Perinatal hypoxic-ischemic encephalopathy (HIE) can lead to neurodevelopmental disorders, including cerebral palsy. Standard care for neonatal HIE includes therapeutic hypothermia, which provides partial neuroprotection; magnetic resonance imaging (MRI) is often used to assess injury and predict outcome after HIE. Immature rodent models of HIE are used to evaluate mechanisms of injury and to examine the efficacy and mechanisms of neuroprotective interventions such as hypothermia. In this study, we first confirmed that, in the CD1 mouse model of perinatal HIE used for our research, MRI obtained 3 h after hypoxic ischemia (HI) could reliably assess initial brain injury and predict histopathological outcome. Mice were subjected to HI (unilateral carotid ligation followed by exposure to hypoxia) on postnatal day 7 and were imaged with T2-weighted MRI and diffusion-weighted MRI (DWI), 3 h after HI. Clearly defined regions of increased signal were comparable in T2 MRI and DWI, and we found a strong correlation between T2 MRI injury scores 3 h after HI and histopathological brain injury 7 days after HI, validating this method for evaluating initial injury in this model of HIE. The more efficient, higher resolution T2 MRI was used to score initial brain injury in subsequent studies. In mice treated with hypothermia, we found a significant reduction in T2 MRI injury scores 3 h after HI, compared to normothermic littermates. Early hypothermic neuroprotection was maintained 7 days after HI, in both T2 MRI injury scores and histopathology. In the normothermic group, T2 MRI injury scores 3 h after HI were comparable to those obtained 7 days after HI. However, in the hypothermic group, brain injury was significantly less 7 days after HI than at 3 h. Thus, early neuroprotective effects of hypothermia were enhanced by 7 days, which may reflect the additional 3 h of hypothermia after imaging or effects on later mechanisms of injury, such as delayed cell death and inflammation. Our results demonstrate that hypothermia has early neuroprotective effects in this model. These findings suggest that hypothermia has an impact on early mechanisms of excitotoxic injury and support initiation of hypothermic intervention as soon as possible after diagnosis of HIE.

A systematic search revealed 68 empirical studies of neurophysiological [EEG, event-related brain potential (ERP), fMRI, PET] variables as potential outcome predictors in patients with Disorders of Consciousness (diagnoses Unresponsive Wakefulness Syndrome [UWS] and Minimally Conscious State [MCS]). Data of 47 publications could be presented in a quantitative manner and systematically reviewed. Insufficient power and the lack of an appropriate description of patient selection each characterized about a half of all publications. In more than 80% studies, neurologists who evaluated the patients' outcomes were familiar with the results of neurophysiological tests conducted before, and may, therefore, have been influenced by this knowledge. In most subsamples of datasets, effect size significantly correlated with its standard error, indicating publication bias toward positive results. Neurophysiological data predicted the transition from UWS to MCS substantially better than they predicted the recovery of consciousness (i.e., the transition from UWS or MCS to exit-MCS). A meta-analysis was carried out for predictor groups including at least three independent studies with N > 10 per predictor per improvement criterion (i.e., transition to MCS versus recovery). Oscillatory EEG responses were the only predictor group whose effect attained significance for both improvement criteria. Other perspective variables, whose true prognostic value should be explored in future studies, are sleep spindles in the EEG and the somatosensory cortical response N20. Contrary to what could be expected on the basis of neuroscience theory, the poorest prognostic effects were shown for fMRI responses to stimulation and for the ERP component P300. The meta-analytic results should be regarded as preliminary given the presence of numerous biases in the data.

