEN at 5 μg ZEN/kg BW, group ZEN10 - at 10 μg ZEN/kg BW, group ZEN15 - at 15 μg ZEN/kg BW, whereas group C received a placebo. Five gilts from every group were euthanized on analytical dates 1, 2 and 3 (days 7, 14 and 42 of the experiment). Qualitative and quantitative changes in the biotransformation of low ZEN doses were observed. These processes were least pronounced in group ZEN5 (MABEL dose) where ZEN metabolites were not detected on the first analytical date, and where β-ZEL was the predominant metabolite on successive dates. The above was accompanied by an increase in the concentration of estradiol (E2) which, together with "free ZEN", probably suppressed progesterone (P4) and testosterone (T) levels.