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In this paper, we study an interaction problem between a 3 D compressible viscous fluid and a 3 D nonlinear viscoelastic solid fully immersed in the fluid, coupled together on the interface surface. The solid is allowed to have self-contact or contact with the rigid boundary of the fluid container. For this problem, a global weak solution with defect measure is constructed by using a multi-layered approximation scheme which decouples the body and the fluid by penalizing the fluid velocity and allowing the fluid to pass through the body, while the body is supplemented with a contact-penalization term. The resulting defect measure is a consequence of pressure concentrations that can appear where the fluid meets the (generally irregular) points of self-contact of the solid. Moreover, we study some geometrical properties of the fluid-structure interface and the contact surface. In particular, we prove a lower bound on area of the interface. [ABSTRACT FROM AUTHOR]

[Display omitted] The aim of the study was to evaluate the effect of thiolation of lipid-based nanoparticles (LNPs) on cellular uptake of nucleic acids. A thiolated surfactant was synthesized by binding palmitic acid covalently to cysteine. Green fluorescent protein (GFP) encoding plasmid DNA (pDNA) was used as model nucleic acid and incorporated via hydrophobic ion-pairing with a cationic cholesterol derivate (DcCholesterol) in LNPs that were prepared by solvent injection method using the thiolated surfactant for surface decoration. LNPs were characterized regarding size, polydispersity index, zeta potential and stability in biorelevant media. The endosomal escape properties of LNPs were evaluated by erythrocytes interaction studies. Cell viability and transfection efficiency on HEK293 cells were investigated. The structure of the thiolated surfactant was confirmed by 1H NMR and FT-IR. LNPs containing the nucleic acid-DcCholesterol complex with and without the thiolated surfactant were developed and displayed sizes in the range from 173 nm to 233 nm with a narrow size distribution (PDI < 0.3) and a negative zeta potential. LNPs showed no significant increase in size after 4 h of incubation in artificial body fluids. Erythrocytes interaction studies revealed enhanced endosomal escape properties for thiolated LNPs compared to non-thiolated LNPs. LNPs showed in concentrations lower than 0.74 mg/mL cell viability ≥ 80 %. Transfection studies on HEK cells with thiolated LNPs compared to non-thiolated LNP showed a 4.6-fold higher expression of GFP. Surface thiolation of LNPs represents a promising tool for enhancing intracellular nucleic acid delivery of LNPs. [ABSTRACT FROM AUTHOR]

In this work, we study the motion of a rigid body in a bounded domain which is filled with a compressible isentropic fluid. We consider the Navier-slip boundary condition at the interface as well as at the boundary of the domain. This is the first mathematical analysis of a compressible fluid-rigid body system where Navier-slip boundary conditions are considered. We prove existence of a weak solution of the fluid-structure system up to collision. [ABSTRACT FROM AUTHOR]

[Display omitted] • Au@hg-C 3 N 4 hybrids were fabricated as a dual-mode matrix of SERS and SALDI-MS. • The holey structure enhances matrix enrichment and prevents Au NPs agglomeration. • Au@hg-C 3 N 4 matrix exhibits high sensitivity and superior reproducibility for l -cys. • The matrix reliably detects l -cys and distinguishes its enantiomers in human serum. Development of reliable sensing strategy combining surface-enhanced Raman scattering (SERS) and surface-assisted laser desorption/ionization-mass spectrometry (SALDI-MS) is of significant interest to distinguish cysteine enantiomers in body fluid for understanding their physiological roles and toxicity hazards. In this work, a SERS/SALDI-MS dual-mode sensing platform of gold nanoparticles (Au NPs) decorated holey carbon nitride (hg-C 3 N 4) was fabricated for sensitive detecting cysteine. The designed Au@hg-C 3 N 4 matrix featured a uniform distribution of Au NPs with the help of anchoring effect of hg-C 3 N 4 holey structure, which was conducive to produce highly repeatable signals. Moreover, the combination of Au NPs and holey g-C 3 N 4 endowed this matrix with superior enrichment capacity, enhanced charge transfer and strong UV absorption. These merits allowed the matrix to acquire high sensitivity and enhanced reproducibility for l -cysteine by means of SERS/SALDI-MS. Likewise, reliable detection of l -cysteine and efficient recognition of d -cysteine in human serum jointly revealed its prospect for detecting cysteine enantiomers in body fluids. This work offers a reliable SERS/SALDI-MS strategy for determining L/D-cysteine enantiomers, and the designed Au@hg-C 3 N 4 matrix becomes a potential application candidate for selective detection of bio-enantiomers. [ABSTRACT FROM AUTHOR]

Significant levels of glyphosate, the world's most widely used herbicide, and its primary metabolites, AMPA and MPA, are detected in various human organs and body fluids, including blood. Several studies have associated the presence of glyphosate in humans with health problems, and effects on immune cells and their functions have been reported. However, the impact of this molecule and its metabolites on neutrophils, the most abundant leukocytes in the human bloodstream, is still poorly documented. We isolated neutrophils from human donor blood and investigated the effects of exposure to glyphosate, AMPA, and MPA on viability, energy metabolism, and essential antimicrobial functions in vitro. We observed that neutrophil viability was unaffected at the blood-relevant average concentrations of the general population and exposed workers, as well as at higher intoxication concentrations. Neutrophil energy metabolism was also not altered following exposure to the chemicals. However, while phagocytosis was unaffected, reactive oxygen species generation and CXCL8/IL-8 production were altered by exposure to the molecules. Alterations in function following exposure to glyphosate and metabolites differed according to the sex of the donors, which could be linked to glyphosate's known role as an endocrine disruptor. While ROS generation was increased in both sexes, male neutrophils exposed to glyphosate had increased intracellular production of CXCL8/IL-8, with no effect on female neutrophils. Conversely, exposure to the metabolites AMPA and MPA decreased extracellular production of this chemokine only in female neutrophils, with MPA also increasing intracellular production in male cells exposed to the chemoattractant N-formyl-methionine-leucyl-phenylalanine. Our study highlights the effects of glyphosate and its metabolites on the antimicrobial functions of neutrophils, which could be associated with health problems as future studies provide a better understanding of the risks associated with glyphosate use. Advances in knowledge will enable better and potentially stricter regulations to protect the public. [Display omitted] • Glyphosate does not affect neutrophil viability, metabolism, or phagocytosis. • Glyphosate increases neutrophil ROS production. • Glyphosate and its metabolites affect CXCL8/IL-8 production in a sex-specific manner. • The metabolites AMPA and MPA also have effects on neutrophil functions. Summary sentence: Glyphosate and its metabolites AMPA and MPA alter the functions of human blood neutrophils differently according to sex. [ABSTRACT FROM AUTHOR]

RNA analysis has shown great value in forensic science, such as body fluids and tissue identification, postmortem interval estimation, biological age prediction, etc. Currently, most RNA follow-up experiments involve reverse transcription (RT) procedures. It has been shown that the RT step is variable and has a greater impact on subsequent data analysis, especially for forensic trace samples. However, the pattern of variation between different RNA template inputs and complementary DNA (cDNA) yield is unclear. In this study, a series of 2-fold gradient dilutions of RNA standards (1 μg/μL - 0.24 ng/μL) and forensic samples (including blood samples, saliva samples, bloodstains, and saliva stains) were reverse-transcribed using EasyQuick RT MasterMix. The obtained cDNA was quantified by droplet digital PCR (ddPCR) to assess the RT yield of the ACTB gene. The results showed that the 125 ng RNA template had the highest RT yield in a 10 μL RT reaction system with the selected kit. For all stain samples, the RT yield improved as the amount of RNA template input increased since RNA quantities were below 125 ng. As many commercialized reverse transcription kits using different kinds of enzymes are available for forensic RNA research, we recommend that systematic experiments should be performed in advance to determine the amount of RNA input at the optimum RT yield when using any kit for reverse transcription experiments. • The variation pattern between different amounts of RNA template inputs and the RT yield was assessed using ddPCR. • 125 ng of RNA template input had the highest RT yield in a 10 μL RT reaction system with the selected kit. • RNA extracted from stained samples was below 125 ng, so add as much RNA as possible in the RT step. • Systematic experiments should be performed to determine the amount of RNA input at the optimal RT yield for any selected kit. [ABSTRACT FROM AUTHOR]