Previous evidence suggests that hallucinations and delusions may be detected in patients with the most severe forms of motor disability including locked-in syndrome (LIS). However, such phenomena are rarely described in LIS and their presence may be underestimated as a result of the severe communication impairment experienced by the patients. In this study, we retrospectively reviewed the clinical history and the neuroimaging data of a cohort of patients with LIS in order to recognize the presence of hallucinations and delusions and to correlate it with the pontine damage and the presence of any cortical volumetric changes. Ten patients with LIS were included (5 men and 5 women, mean age 50.1 ± 14.6). According to the presence of indicators of symptoms, these patients were categorized as hallucinators (n = 5) or non-hallucinators (n = 5). MRI images of patients were analyzed using Freesurfer 6.0 software to evaluate volume differences between the two groups. Hallucinators showed a selective cortical volume loss involving the fusiform (p = 0.001) and the parahippocampal (p = 0.0008) gyrus and the orbital part of the inferior frontal gyrus (p = 0.001) in the right hemisphere together with the lingual (p = 0.01) and the fusiform gyrus (p = 0.01) in the left hemisphere. Moreover, a volumetric decrease of bilateral anterior portions of the precuneus was recognized in the hallucinators (right p = 0.01; left p = 0.001) as compared to non-hallucinators. We suggested that the presence of hallucinations and delusions in some LIS patients could be accounted for by the combination of a damage of the corticopontocerebellar pathways with cortical changes following the primary brainstem injury. The above areas are embedded within cortico-cortical and cortico-subcortical loops involved in self-monitoring and have been related to the presence of hallucinations in other diseases. The two main limitations of our study are the small sample of included patients and the lack of a control group of healthy individuals. Further studies would be of help to expand this field of research in order to integrate existing theories about the mechanisms underlying the generation of hallucinations and delusions in neurological patients.

Oxidative stress plays a pivotal role in the initiation and progression of cardiac diseases. Estrogens have been demonstrated to exert pleiotropic cardioprotective effects, among which antioxidative stress is one of the key effects linking estrogens to cardioprotection. By using a microRNAs (miRs) microarray screening approach, we discovered an increase in miR-494, which is known to exert cardioprotective effects, in estrogen-treated cardiomyocytes. We hypothesized that the upregulation of miR-494 might contribute to estrogen-mediated cardioprotection against oxidative stress. We found that E2 stimulates miR-494 expression via ERα in both cardiomyocytes and the myocardium of female mice. The miR-494 inhibitor attenuated the protective effect of 17β-estradiol (E2) against oxidative stress-induced injury in cardiomyocytes. By contrast, the miR-494 mimic protected cardiomyocytes against oxidative stress-induced cardiomyocyte injury. Using real-time PCR, western blot and dual-luciferase reporter gene analyses, we identified nuclear factor kappa B (NF-κB) repressing factor (NKRF) as the miR-494 target in cardiomyocytes. E2 was found to inhibit NKRF, thus activating NF-κB through a miR-494-dependent mechanism. In addition, the protective effects of E2 and miR-494 against oxidative stress in cardiomyocytes were eliminated by the NF-κB inhibitor. In summary, this study demonstrates for the first time that estrogen inhibits NKRF expression through ERα-mediated upregulation of miR-494 in cardiomyocytes, leading to the activation of NF-κB, which in turn results in an increase in antioxidative defense. ERα-mediated upregulation of miR-494 may contribute to estrogen protection of cardiomyocytes against oxidative stress.

Pseudomonas aeruginosa is a severe opportunistic pathogen and is one of the major causes of hard to treat burn wound infections. Herein we have used an RNA-seq transcriptomic approach to study the behavior of P. aeruginosa PAO1 growing directly on human burn wound exudate. A chemical analysis of compounds used by this bacterium, coupled with kinetics expression of central genes has allowed us to obtain a global view of P. aeruginosa physiological and metabolic changes occurring while growing on human burn wound exudate. In addition to the numerous virulence factors and their secretion systems, we have found that all iron acquisition mechanisms were overexpressed. Deletion and complementation with pyoverdine demonstrated that iron availability was a major limiting factor in burn wound exudate. The quorum sensing systems, known to be important for the virulence of P. aeruginosa, although moderately induced, were activated even at low cell density. Analysis of bacterial metabolism emphasized importance of lactate, lipid and collagen degradation pathways. Overall, this work allowed to designate, for the first time, a global view of P. aeruginosa characteristics while growing in human burn wound exudate and highlight the possible therapeutic approaches to combat P. aeruginosa burn wound infections.