• AdipoQ and visfatin are more expressed in the allantoic that in amniotic membranes. • Extra-embryonic annexes AdipoQ and visfatin are higher expressed in layer than broiler. • AdipoQ and visfatin are absent in amniotic fluid at ED7 in layer than broiler. • AdipoQ and visfatin in amniotic fluid are positively correlated with embryo weight. • In ovo injection of visfatin antibodies increases embryo mortality in layer and broiler. Some evidence showed differences between layer and broiler embryo development. We recently showed that two adipokines, adiponectin and visfatin are expressed in the extra embryonic membranes and fluids. However, their role in the embryo development is unknown. Thus, our objectives were 1. to compare the expression of AdipoQ and its receptors AdipoR1 and AdipoR2 and visfatin in extra-embryonic annexes in broiler and layer breeders during the embryo development and 2. to investigate the role of two adipokines in embryo development in both broiler and layer breed after in ovo injection of blocking antibodies against chicken adiponectin or visfatin. We found that adiponectin, AdipoR1, AdipoR2 and visfatin were mainly more expressed in the allantoic that in amniotic membranes. In addition, these expressions increased according the stage of embryo development. We observed a higher expression in layer than in broiler of AdipoQ in allantoic membranes at ED14 and ED18, of AdipoR1 and AdipoR2 in both allantoic and amniotic membranes at ED7 and ED14 and of visfatin only in allantoic membrane from ED7 to ED18. AdipoQ and visfatin were absent in amniotic fluid at ED7 but present at ED14 or ED18 where higher concentrations were detected in layer than in broiler. Interestingly, we showed a strong positive correlation between Adipo and visfatin concentration in amniotic fluid and the body weight of embryo in both breeds. However, after in ovo injection of Adipo antibodies we did not observe any effect on the embryo mortality whereas injection of visfatin antibodies increased in a dose dependent manner the embryo mortality in both breeds. Taken together, Adipo and visfatin are higher expressed in layer than broiler in extra-embryonic membranes and amniotic fluid. Our data suggest also that visfatin could be a main regulator of embryo development. [ABSTRACT FROM AUTHOR]

Streptococcus suis serotype 2 is a zoonotic agent that causes substantial economic losses to the swine industry and threatens human public health. Factors that contribute to its ability to cause disease are not yet fully understood. Glutamate dehydrogenase (GDH) is an enzyme found in living cells and plays vital roles in cellular metabolism. It has also been shown to affect pathogenic potential of certain bacteria. In this study, we constructed a S. suis serotype 2 GDH mutant (Δ gdh) by insertional inactivation mediated by a homologous recombination event and confirmed loss of expression of GDH in the mutant by immunoblot and enzyme activity staining assays. Compared with the wild type (WT) strain, Δ gdh displayed a different phenotype. It exhibited impaired growth in all conditions evaluated (solid and broth media, increased temperature, varying pH, and salinity) and formed cells of reduced size. Using a swine infection model, pigs inoculated with the WT strain exhibited fever, specific signs of disease, and lesions, and the strain could be re-isolated from the brain, lung, joint fluid, and blood samples collected from the infected pigs. Pigs inoculated with the Δ gdh strain did not exhibit any clinical signs of disease nor histologic lesions, and the strain could not be re-isolated from any of the tissues nor body fluid sampled. The Δ gdh also showed a decreased level of survival in pig blood. Taken together, these results suggest that the gdh is important in S. suis physiology and its ability to colonize, disseminate, and cause disease. • Loss of expression of the glutamate dehydrogenase of Streptococcus suis serotype 2 compromises growth and pathogenicity. • The gdh is important in stress tolerance. • The gdh plays a role in S. suis physiology with implications to colonize, disseminate and cause disease. • The GDH is critical in host-pathogen interactions. [ABSTRACT FROM AUTHOR]

Zika virus has been identified in various body fluids such as semen, urine, saliva, cerebrospinal fluid, and vaginal secretion of an infected individual. The pH of these fluids varies from mildly acidic to mildly alkaline. So it is imperative to understand the impact of these conditions on viral protein functioning. We investigated the NS2B-NS3 protease stability and its activity in different denaturing environments. Finding indicates that NS2B-NS3 protease maintains stability at pH 4.8–8.7. Thus it suggests that the complex remains functionally active to hydrolyze the polyprotein within a diverse environmental condition such as variable pH. Despite a stable structure at a broad pH range, a change in environmental conditions dramatically influence its protease activity. Moreover, it is susceptible to structural transformation leading to increased β-strand or helix content in the presence of alcohol. This study may help further to understand the folding-function relationship of the general flaviviral protease complex. Image 1 • Folding dynamics of NS2B-NS3 protease of Zika virus. • NS2B-NS3 protease has high structure stability at wide pH range and temperature. • HFIP and TFE induces helix rich secondary structure in NS2B-NS3 protease. • The NS2B-NS3 protease structure is susceptible to malleable folding. [ABSTRACT FROM AUTHOR]

How developing and growing organisms attain their proper shape is a central problem of developmental biology. In this review, we investigate this question with respect to how the body axis and spine form in their characteristic linear head-to-tail fashion in vertebrates. Recent work in the zebrafish has implicated motile cilia and cerebrospinal fluid flow in axial morphogenesis and spinal straightness. We begin by introducing motile cilia, the fluid flows they generate and their roles in zebrafish development and growth. We then describe how cilia control body and spine shape through sensory cells in the spinal canal, a thread-like extracellular structure called the Reissner fiber, and expression of neuropeptide signals. Last, we discuss zebrafish mutants in which spinal straightness breaks down and three-dimensional curves form. These curves resemble the common but little-understood human disease Idiopathic Scoliosis. Zebrafish research is therefore poised to make progress in our understanding of this condition and, more generally, how body and spine shape is acquired and maintained through development and growth. [ABSTRACT FROM AUTHOR]

• The physiology of hyperthermia or heat stress in mammals is complex. • The bioclimatic indices are a guide to livestock wellbeing under increased heat load. • Monitoring animal physiological responses will be more accurate and informative. • Respiration rate or panting score are useful to assess heat stress in ruminants. • Technology development will enable large scale monitoring of animal core temperature. The physiology of hyperthermia or heat stress in mammals is complex. It is a totally systemic condition that in varying degrees involves all organs, tissues and body fluid compartments. The nature and magnitude of the response is influenced by animal specific characteristics (e.g. age, diet, body condition, gender, reproductive stage), environment and animal management. Given the multifaceted nature of heat stress, and the varied ruminant production systems based in varied geoclimatic zones, it has been difficult to find appropriate measures of heat stress for production ruminants. This has become an urgent challenge as production systems intensify globally in a warming climate. Bioclimatic indices such as the Temperature-Humidity Index (THI) have evolved to incorporate some measure of animal physiology. However, these indices do not have strong relationships with core temperature trajectories and altered respiratory dynamics of animals with excessive heat load. In recent decades, the careful physiology studies of the 1950–80s, have given way to numerous studies trialling a plethora of new technologies and computational approached to measure heat stress. Infrared thermography of body surface temperatures, automated measures of respiration rate and radiotelemetry of internal body temperatures are the most intensively researched. The common goal has been to find the 'holy grail' decision-making threshold or timepoint as to the animal's wellbeing. Are we making any progress? [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are involved in a series of pathology of spinal cord injury (SCI). Although, locally expressed miRNAs have advantages in studying the pathological mechanism, they cannot be used as biomarkers. The "free circulation" miRNAs can be used as biomarkers, but they have low concentration and poor stability in body fluids. Exosomal miRNAs in body fluids have many advantages comparing with free miRNAs. Therefore, we hypothesized that the specific miRNAs in the central nervous system might be transported to the peripheral circulation and concentrated in exosomes after injury. Using next-generation sequencing, miRNA profiles in serum exosomes of sham and subactue SCI rats were analyzed. The results showed that SCI can lead to changes of serum exosomal miRNAs. These changed miRNAs and their associated signaling pathways may explain the pathological mechanism of suacute SCI. More importantly, we found some valuable serum exosomal miRNAs for diagnosis and prognosis of SCI. • Serum exosomes of sham and subactue SCI rats were isolated and identified. • Serum exosomal microRNA transcriptome profiling in subacute spinal cord injured rats is investigated. • The changed miRNAs and their associated signaling pathways have been systematically determined. • Our results will provide a basis for the pathological mechanism, diagnosis and prognosis of SCI. [ABSTRACT FROM AUTHOR]

• This review presents the step-by-step protocols for EV separation methods from brain tissue. • This review describes EV separation methods from human cerebrospinal fluids. • This review compares the quality control measures of separation protocols by biophysical and proteomic characterizations. Extracellular vesicle (EV) is a unified terminology of membrane-enclosed vesicular species ubiquitously secreted by almost every cell type and present in all body fluids. They carry a cargo of lipids, metabolites, nucleic acids and proteins for their clearance from cells as well as for cell-to-cell communications. The exact composition of EVs and their specific functions are not well understood due to the underdevelopment of the separation protocols, especially those from the central nervous system including animal and human brain tissues as well as cerebrospinal fluids, and the low yield of proteins in the separated EVs. To understand their exact molecular composition and their functional roles, development of the reliable protocols for EV separation is necessary. Here we report the methods for EV separation from human and mouse unfixed frozen brain tissues by a sucrose step gradient ultracentrifugation method, and from human cerebrospinal fluids by an affinity capture method. The separated EVs were assessed for morphological, biophysical and proteomic properties of separated EVs by nanoparticle tracking analysis, transmission electron microscopy, and labeled and label-free mass spectrometry for protein profiling with step-by-step protocols for each assessment. [ABSTRACT FROM AUTHOR]

In this work we study the coupled system of partial and ordinary differential equations describing the interaction between a compressible isentropic viscous fluid and a rigid body moving freely inside the fluid. In particular the position and velocity of the rigid body in the fluid are unknown and the motion of the rigid body is driven by the normal stress forces of the fluid acting on the boundary of the body. We prove that the strong solution, which is known to exist under certain smallness assumptions, is unique in the class of weak solutions to the problem. The proof relies on a correct definition of the relative energy, to use this tool we then have to introduce a change of coordinates to transform the strong solution to the domain of the weak solution in order to use it as a test function in the relative energy inequality. Estimating all arising terms we prove that the weak solution has to coincide with the transformed strong solution and finally that the transformation has to be in fact an identity. [ABSTRACT FROM AUTHOR]

The islets of Langerhans harbor multiple endocrine cell types that continuously respond to circulating nutrient levels in order to adjust their secretion of catabolic and anabolic hormones. Stimulus–secretion coupling in these cells is largely of metabolic nature; that is, metabolism of nutrient fuels yields signals that trigger and amplify secretion of hormones. Hence, metabolism in this micro -organ is in a major way in control of whole-body metabolism. Therefore, insights into islet metabolism are critical to understand how secretion of insulin is regulated and why it is perturbed in type 2 diabetes. Metabolomics aims at characterizing a wide spectrum of metabolites in cells, tissues and body fluids. For this reason, this technique is well suited to supply information on stimulus–secretion coupling. Here, we summarize metabolomics studies in islets and β-cells, highlight important discoveries that would have been difficult to make without this technology but also raise awareness of challenges and bottlenecks that curtail its use in metabolic research. Unlabelled Image [ABSTRACT FROM AUTHOR]

Human biomonitoring measures the concentrations of environmental chemicals or their metabolites in body fluids or tissues. Complementing exposure biomarkers with mechanistically based effect biomarkers may further elucidate causal pathways between chemical exposure and adverse health outcomes. We combined information on effect biomarkers previously implemented in human observational studies with mechanisms of action reported in experimental studies and with information from published Adverse Outcome Pathways (AOPs), focusing on adverse reproductive effects of phthalate exposure. Phthalates constitute a group of chemicals that are ubiquitous in consumer products and have been related to a wide range of adverse health effects. As a result of a comprehensive literature search, we present an overview of effect biomarkers for reproductive toxicity that are substantiated by mechanistic information. The activation of several receptors, such as PPARα, PPARγ, and GR, may initiate events leading to impaired male and female fertility as well as other adverse effects of phthalate exposure. Therefore, these receptors appear as promising targets for the development of novel effect biomarkers. The proposed strategy connects the fields of epidemiology and toxicology and may strengthen the weight of evidence in observational studies that link chemical exposures to health outcomes. Image 1 • We present a strategy to support exposure-effect relations in biomonitoring studies. • Effect biomarkers for phthalates were comprehensively collected from literature. • Available toxicological and AOP information was linked to the effect biomarkers. • This approach led to the identification of promising novel human effect biomarkers. • PPAR and GR activation emerged as early markers of phthalates' reproductive effects. [ABSTRACT FROM AUTHOR]

Abstract Over recent years, quantification of multiple proteins in body fluids has become increasingly prominent, which is beneficial to a number of scientific fields, not least biomedical. Several techniques have been developed based on conventional ELISA; one of these techniques is analysis of proteins labelled with element-tagged antibodies by ICP-MS in serum, allowing quantification of multiple targets within a single sample. This research aimed to quantify albumin and immunoglobulin G (IgG) levels in plasma, whole blood and dried blood spots using NANOGOLD® and Europium labelled antibodies analysed by ICP-MS. Before the proteins were quantified simultaneously, albumin and IgG concentrations were measured separately and compared to protein levels obtained by ELISA. It was found that protein concentrations for both albumin and IgG obtained with element-labelled antibody detection correspond to those determined by ELISA. Furthermore, albumin and IgG levels measured simultaneously by ICP-MS correspond to concentrations found when the proteins were analysed separately by ICP-MS. Finally, development of this method has provided a positive indication that it can be extended to quantification of additional proteins, which could be related to a disease or as a minimum provide additional information for a protein profile of an individual. Highlights • Simultaneous analysis of two proteins in plasma, whole blood and dried blood spots • Element-labelled antibody detection of albumin and IgG by ICPMS was proven • Protein quantification was achieved in plasma, whole blood and dried blood spots • Protein concentrations determined by ICP-MS correspond to those determined by ELISA [ABSTRACT FROM AUTHOR]

Abstract A UHPLC-MS/MS untargeted serum metabonomic method combined with quantitative analysis of five potential biomarkers in rat serum was developed and validated, to further understand the anti-liver injury effect of Si-Ni-San and its mechanism on liver injury rats in this study. The metabolites were separated and identified on BEH C 18 column (100 mm × 2.1 mm, 1.7 μm) using the ACQUITY UHPLC-MS system (Waters Corp., Milford, MA, USA). Principal component analysis (PCA) was used to identify potential biomarkers. Primary potential biomarkers including phenylalanine, tryptophan, Glycochenodeoxycholic acid (GCDCA) and hysophosphatidylcholine (LPC), which were related to amino acid metabolism, lipid metabolism, bile acid biosynthesis and oxidation-antioxidation balance, were found in the untargeted metabonomic research. Moreover, these targeted biomarkers were further separated and quantified in multiple-reaction monitoring (MRM) with positive ionization mode. The proposed method was linear for each analyte with correlation coefficients over 0.99. The intra- and inter-day precision values (relative standard deviation, RSD) were less than 13.1% and accuracy (relative error, RE) was from −9.5% to 10.3% at all quality control (QC) levels. The validated method was successfully applied to study the serum samples of control group, model group, positive control group (silymarin group) and Si-Ni-San group in rats. Graphical abstract Image 1 Highlights • A UHPLC-MS/MS untargeted metabonomic method combined with quantitative analysis. • The validated method was applied to control group, model group and Si-Ni-San group. • The changes of potential biomarkers and relevant metabolic pathways were demonstrated. • Understand the effect and mechanism of Si-Ni-San on liver injury rats. [ABSTRACT FROM AUTHOR]