Merkel cell carcinoma (MCC), a rare skin cancer, is associated with high mortality, especially in a metastatic setting. Though conventional chemotherapy with platinum and etoposide has had high response rates, many of the patients have had early relapse without any effective therapy thereafter. Recently, immune check point inhibitors have shown very good durable responses, leading to the approval of a programmed death-ligand 1 inhibitor Avelumab for these patients. We briefly review the epidemiology and immune basis of the pathogenesis of MCC, which therefore explains the excellent response to check point inhibitors, and throw light on future directions of immunotherapy for this cancer.

For exploring maternal death, supply and demand-side factors can be characterized by the three delays model developed by Thaddeus and Maine (1994). The model comprises delay in deciding to seek care (delay 1), delay in reaching the health facility (delay 2), and delay in receiving quality care once at the health facility (delay 3). Few studies have comprehensively dealt with the health systems delays that prevent the receipt of timely and appropriate obstetric care once a woman reaches a health facility (phase III delays). The objective of the present study was to identify facility-level barriers in West African health facilities.

The enzyme telomerase reverse transcriptase (TERT) is essential for telomere maintenance. In replicating cells, maintenance of telomere length is important for the preservation of vital genetic information and prevention of genomic instability. A common genetic variant in TERT, rs2736100 C/A, is associated with both telomere length and multiple diseases. Carriage of the C allele is associated with longer telomere length, while carriage of the A allele is associated with shorter telomere length. Furthermore, some diseases have a positive association with the C and some with the A allele. In this study, meta-analyses were performed for two groups of diseases, cancerous diseases, e.g., lung cancer and non-cancerous diseases, e.g., pulmonary fibrosis, using data from genome-wide association studies and case-control studies. In the meta-analysis it was found that cancer positively associated with the C allele (pooled OR 1.16 [95% CI 1.09-1.23]) and non-cancerous diseases negatively associated with the C allele (pooled OR 0.81 [95% CI 0.65-0.99]). This observation illustrates that the ambiguous role of telomere maintenance in disease hinges, at least in part, on a single locus in telomerase genes. The dual role of this single nucleotide polymorphism also emphasizes that therapeutic agents aimed at influencing telomere maintenance should be used with caution.

Primary care providers are critical in providing and optimizing health care to an aging population. This paper describes the volunteer component of a program (Health TAPESTRY) which aims to encourage the delivery of effective primary health care in novel and proactive ways. As part of the program, volunteers visited older adults in their homes and entered information regarding health risks, needs, and goals into an electronic application on a tablet computer. A total of 657 home visits were conducted by 98 volunteers, with 22.45% of volunteers completing at least 20 home visits over the course of the program. Information was summarized in a report and electronically sent to the health care team via clients' electronic medical records. The report was reviewed by the interprofessional team who then plan ongoing care. Volunteer recruitment, screening, training, retention, and roles are described. This paper highlights the potential role of a volunteer in a unique connection between primary care providers and older adult patients in their homes.

Transplantation of myogenic cells has potential applications in the treatment of muscle pathologies. Excluding purely autologous cell transplantation, graft viability depends on an adequate control of acute rejection (AR). To contribute in understanding AR in this context, we analyzed whether de novo circulating antibodies against donor's cells are detected during induced AR of graft-derived myofibers in nonhuman primates.

We report the first characterization study of commercial prototype carbon nanotube (CNT) membranes consisting of sub-1.27-nm-diameter CNTs traversing a large-area nonporous polysulfone film. The membranes show rejection of NaCl and MgSO4 at higher ionic strengths than have previously been reported in CNT membranes, and specific size selectivity for analytes with diameters below 1.24 nm. The CNTs used in the membranes were arc discharge nanotubes with inner diameters of 0.67 to 1.27 nm. Water flow through the membranes was 1000 times higher than predicted by Hagen-Poiseuille flow, in agreement with previous CNT membrane studies. Ideal gas selectivity was found to deviate significantly from that predicted by both viscous and Knudsen flow, suggesting that surface diffusion effects may begin to dominate gas selectivity at this size scale.