Abstract Predictive models allow subject-specific inference when analyzing disease related alterations in neuroimaging data. Given a subject's data, inference can be made at two levels: global, i.e. identifiying condition presence for the subject, and local, i.e. detecting condition effect on each individual measurement extracted from the subject's data. While global inference is widely used, local inference, which can be used to form subject-specific effect maps, is rarely used because existing models often yield noisy detections composed of dispersed isolated islands. In this article, we propose a reconstruction method, named RSM, to improve subject-specific detections of predictive modeling approaches and in particular, binary classifiers. RSM specifically aims to reduce noise due to sampling error associated with using a finite sample of examples to train classifiers. The proposed method is a wrapper-type algorithm that can be used with different binary classifiers in a diagnostic manner, i.e. without information on condition presence. Reconstruction is posed as a Maximum-A-Posteriori problem with a prior model whose parameters are estimated from training data in a classifier-specific fashion. Experimental evaluation is performed on synthetically generated data and data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Results on synthetic data demonstrate that using RSM yields higher detection accuracy compared to using models directly or with bootstrap averaging. Analyses on the ADNI dataset show that RSM can also improve correlation between subject-specific detections in cortical thickness data and non-imaging markers of Alzheimer's Disease (AD), such as the Mini Mental State Examination Score and Cerebrospinal Fluid amyloid- β levels. Further reliability studies on the longitudinal ADNI dataset show improvement on detection reliability when RSM is used. [ABSTRACT FROM AUTHOR]

Abstract The objective of this study is to test the feasibility of using serum neurofilament light chain (NfL) as a disease biomarker in Chemotherapy Induced Peripheral Neuropathy (CIPN) since this easy accessible biological test may have a large impact on clinical management and safety of cancer patients. We performed this preclinical study using a well-characterized rat model based on repeated administration of the cytostatic drug vincristine (VCR, 0.2 mg/kg intravenously via the tail vein once/week for 4 times). Serial NfL serum concentration was measured using the in-house Simoa NfL assay and peripheral neuropathy onset was measured by sensory and motor nerve conduction studies. Serum NfL measure in untreated and VCR-treated rats demonstrated a steady, and significant increase during the course of VCR administration, with a final 4-fold increase with respect to controls ( p <.001) when sign of axonopathy and loss of intraepidermal nerve fibers were clearly evident and verified by behavioral, neurophysiological and pathological examination. This simple monitoring approach based on serum NfL concentration measures may be easily translated to clinical practice and should be considered as a putative marker of CIPN severity in a typical oncology outpatient setting. Further studies are needed to validate its utility in cancer patients treated with different neurotoxic drugs. [ABSTRACT FROM AUTHOR]

The kidneys are vital organs responsible for maintaining body fluid homeostasis within proper physiologic ranges. Kidney disease is an epidemic clinical problem causing significant morbidity and mortality, and current treatments are limited to renin-angiotensin system blockade or renal replacement therapy for the majority of affected individuals. There is a critical, unmet need for novel pharmacological agents to improve the outcome of patients with kidney disease. Nitro-oleic acid (NO 2 -OA) is an endogenously generated electrophilic compound with the capacity to modify thiols in proteins, altering their function. The most important targets appear to be the Keap1/Nrf2 and NF-κB pathways, which have widespread effects on antioxidant, detoxifying, and inflammatory responses in cells and tissues. Through these and potentially additional protective actions, NO 2 -OA may be capable of preserving or enhancing kidney function in acute and chronic kidney diseases. [ABSTRACT FROM AUTHOR]

Arginine Vasopressin (AVP) is one of the key hormones in the human body. AVP is clinically important because it maintains body fluid balance and vascular tone. Unfortunately, AVP laboratory measurements are always difficult and with low accuracy. Copeptin, the C-terminal of the AVP precursor, is released in equal amounts with AVP, making it a sensitive marker of AVP release. Despite being a non-specific biomarker, copeptin earned a lot of attention as a novel biomarker due to easy and quick laboratory measurements. Recent studies have reported the critical role of copeptin as a clinical indicator, especially in the diagnosis and prognosis of many diseases. Besides, it was reported that the combination between copeptin and gold standard biomarkers improved the prognostic values of those biomarkers. In this review, the role of copeptin as a new predictive diagnostic and prognostic biomarker of various diseases is highlighted according to the most recent studies. In addition, the importance of using copeptin as a marker in different medical departments and the impact of this on improving healthcare service was discussed. • Copeptin and arginine vasopressin are released from the pituitary gland in equimolar amounts in response to stress. • Copeptin is a surrogate marker of arginine vasopressin. • Copeptin appears to play an important role as a prognostic marker in some acute diseases. [ABSTRACT FROM AUTHOR]

Fabry disease is an X-linked lysosomal storage disorder caused by the accumulation of glycosphingolipids in various tissues and body fluids, leading to progressive organ damage and life-threatening complications. Phenotypic classification is based on disease progression and severity and can be used to predict outcomes. Patients with a classic Fabry phenotype have little to no residual α-Gal A activity and have widespread organ involvement, whereas patients with a later-onset phenotype have residual α-Gal A activity and disease progression can be limited to a single organ, often the heart. Diagnosis and monitoring of patients with Fabry disease should therefore be individualized, and biomarkers are available to support with this. Disease-specific biomarkers are useful in the diagnosis of Fabry disease; non-disease-specific biomarkers may be useful to assess organ damage. For most biomarkers it can be challenging to prove they translate to differences in the risk of clinical events associated with Fabry disease. Therefore, careful monitoring of treatment outcomes and collection of prospective data in patients are needed. As we deepen our understanding of Fabry disease, it is important to regularly re-evaluate and appraise published evidence relating to biomarkers. In this article, we present the results of a literature review of evidence published between February 2017 and July 2020 on the impact of disease-specific treatment on biomarkers and provide an expert consensus on clinical recommendations for the use of those biomarkers. [ABSTRACT FROM AUTHOR]

Fish have sophisticated mechanisms of ionic and acid-base regulation for maintaining body fluid homeostasis. Many hormones have been proposed to control the ionic and acid-base regulation mechanisms in fishes; however, lots of the proposed actions lack convincing cellular/molecular evidence. With the advantages of available genetic databases and molecular manipulation techniques, zebrafish has become an emerging model for research into ion transport physiology and functional regulation. Different types of ionocytes were found to transport ions through various sets of ion transporters, and the molecular mechanisms of ionocyte proliferation and differentiation have also been dissected, providing a competent platform with which to precisely study the ion transport pathways and ionocytes targeted by hormones, including isotocin, prolactin, cortisol, stanniocalcin-1, calcitonin, endothelin-1, vitamin D, parathyroid hormone 1, catecholamines, the renin-angiotensin-system, estrogen-related receptor α, and calcitonin gene-related peptide, which have been demonstrated to positively or negatively regulate ion transport through specific receptors at different molecular levels (transcriptional, translational, or posttranslational) or at different developmental stages of ionocytes (proliferation or differentiation). The knowledge obtained in zebrafish not only enhances our understanding of the hormonal control of fish ion regulation, but also informs studies on other animal species, thereby providing insights into related fields. [ABSTRACT FROM AUTHOR]

In this two-part paper, a high-order accurate implicit mesh discontinuous Galerkin (dG) framework is developed for fluid interface dynamics, facilitating precise computation of interfacial fluid flow in evolving geometries. The framework uses implicitly defined meshes—wherein a reference quadtree or octree grid is combined with an implicit representation of evolving interfaces and moving domain boundaries—and allows physically prescribed interfacial jump conditions to be imposed or captured with high-order accuracy. Part one discusses the design of the framework, including: (i) high-order quadrature for implicitly defined elements and faces; (ii) high-order accurate discretisation of scalar and vector-valued elliptic partial differential equations with interfacial jumps in ellipticity coefficient, leading to optimal-order accuracy in the maximum norm and discrete linear systems that are symmetric positive (semi)definite; (iii) the design of incompressible fluid flow projection operators, which except for the influence of small penalty parameters, are discretely idempotent; and (iv) the design of geometric multigrid methods for elliptic interface problems on implicitly defined meshes and their use as preconditioners for the conjugate gradient method. Also discussed is a variety of aspects relating to moving interfaces, including: (v) dG discretisations of the level set method on implicitly defined meshes; (vi) transferring state between evolving implicit meshes; (vii) preserving mesh topology to accurately compute temporal derivatives; (viii) high-order accurate reinitialisation of level set functions; and (ix) the integration of adaptive mesh refinement. In part two, several applications of the implicit mesh dG framework in two and three dimensions are presented, including examples of single phase flow in nontrivial geometry, surface tension-driven two phase flow with phase-dependent fluid density and viscosity, rigid body fluid–structure interaction, and free surface flow. A class of techniques known as interfacial gauge methods is adopted to solve the corresponding incompressible Navier–Stokes equations, which, compared to archetypical projection methods, have a weaker coupling between fluid velocity, pressure, and interface position, and allow high-order accurate numerical methods to be developed more easily. Convergence analyses conducted throughout the work demonstrate high-order accuracy in the maximum norm for all of the applications considered; for example, fourth-order spatial accuracy in fluid velocity, pressure, and interface location is demonstrated for surface tension-driven two phase flow in 2D and 3D. Specific application examples include: vortex shedding in nontrivial geometry, capillary wave dynamics revealing fine-scale flow features, falling rigid bodies tumbling in unsteady flow, and free surface flow over a submersed obstacle, as well as high Reynolds number soap bubble oscillation dynamics and vortex shedding induced by a type of Plateau–Rayleigh instability in water ripple free surface flow. These last two examples compare numerical results with experimental data and serve as an additional means of validation; they also reveal physical phenomena not visible in the experiments, highlight how small-scale interfacial features develop and affect macroscopic dynamics, and demonstrate the wide range of spatial scales often at play in interfacial fluid flow. [ABSTRACT FROM AUTHOR]