Monitoring subcellular functional and structural changes associated with metabolism is essential for understanding healthy tissue development and the progression of numerous diseases, including cancer, diabetes, and cardiovascular and neurodegenerative disorders. Unfortunately, established methods for this purpose either are destructive or require the use of exogenous agents. Recent work has highlighted the potential of endogenous two-photon excited fluorescence (TPEF) as a method to monitor subtle metabolic changes; however, mechanistic understanding of the connections between the detected optical signal and the underlying metabolic pathways has been lacking. We present a quantitative approach to detecting both functional and structural metabolic biomarkers noninvasively, relying on endogenous TPEF from two coenzymes, NADH (reduced form of nicotinamide adenine dinucleotide) and FAD (flavin adenine dinucleotide). We perform multiparametric analysis of three optical biomarkers within intact, living cells and three-dimensional tissues: cellular redox state, NADH fluorescence lifetime, and mitochondrial clustering. We monitor the biomarkers in cells and tissues subjected to metabolic perturbations that trigger changes in distinct metabolic processes, including glycolysis and glutaminolysis, extrinsic and intrinsic mitochondrial uncoupling, and fatty acid oxidation and synthesis. We demonstrate that these optical biomarkers provide complementary insights into the underlying biological mechanisms. Thus, when used in combination, these biomarkers can serve as a valuable tool for sensitive, label-free identification of changes in specific metabolic pathways and characterization of the heterogeneity of the elicited responses with single-cell resolution.

Stretchable, bendable, and foldable conductive coatings are crucial for wearable electronics and biometric sensors. These coatings should maintain functionality while simultaneously interfacing with different types of surfaces undergoing mechanical deformation. MXene sheets as conductive two-dimensional nanomaterials are promising for this purpose, but it is still extremely difficult to form surface-agnostic MXene coatings that can withstand extreme mechanical deformation. We report on conductive and conformal MXene multilayer coatings that can undergo large-scale mechanical deformation while maintaining a conductivity as high as 2000 S/m. MXene multilayers are successfully deposited onto flexible polymer sheets, stretchable poly(dimethylsiloxane), nylon fiber, glass, and silicon. The coating shows a recoverable resistance response to bending (up to 2.5-mm bending radius) and stretching (up to 40% tensile strain), which was leveraged for detecting human motion and topographical scanning. We anticipate that this discovery will allow for the implementation of MXene-based coatings onto mechanically deformable objects.

Gas-forming pyogenic liver abscess (GFPLA) has an incidence of up to 30% of all pyogenic liver abscesses (PLA). GFPLA has higher mortality compared to non-GFPLA. Mere presence of gas within abscess may not determine clinical outcome. Hence it is important to study biologic characteristics that make GFPLA a distinct clinical entity. The aim of this study was to conduct a world review on GFPLA.

111In-DOTA-butylamino-NorBIRT (DANBIRT) is a novel radioligand which binds to Leukocyte Function-associated Antigen-1 (LFA-1), expressed on inflammatory cells. This study evaluated 111In-DANBIRT for the visualization of atherosclerotic plaque inflammation in mice.

Vanillin is valuable and popular flavor used in foods and cosmetics. Many bacteria species have the ability to decarboxylate substituted cinnamic acids in order to form vanillin. However, the phenolic biotransformation including vanillin production in a common fungus, the Aspergillus luchuensis, which is used in distilled beverages, has not yet been clarified. This study focused on elucidating the vanillin production due to phenolic biotransformation in A. luchuensis during fermentation. The phenolic metabolites were extracted by a solid phase column and they were determined using on LC/MS and LC/MS/MS in a selective ion mode. As a result, ferulic acid, vanillin and vanillic acid, were detected in the rice koji fermentationed by A. luchuensis and also fermentated with yeast. In addition, the accurate molecular formula of vanillin glucoside (C14H17O8, 313.0927, (M-H)- and its production ions was also determined by HRESI-mass spectrometry. Based on the results including the phenolic metabolites and related genes found in A. luchuensis genome, this study proposed the vanillin production mechanism due to the side chain cleavage of ferulic acid through Coenzyme A (CoA) and feruloyl-CoA hydratase/lyase, to form vanillin and acetyl-COA. In this study, another possible vanillin production pathway also was proposed due to the neutral hexose hydrolysis of vanillin glucoside. The subsequent dehydrogenation of vanillin produced vanillic acid. In addition, vanillin was detected in the distilled alcohol indicating its contribution to the aroma profile of beverages. It has been unknown that the vanillin in the distilled solution is derived from the vanillin produced during rice-koji and/or moromi mash fermentations.