Accumulation of neurofilaments (NFs), the major constituents of the neuronal cytoskeleton, is a distinctive feature of neurological diseases and several studies have shown that soluble NFs can be detected in the cerebrospinal fluid (CSF) of patients with neurological diseases, such as multiple sclerosis and frontotemporal dementia. Here we have used an inducible transgenic mouse model of neurodegeneration, CamKII-TetOp25 mice, to evaluate whether NF-L levels in CSF or blood can be used as a biochemical biomarker of neurodegeneration. Induction of p25 transgene brain expression led to increase in CSF and serum NF-L levels that correlated with ongoing neurodegeneration. Switching off p25 prevented further increases in both CSF and serum NF-L levels and concomitantly stopped the progression of neurodegeneration. The levels of CSF NF-L detected in p25 mice are about 4–fold higher than the CSF levels detected in patients with chronic neurodegenerative diseases, such as symptomatic FTD (bvFTD). In addition, our data indicate that the NF-L detected in CSF is most likely a cleaved form of NF-L. These results suggest that CSF and serum NF-L are of interest to be further explored as potential translational dynamic biomarkers of neurodegeneration or as pharmacodynamics biomarkers at least in preclinical animal studies. [ABSTRACT FROM AUTHOR]

The numerical prediction of two-phase flows with an interface is challenging, to a considerable extent because of the high density ratio at the interface. Numerical results become affected by momentum losses, diverging spurious interface velocities, free surface distortion, and even numerical instability. To prevent issues like these, consistent momentum and mass transport with an additional continuity equation were introduced. In this article, we describe how a consistent discretization was incorporated into our own method and extended for fluid-structure interaction (FSI) with moving rigid bodies. The new method was tested against benchmark simulations from literature confirming that consistent transport modeling gives a significant improvement compared to non-consistent modeling for the dynamics of two-phase flows. Newly devised proof of principle FSI simulations with momentum transfer from fluid to body in the presence of a high-density ratio between fluids are introduced that could serve as a benchmark for future studies. The simulations demonstrate that consistent modeling gives an order of magnitude improvement in terms of momentum conservation compared to non-consistent modeling. Simulations with the new method are also compared to FSI experiments from literature. Results obtained with the consistent method are closer to the measurements than results of the non-consistent method. The merit of consistent modeling with and without FSI becomes especially apparent for two-phase flows with a high-density ratio between fluids. [ABSTRACT FROM AUTHOR]

Background Exposure to inorganic arsenic increases the risk of cancer and non-malignant diseases. Inefficient arsenic metabolism is a marker for susceptibility to arsenic toxicity. Arsenic may alter gene expression, possibly by altering DNA methylation. Objectives To elucidate the associations between arsenic exposure, gene expression, and DNA methylation in peripheral blood, and the modifying effects of arsenic metabolism. Methods The study participants, women from the Andes, Argentina, were exposed to arsenic via drinking water. Arsenic exposure was assessed as the sum of arsenic metabolites in urine (U-As), using high performance liquid-chromatography hydride-generation inductively-coupled-plasma-mass-spectrometry, and arsenic metabolism efficiency was assessed by the urinary fractions (%) of the individual metabolites. Genome-wide gene expression ( N = 80 women) and DNA methylation ( N = 93; 80 overlapping with gene expression) in peripheral blood were measured using Illumina DirectHyb HumanHT-12 v4.0 and Infinium Human-Methylation 450K BeadChip, respectively. Results U-As concentrations, ranging 10–1251 μg/L, was associated with decreased gene expression: 64% of the top 1000 differentially expressed genes were down-regulated with increasing U-As. U-As was also associated with hypermethylation: 87% of the top 1000 CpGs were hypermethylated with increasing U-As. The expression of six genes and six individual CpG sites were significantly associated with increased U-As concentration. Pathway analyses revealed enrichment of genes related to cell death and cancer. The pathways differed somewhat depending on arsenic metabolism efficiency. We found no overlap between arsenic-related gene expression and DNA methylation for individual genes. Conclusions Increased arsenic exposure was associated with lower gene expression and hypermethylation in peripheral blood, but with no evident overlap. [ABSTRACT FROM AUTHOR]

An immunosensor for the sensitive detection and estimation of tumor necrosis factor-alpha (TNF-α) in undiluted serum has been developed via an electrochemical enzyme-linked immunosorbent assay (ELISA) process. Electrochemical sensing was performed using a TNF-α specific monoclonal antibody modified self-assembled monolayer of dithiobis(succinimidyl propionate) on a comb-shaped gold electrode microarray. After anti-TNF-α antibody binding, unreacted active groups of DTSP were blocked using ethanol amine (EA) and nonspecific binding was prevented using phosphate buffer based starting block T20 (SB). Sensitive and disposable SB-EA-anti-TNF-α/DTSP/Au electrodes were exposed to solutions with different TNF-α concentrations for 20 min in undiluted serum. Conversion of 4-aminophenyl phosphate to 4-aminophenol and its electrochemical oxidation was utilized for indirect estimation of TNF-α. Results for SB-anti-TNF-α/DTSP/Au electrodes indicate that the sensors can be used for the sensitive estimation of TNF-α in undiluted serum in the range 500 pg/ml to 100 ng/ml with a detection limit of 60 pg/ml and sensitivity of 0.46 (ng/ml)-1. Negligible interference from serum and other biomarker proteins was observed. The described electrochemical ELISA is much faster than conventional ELISA and can be applied for sensing of a range of analytes in real patient samples. [ABSTRACT FROM AUTHOR]