Fingolimod (FTY720) is used as an immunosuppressant for multiple sclerosis. Numerous studies indicated its neuroprotective effects in stroke. However, the mechanism remains to be elucidated. This study was intended to investigate the mechanisms of phosphorylated FTY720 (pFTY720), which was the principle active molecule in regulating astrocyte-mediated inflammatory responses induced by oxygen-glucose deprivation (OGD). Results demonstrated that pFTY720 could protect astrocytes against OGD-induced injury and inflammatory responses. It significantly decreased pro-inflammatory cytokines, including high mobility group box 1 (HMGB1) and tumour necrosis factor-α (TNF-α). Further, studies displayed that pFTY720 could prevent up-regulation of Toll-like receptor 2 (TLR2), phosphorylation of phosphoinositide 3-kinase (PI3K) and nuclear translocation of nuclear factor kappa B (NFκB) p65 subunit caused by OGD. Sphingosine-1-phosphate receptor 3 (S1PR3) knockdown could reverse the above change. Moreover, administration of TLR2/4 blocker abolished the protective effects of pFTY720. Taken together, this study reveals that pFTY720 depends on S1PR3 to protect astrocytes against OGD-induced neuroinflammation, due to inhibiting TLR2/4-PI3K-NFκB signalling pathway.

Several metabolic adaptations emerge during pregnancy and continue through lactation, including increases in food intake and body weight, as well as insulin and leptin resistance. These maternal adaptations are thought to play a role in offspring viability and success. Using a model of attenuated maternal metabolic adaptations induced by ablation of the Socs3 gene in leptin receptor expressing cells (SOCS3 KO mice), our study aimed to investigate whether maternal metabolic changes are required for normal offspring development, and if their absence causes metabolic imbalances in adulthood. The litters were subjected to a cross-fostering experimental design to distinguish the prenatal and postnatal effects caused by maternal metabolic adaptations. Males either born or raised by SOCS3 KO mice showed reduced body weight until 8 weeks of life. Both adult males and females born or raised by SOCS3 KO mice also had lower body adiposity. Despite that, no significant changes in energy expenditure, glucose tolerance or insulin resistance were observed. However, males either born or raised by SOCS3 KO mice showed reduced brain mass in adulthood. Furthermore, animals born from SOCS3 KO mice also had lower proopiomelanocortin fiber density in the paraventricular nucleus of the hypothalamus. In conclusion, these findings indicate that the commonly observed metabolic changes in pregnancy and lactation are necessary for normal offspring growth and brain development.

Being the primary sulfonamide among the most efficient zinc binding group (ZBG) to design inhibitors for the metallo-enzymes carbonic anhydrases (CA, EC 4.2.1.1), herein, we propose an investigation on four physiologically important human (h) CAs (hCA I, II, IV, and IX) with N1-substituted secondary sulfonamides incorporating thiazolinone or imidazolone-indole tails. The effect of the functionalisation of the sulfonamide group with five different substitution patterns, namely acetyl, pyridine, thiazole, pyrimidine, and carbamimidoyl, was evaluated in relation to the inhibition profile of the corresponding primary sulfonamide analogues. With most of these latter being nanomolar inhibitors of all four considered isoforms, a totally counterproductive effect on the inhibition potency can be ascribed to N1-functionalisations of the ZBG primary sulfonamide structure with pyridine, thiazole, and pyrimidine moieties. On the other hand, incorporation of less hindered groups, such as sulfonylacetamides and sulfonylguanidines, maintained a certain degree of activity dependent on the tailing moiety, with KIs spanning in the low micromolar range.

System toxicology aims at understanding the mechanisms used by biological systems to respond to toxicants. Such understanding can be leveraged to assess the risk of chemicals, drugs, and consumer products in living organisms. In system toxicology, machine learning techniques and methodologies are applied to develop prediction models for classification of toxicant exposure of biological systems. Gene expression data (RNA/DNA microarray) are often used to develop such prediction models.