Objective Meta-analyses of cross-sectional studies confirm an increase in circulating inflammatory markers during acute psychosis. Longitudinal studies are scarce but are needed to understand whether elevated inflammatory markers are a cause or consequence of illness. We report a longitudinal study of serum C-reactive protein (CRP) in adolescence and subsequent risk of schizophrenia and related psychoses in adulthood in the Northern Finland Birth Cohort 1986. Method Serum high-sensitivity CRP was measured at age 15/16 years in 6362 participants. ICD-10 diagnoses of schizophrenia and related psychoses were obtained from centralised hospital inpatient and outpatient registers up to age 27 years. Logistic regression calculated odds ratios (ORs) for psychotic outcomes associated with baseline CRP levels analysed as both continuous and categorical variables using American Heart Association criteria. Age, sex, body mass index, maternal education, smoking, and alcohol use were included as potential confounders. Results By age 27 years, 88 cases of non-affective psychosis (1.38%), of which 22 were schizophrenia (0.35%), were identified. Adolescent CRP was associated with subsequent schizophrenia. The adjusted OR for schizophrenia by age 27 years for each standard deviation (SD) increase in CRP levels at age 15/16 years was 1.25 (95% CI, 1.07–1.46), which was consistent with a linear, dose-response relationship ( P- value for quadratic term 0.23). Using CRP as a categorical variable, those with high (>3 mg/L) compared with low (<1 mg/L) CRP levels at baseline were more likely to develop schizophrenia; adjusted OR 4.25 (95% CI, 1.30–13.93). There was some indication that higher CRP was associated with earlier onset of schizophrenia ( r s = −0.40 ; P = 0.07). Conclusions A longitudinal association between adolescent CRP levels and adult schizophrenia diagnosis indicates a potentially important role of inflammation in the pathogenesis of the illness, although the findings, based on a small number of cases, need to be interpreted with caution and require replication in other samples. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) associated with lung cancer are diversifying. MiR-21, Let-7, and miR-141 are common diagnostic targets. Some new lung cancer miRNAs, such as miR-25, miR-145, and miR-126, have received increasing attention. Although various techniques are available for the analysis of lung cancer miRNAs, electrochemistry has been recognized for its high sensitivity, low cost, and rapid response. However, how to realize the signal amplification is one of the most important contents in the design of electrochemical biosensors. Herein, we mainly introduce the amplification strategy based on enzyme-free amplification and signal conversion, including non-linear HCR, catalytic hairpin assembly (CHA), electrochemiluminescence (ECL), and Faraday cage. Furthermore, new progress has emerged in the fields of nanomaterials, low oxidation potential, and simultaneous detection of multiple targets. Finally, we summarize some new challenges that electrochemical techniques may encounter in the future, such as improving single-base discrimination ability, shortening electrochemical detection time, and providing real body fluid samples assay. [Display omitted] • Advances in nanomaterials, signal amplification, low oxidation potential, and dual-target detection. • Some uncommon lung cancer-related miRNA markers, such as miR-25, miR-126, and miR-145, etc. • The detection limits of various electrochemical sensors are compared. • Enumerate some challenges that electrochemical technology will face. [ABSTRACT FROM AUTHOR]

In fish, skin mucus forms a protective barrier between the body surface and the external water environment, thus providing the most direct and intuitive clues to monitor the subject's health condition. To explore the impact of the Vibrio harveyi pathogen on teleost, the proteome of epidermal mucus from control and sick Cynoglossus semilaevis were screened through iTRAQ followed with LC-MS/MS. 1531 credible proteins were obtained relating to structural, metabolic and immunological functions. 335 different expressed proteins (DEPs) were identified, with 166 up-regulated and 169 down-regulated in MS. 62 proteins were characterized, including 22 up-regulated proteins and 40 down-regulated proteins. Integrated analysis of DE-miRNAs and DEPs from miRomics and proteomics were conducted to show the indirect regulatory relationship. Comparative analysis of DEPs between mucus and exosomes demonstrated that exosomes contributed the most DEPs of all mucus DEPs. 125 proteins are DEPs only in exosomes, which presented minor difference in total mucus. Expression of Aminopeptidase (anpep), Calcium-transporting ATPase, Histone H2B and H2A confirmed implied fine discriminative power with infected C. semilaevis , among which Calcium-transporting ATPase and H2B also appeared in list of exosomal markers. This study might shed the light on effective biomarker digging at other extended screening scenarios. • Exosomes in mucus were the main contributor of DEPs pool. • The enrichment of exosomes and the dilution effect of mucus made the common DEPs. • Four verified proteins could be recruited as candidate markers in mucus. • This study indicated the feasibility of biomarkers developing from body fluid compared with exosomes. [ABSTRACT FROM AUTHOR]

Phytate is considered an anti-nutrient, because it is not digestible for humans given our lack of phytase activity (PhyA). It has been hypothesized that Lactobacilli may act as carriers of phytate-degrading activity in the gastrointestinal tract. Therefore, the aim of this work was to assess the PhyA of nineteen probiotic bacteria exposed to simulated gastrointestinal fluids. Each culture was inoculated to three different growth media (MRS, MRS-MOPS and MRS-MOPS + AA). Cell-free extracts were used to test for PhyA assay. The highest PhyA ( P < 0.05) was observed in MRS-MOPS, which was higher than MRS (control). A decrease in PhyA was observed in crude enzyme extracts (CEE) after exposure to gastrointestinal fluids. However, PhyA was higher at low gastric pH values. PhyA was greater in CEE obtained from bacteria that were previously exposed to simulated gastrointestinal conditions, than in those that were not exposed. CEE from Lc-L9 and Lc-12A strains showed the highest activities under intestinal conditions; while Lc-7R1 and Ls-B1917 were the highest under gastric conditions. The ability of specific probiotic bacteria to degrade phytate after exposure to simulated gastrointestinal conditions was demonstrated, which suggests that these bacteria may contribute to improve phytate degradation in humans during digestion. [ABSTRACT FROM AUTHOR]

Chicken growth hormone secretagogue receptor (GHSR) is a receptor for ghrelin (GHRL), a peptide hormone produced by chicken proventriculus, which stimulates growth hormone (GH) release and food intake. The purpose of this study was to search for single nucleotide polymorphisms (SNPs) in exon 2 of GHSR gene and to analyze their effect on the appetite, growth traits and expression levels of GHSR , GHRL , and GH genes as well as serum levels of GH and GHRL in Mandara chicken. Two adjacent SNPs, A239G and G244A, were detected in exon 2 of GHSR gene. G244A SNP was non-synonymous mutation and led to replacement of lysine amino acid (aa) by arginine aa, while A239G SNP was synonymous mutation. The combined genotypes of A239G and G244A SNPs produced three haplotypes; GG/GG, GG/AG, AG/AG, which associated significantly (P < 0.05) with growth traits (body weight, average daily gain, shank length, keel length, chest circumference) at age from >4 to 16 w. Chickens with the homozygous GG/GG haplotype showed higher growth performance than other chickens. The two SNPs were also correlated with mRNA levels of GHSR and GH (in pituitary gland), and GHRL (in proventriculus and hypothalamus) as well as with serum level of GH and GHRL. Also, chickens with GG/GG haplotype showed higher mRNA and serum levels. This is the first study to demonstrate that SNPs in GHSR can increase appetite, growth traits, expression and level of GHRL, suggesting a hunger signal role for endogenous GHRL. [ABSTRACT FROM AUTHOR]

To control the degradation rate of medical magnesium in body fluid environment, biocompatible films composed of Mussel Adhesive Protein ( Mefp-1 ) and chitosan were electrodeposited on magnesium surface in cathodic constant current mode. The compositions and structures of the films were characterized by atomic force microscope (AFM), scanning electron microscope (SEM) and infrared reflection absorption spectroscopy (IRAS). And the corrosion protection performance was investigated using electrochemical measurements and immersion tests in simulated body fluid (Hanks’ solution). The results revealed that Mefp-1 and chitosan successfully adhered on the magnesium surface and formed a protective film. Compared with either single Mefp-1 or single chitosan film, the composite film of chitosan/ Mefp-1 /chitosan (CPC (chitosan/ Mefp-1 /chitosan)) exhibited lower corrosion current density, higher polarization resistance and more homogenous corrosion morphology and thus was able to effectively control the degradation rate of magnesium in simulated body environment. In addition, the active attachment and spreading of MC3T3-E1 cells on the CPC film coated magnesium indicated that the CPC film was significantly able to improve the biocompatibility of the medical magnesium. [ABSTRACT FROM AUTHOR]

Abstract Glycosaminoglycans (GAGs) were recovered from human cerebral spinal fluid (CSF) and after their conversion to disaccharides using polysaccharide lyases were analyzed by liquid chromatography tandem mass spectrometry using multiple reaction monitoring. CSF showed ng/mL levels of heparan sulfate, chondroitin sulfates and hyaluronan. The amounts and disaccharide composition of these GAGs differed from those found in human plasma. This approach may offer a new method for the discovery of biomarkers for diseases of the central nervous system. Highlights • Glycosaminoglycans in CSF were: heparan sulfate, 126 ng/mL; chondroitin sulfate, 421 ng/mL; and hyaluronan, 260 ng/mL. • HS was comprised of the 0S disaccharide (68.7%), followed by the NS (10.5%), 6S (9.5%), NS2S (7.2%) and NS6S (3.8%). • CS was comprised of the 4S disaccharide (91.4%), followed by 4S6S (3.2%), 2S4S (2.3%) and 0S (1.5%). • Robust LC/MS/MS MRM showing only 5% variability between analytical replicates and 15% variability in biological replicates. [ABSTRACT FROM AUTHOR]

The plasticizer bisphenol A (BPA) is one of the highest volume chemicals produced worldwide. Human exposure to BPA occurs almost constantly. BPA is an endocrine disruptor that interferes in estrogen receptor functions. This is important for the developing brain, which is particularly sensitive to the estrogenic effects of BPA. Body fluid balance is maintained by a complex network of systems that regulate sodium and water intakes and electrolyte excretion. The development of these control systems occurs during early life and therefore, may be susceptible to changes in the uterine environment. The aim of this work was to study the effects of two low BPA doses in the dam, during pregnancy and lactation, on adult offspring drinking and sodium and urine excretion after dipsogenic challenge. Dams were exposed to BPA in drinking water to mimic the most likely route of human exposure. The results showed that BPA did not disrupt spontaneous fluid balance, but altered sodium and fluid intakes in the BPA offspring under osmotic challenges. In experiments, both 24h fluid deprivation and sodium depletion modified fluid ingestive response in BPA offspring compared to control offspring. The increased preference for 2.7% NaCl solution in male BPA offspring is similar to female control offspring, altered ingestive behavior appears to be due to feminization of males and "hyperfeminization" of female BPA offspring, as they drink more than female control offspring. Our results indicate that exposure to low doses of BPA in early life may disrupt the development of sex-specific drinking behaviors by altering the steroid programming of the brain, and this disruption affects males and females differently. [ABSTRACT FROM AUTHOR]

Objectives To conduct a comprehensive quantitative proteomics analysis of novel serum protein biomarkers based on synovitis status associated with matrix metalloproteinase-3 (MMP-3) and to determine the clinical significance of these biomarkers in rheumatoid arthritis (RA). Methods Patients with untreated RA ( n = 28), primary Sjogren’s syndrome (pSS) ( n = 30), and healthy controls (HCs) ( n = 30) were enrolled for the screening assay. A total of 1128 serum proteins were analyzed using the SOMAscan™ assay. Serum levels of MMP-3 and interleukin (IL)-16 were measured using a latex turbidimetric immunoassay and ELISA at baseline and 12 weeks after treatment with methotrexate (MTX) for MTX-naïve RA patients ( n = 28) or with the biologics tocilizumab (TCZ) ( n = 7), abatacept (ABT) ( n = 11) or infliximab ( n = 22) for MTX-inadequate response (IR) RA patients. Correlation analysis was conducted using Spearman’s rank correlation method. Results Proteomics showed that serum IL-16 levels were most positively correlated with those of MMP-3 ( ρ = 0.51, p < 0.01) and were significantly increased in patients with untreated active RA compared to HCs ( p < 0.01) or those with pSS ( p < 0.01). IL-16 levels decreased following treatment in both the MTX-naïve and MTX-IR groups. Regarding clinical response, fluctuations in IL-16 levels were positively associated with changes in clinical indicators, particularly the Clinical Disease Activity Index ( ρ = 0.89, p < 0.01) in the TCZ and ABT-treated group. However, no similar correlation was noted in MMP-3 and acute phase reactants in any groups. Conclusions IL-16 was a more effective clinical parameter than MMP-3, C-reactive protein, or erythrocyte sedimentation rate in both MTX-naive and MTX-IR RA patients. IL-16 might be a useful biomarker for evaluating clinical response in RA patients. [ABSTRACT FROM AUTHOR]

Chronic stress has been associated with several negative health outcomes and psychopathological conditions. One source of chronic stress might be from ones social environment (e.g., being excluded from a group, losing a loved one, etc.). Specifically, social instability, or frequent changes in the social environment, can result in both physiological and behavioral stress responses. Corticosterone is the primary stress-responsive biomarker in rodents, and it reflects the activity of the hypothalamic-pituitary-adrenal (HPA) axis. Historically, research on the effects of stress has relied on collection of blood, saliva, or other bodily fluids that yield information about moment-to-moment changes in stress physiology. Recently, new sampling techniques involving quantification of glucocorticoids in hair has allowed researchers to view patterns of stress physiology over extended periods of time. This study assessed the effects of chronic social instability on corticosterone levels in female mice. Mice that were subjected to social instability showed elevated hair corticosterone compared to baseline levels and as compared to controls. Additionally, when mice were returned to stable social environments, corticosterone levels returned to levels comparable to baseline and to control animals. This suggests that the corticosterone in hair from female mice can serve as a useful biomarker of chronic stress, and that social instability is a sufficient stressor to elicit an extended HPA response. [ABSTRACT FROM AUTHOR]

Background Esophagectomy is associated with significant morbidity. Optimizing perioperative fluid administration is one potential strategy to mitigate morbidity. We sought to investigate the relationship of intraoperative fluid (IOF) administration to outcomes in patients undergoing transhiatal esophagectomy with particular attention to malnourished patients, who may be more susceptible to the effects of fluid overload. Material and methods Patients who underwent transhiatal esophagectomy from 2000-2013 were identified from a retrospective database. IOF rates (mL/kg/hr) were determined and their relationship to outcomes compared. To examine the impact of malnutrition, we stratified patients based on median preoperative serum albumin and compared outcomes. Results and discussion 211 patients comprised the cohort. 74% of patients underwent esophagectomy for esophageal adenocarcinoma. Linear regression analyses were performed comparing independent perioperative variables to four outcomes variables: length of stay, complications per patient, major complications, and Clavien-Dindo classification. IOF rate was significantly associated with three of four outcomes on univariate analysis. Significantly more patients with a preoperative albumin level ≤3.7 g/dL who received more than the median IOF rate experienced more severe complications. Conclusions Increased intraoperative fluid administration is associated with perioperative morbidity in patients undergoing transhiatal esophagectomy. Patients with lower preoperative albumin levels may be particularly sensitive to the effects of volume overload. [ABSTRACT FROM AUTHOR]

Background Hemorrhage is a frequent event in hospital and prehospital settings. The aim of the present study was to investigate whether centhaquin improves 24-h survival and reduces the total volume of required fluids in an established model of swine hemorrhagic shock. Material and methods Twenty-five pigs were instrumented and subjected to hemorrhagic shock. The animals were randomly allocated in two experimental groups, the control (vehicle) ( n = 10) and the centhaquin groups (0.015 mg/kg, n = 10); all animals received lactated Ringer solution in the resuscitation phase until their mean arterial pressure reached 90% of the baseline. A sham group ( n = 5) was added a posteriori to mimic the hemodynamic profile of the centhaquin group. Results A statistically significant difference was observed in the time required for the three groups to reach their target mean aortic pressure, 36.88 ± 3.26 min for the control group versus 9.40 ± 1.01 min for the sham group and 7.10 ± 0.97 min for the centhaquin group ( P < 0.001). The total amount of fluids in the control and the sham groups was significantly higher when compared with that of the centhaquin-treated animals ( P < 0.001). All 10 animals in the centhaquin group survived for 24 h, whereas only three animals survived in the control group and one animal in the sham group ( P = 0.002). Conclusions Centhaquin 0.015 mg/kg administered in the fluid resuscitation phase resulted in lower volume of fluids and better survival compared with control and sham-operated animals. [ABSTRACT FROM AUTHOR]

Genome-wide association studies with concentrations of hundreds of small molecules in samples collected from thousands of individuals (mGWAS) access otherwise inaccessible natural genetic experiments and their influence on the metabolic capacities of the human body. By sampling the natural metabolic and genetic variability that is present in the general population, mGWAS identified over 150 associations between genetic variants and variation in the metabolic composition of human body fluids. Many of these genetic variants were found to be located in enzyme or transporter coding genes, whose functions match the biochemical nature of the associated metabolites. Associations identified by mGWAS can reveal novel biochemical knowledge, such as the function of uncharacterized genes, the biochemical identity of small molecules, and the structure of entire biochemical pathways. Here we review findings of recent mGWAS and discuss concrete examples of how their results can be interpreted in a biochemical context. We describe online resources that are available for mining mGWAS results. In this context, we present two concepts that also find more general applications in the field of metabolomics: strengthening of associations by looking at ratios between metabolite pairs and reconstruction of metabolic pathways by Gaussian graphical modeling. [ABSTRACT FROM AUTHOR]

Down-regulation of immune-mediated angiogenesis seems to be an important mechanism in anti-tumor necrosis factor α (anti-TNFα) therapy for Crohn’s disease (CD). However, it remains to be established whether the baseline pro-angiogenic activity as reflected by the level of vascular endothelial growth factor (VEGF) could be of predictive value for successful clinical outcome of such treatment. Here, the levels of serum VEGF and other crucial angiogenesis-regulating peptides were assessed before and after induction anti-TNFα therapy in CD patients, and in age- and sex-matched healthy controls. Clinical, endoscopic, and biochemical activity of CD was estimated in parallel. CD patients were divided into two subgroups, depending on baseline VEGF levels: a “low-VEGF” subgroup with VEGF levels similar to those detected in healthy people, and a “high-VEGF” subgroup with VEGF levels significantly increased. VEGF levels were found to significantly correlate with CD clinical activity. Compared to the “low-VEGF” subgroup, the reduction in CD clinical activity as assessed by Crohn’s Disease Activity Index was significantly greater in “high-VEGF” patients both in absolute numbers, and as a percentage of pre-treatment values. Accordingly, the fraction of patients who did not respond adequately to treatment was significantly greater in the “low-VEGF” group. These data indicate that VEGF may serve as an additional marker of CD activity and that baseline VEGF levels can be helpful in predicting the efficacy of anti-TNFα therapy. [ABSTRACT FROM AUTHOR]

Numerous studies have indicated that microRNAs (miRNAs) are present and stable in multiple biological fluids, suggesting a great potential as biomarkers for molecular diagnostics and prognostics. Variations in the amount of starting material and isolation method to obtain miRNA may introduce bias and contribute to quantification errors. Given these concerns, we compared five commercially available kits for serum/plasma miRNA isolation to determine whether the plasma miRNA profile varies with the isolation method. We isolated miRNAs in blood plasma from colorectal cancer patients and healthy donors with five commercially available kits: Exiqon, Norgen, Macherey–Nagel, Qiagen, and Zymo Research. First, we assessed the robustness of the RNA isolation process and the quality of isolated miRNAs with the miRCURY microRNA QC PCR Panel (Exiqon), which contains six RNA spike-ins for quality control of RNA isolation (UniSp2, -4, and -5), complementary DNA (cDNA) synthesis (UniSp6 and cel-miR-39-3p), and polymerase chain reaction (PCR) amplification (UniSp3). This panel also includes circulating human miR-103, miR-191, miR-23a, and miR-451. Second, to evaluate the variability in miRNA profiling in relation to the extraction method, we analyzed plasma levels of candidate miRNA biomarkers for colorectal cancer (miR-18a, miR-21, and miR-29a). To determine PCR efficiencies per amplicon and per sample, we used LinRegPCR software. We found that all isolation methods were suitable for extracting miRNA from plasma samples and that all had similar C q values in the three steps analyzed: RNA isolation, cDNA synthesis, and quantitative reverse transcription (qRT)–PCR. However, although the PCR replicates were excellent, the intersample variability of the spike-ins was unsatisfactorily high and all kits yielded suboptimal PCR efficiencies for some amplicons. Overall, our results underline the great difficulties involved in measuring miRNAs in plasma. The use of spike-ins is critical to control technical factors that affect final miRNA levels. We recommend that researchers investigating circulating miRNAs verify the PCR efficiency for each amplicon because quantification may be influenced by sample and PCR components. [ABSTRACT FROM AUTHOR]

During the epileptogenic process, several events may occur, such as an important activation of the immune system in the central nervous system. The response to seizure activity results in an inflammation in the brain as well as in the periphery. Moreover, CRP and cytokines may be able to interact with numerous ligands in response to cardiac injury caused by sympathetic stimulation in ictal and postictal states. Based on this, we measured the serum levels of C-reactive protein (CRP) and cytokines during acute, silent, and chronic phases of rats submitted to the pilocarpine model of epilepsy. We have also analyzed the effect of a chronic treatment of these rats with omega-3 fatty acid in CRP and cytokine levels, during an epileptic focus generation. C-reactive protein and cytokines such as IL-1β, IL-6, and TNF-α presented high concentration in the blood of rats, even well after the occurrence of SE. We found reduced levels of CRP and all proinflammatory cytokines in the blood of animals with chronic seizures, treated with omega-3, when compared with those treated with vehicle solution. Taken together, our results strongly suggest that the omega-3 is an effective treatment to prevent SUDEP occurrence due to its capability to act as an anti-inflammatory compound, reducing the systemic inflammatory parameters altered by seizures. [ABSTRACT FROM AUTHOR]

Tau protein is a phosphorylated microtubule-associated protein, principally localized at neuronal level in the central nervous system (CNS). Tau levels in the cerebrospinal fluid (CSF) are considered to index both axonal and neuronal damage. To date, however, no study has specifically evaluated the CSF levels of tau proteins in patients with status epilepticus (SE). We evaluated these established biomarkers of neuronal damage in patients with SE who received a lumbar puncture during SE between 2007 and 2014. Status epilepticus cases due to acute structural brain damage, including CNS infection, were excluded. Clinical, biological, therapeutic, and follow-up data were collected. Group comparison between patients stratified according to SE response to antiepileptic drugs (AEDs), disability, and epilepsy outcomes were performed. Twenty-eight patients were considered for the analyses (mean age 56 years): 14 patients had abnormally high CSF t-tau level, six patients had abnormally high CSF p-tau level, and only three patients had abnormally low Aβ 1–42 level. Cerebrospinal fluid t-tau value was higher in patients who developed a refractory SE compared to patients with seizures controlled by AED. Cerebrospinal fluid t-tau values were positively correlated with SE duration and were higher in patients treated with propofol anesthesia compared to patients that had not received this treatment. Patients with higher CSF t-tau had higher risk of developing disability (OR = 32.5, p = 0.004) and chronic epilepsy (OR = 12; p = 0.016) in comparison with patients with lower CSF t-tau level. Our results suggest that CSF t-tau level might be proposed as a biomarker of SE severity and prognosis. Prospective studies are needed to evaluate the effects of propofol on tau pathology in this setting. This article is part of a Special Issue entitled “Status Epilepticus” . [ABSTRACT FROM AUTHOR]

The lung must maintain a proper barrier between airspaces and fluid filled tissues in order to maintain lung fluid balance. Central to maintaining lung fluid balance are epithelial cells which create a barrier to water and solutes. The barrier function of these cells is mainly provided by tight junction proteins known as claudins. Epithelial barrier function varies depending on the different needs within the segments of the respiratory tree. In the lower airways, fluid is required to maintain mucociliary clearance, whereas in the terminal alveolar airspaces a thin layer of surfactant enriched fluid lowers surface tension to prevent airspace collapse and is critical for gas exchange. As the epithelial cells within the segments of the respiratory tree differ, the composition of claudins found in these epithelial cells is also different. Among these differences is claudin-18 which is uniquely expressed by the alveolar epithelial cells. Other claudins, notably claudin-4 and claudin-7, are more ubiquitously expressed throughout the respiratory epithelium. Claudin-5 is expressed by both pulmonary epithelial and endothelial cells. Based on in vitro and in vivo model systems and histologic analysis of lungs from human patients, roles for specific claudins in maintaining barrier function and protecting the lung from the effects of acute injury and disease are being identified. One surprising finding is that claudin-18 and claudin-4 control lung cell phenotype and inflammation beyond simply maintaining a selective paracellular permeability barrier. This suggests claudins have more nuanced roles for the control of airway and alveolar physiology in the healthy and diseased lung. [ABSTRACT FROM AUTHOR]

Urinary levels of human serum albumin (hSA) fragment 408–423 have been proposed to represent an early marker for graft-versus-host disease (GvHD) and chronic kidney diseases. Here, we developed an enzyme-linked immunosorbent assay (ELISA) for the quantification of hSA(408–423). The sandwich ELISA has a detection limit of 0.5 ng/ml and is highly specific for hSA(408–423) because it does not cross-react with other albumin fragments or the full-length precursor. This ELISA allows rapid and convenient quantification of hSA(408–423) in bodily fluids, further clarifying the prognostic and diagnostic value of this peptide in GvHD, kidney disease, and other disorders. [ABSTRACT FROM AUTHOR]