Resetting thermal limits: 10-year-old white sturgeon display pronounced but reversible thermal plasticity.

While many ectotherms improve thermal tolerance in response to prolonged thermal stress, little is known about the lasting effects of warm acclimation after returning to cooler temperatures. Furthermore, thermal stress may disproportionately impact threatened and endangered species. To address this, we repeatedly measured critical thermal maxima (CTmax; °C) and associated stress responses (hematocrit, hemoglobin concentration, plasma cortisol) of endangered subadult white sturgeon (Acipenser transmontanus) in response to control temperature (pre-acclimation; 14°C), after 1 month at either control or warm temperature (acclimation; 14°C or 20°C), and after one smonth following return to control temperature (post-acclimation; 14°C). While control fish demonstrated fairly repeatable thermal tolerance (interclass correlation coefficient = 0.479), warm-acclimated fish experienced a ∼3.1°C increase in thermal tolerance and when re-acclimated to control temperature, decreased thermal tolerance ∼1.9°C. Hematocrit, hemoglobin concentration, and final splenic somatic index (spleen mass relative to whole body mass, collected after post-acclimation CTmax) were not significantly different between control and treatment fish, suggesting no effects of warm acclimation on aerobic capacity. Plasma cortisol was significantly higher in control fish after pre-acclimation and post-acclimation CTmax trials, but importantly, acclimation temperature did not affect this response. Strikingly, final hepatosomatic index (relative liver size) was 45% lower in treatment fish, indicating warm acclimation may have lasting effects on energy usage and metabolism, even after reacclimating to control temperature. To our knowledge, these 10-year-old subadult sturgeon are the oldest sturgeon experimentally tested with regards to thermal plasticity and demonstrate incredible capacity for thermal acclimation relative to other fishes. However, more research is needed to determine whether the ability to acclimate to warm temperature may come with a persistent cost.

Pregnancy outcomes for women with myasthenia gravis and their newborns: A nationwide register-based cohort study.

BACKGROUND AND PURPOSE: Few large-scale studies examine whether maternal myasthenia gravis (MG) is a risk factor for complications during pregnancy and childbirth. This study evaluated whether maternal MG is associated with an increased risk of adverse pregnancy, delivery, and neonatal outcomes. METHODS: We conducted a nationwide Swedish register-based cohort study of women who gave birth to singleton infants (≥22 gestational weeks) during 1987-2019. Exposed women were diagnosed with MG before or during the index pregnancy (N = 443). Unexposed women comprised 4249 women without a diagnosis of MG, matched for age, parity, hospital, and year of childbirth. The risks of adverse pregnancy, delivery, and neonatal outcomes for women with MG were estimated using regression modeling and presented as adjusted odds ratios (aOR). RESULTS: There was no increased risk of pregnancy complications in women with MG. Women with MG had a spontaneous onset of labor less often than women without MG (69.8% vs. 79.5%; aOR 0.59; p < 0.001) as well as higher labor induction rates and elective cesarean section deliveries (16.0% vs. 12.3%, aOR 1.42; p = 0.02 and 12.0% vs. 8.1%, aOR 1.59; p = 0.009). Infants of women with MG were born on average 2 days earlier (p = 0.002); however, these infants did not have a higher risk of having low APGAR, being small for gestational age, or having a congenital malformation. CONCLUSION: This first nationwide study of pregnancy in women with MG in Sweden demonstrates reassuring results overall, suggesting generally safe pregnancy outcomes for women with MG and their infants.

Characterization of the real-time internalization of nine GPCRs reveals distinct dependence on arrestins and G proteins.

G protein-coupled receptors (GPCRs) are seven transmembrane receptors that respond to external stimuli and undergo conformational changes to activate G proteins and modulate cellular processes leading to biological outcomes. To prevent overstimulation and prolonged exposure to stimuli, GPCRs are regulated by internalization. While the canonical GPCR internalization mechanism in mammalian cells is arrestin-dependent, clathrin-mediated endocytosis, more diverse GPCR internalization mechanisms have been described over the years. However, there is a lack of consistent methods used in the literature making it complicated to determine a receptor's internalization pathway. Here, we utilized a highly efficient time-resolved Förster resonance energy transfer (TR-FRET) internalization assay to determine the internalization profile of nine distinct GPCRs representing the GPCR classes A, B and C and with different G protein coupling profiles. This technique, coupled with clustered regularly interspaced palindromic repeats (CRISPR) engineered knockout cells allows us to effectively study the involvement of heterotrimeric G proteins and non-visual arrestins. We found that all the nine receptors internalized upon agonist stimulation in a concentration-dependent manner and six receptors showed basal internalization. Yet, there is no correlation between the receptor class and primary G protein coupling to the arrestin and G protein dependence for GPCR internalization. Overall, this study presents a platform for studying internalization that is applicable to most GPCRs and may even be extended to other membrane proteins. This method can be easily applicable to other endocytic machinery of interest and ultimately will lend itself towards the construction of comprehensive receptor internalization profiles.

Evaporation of serum after long-term biobank storage: A chemical analysis of maternal serum from a large Danish pregnancy screening registry.

BACKGROUND: Relying on freezer stored biospecimens is preferred in epidemiolocal studies exploring environmental pregnancy exposures and later offspring health. Storage duration may increase the pre-analytical variability, potentially adding measurement uncertainty. We investigated evaporation of maternal serum after long-term biobank storage using ions (sodium, Na+; chloride, Cl-) recognized for stability and relatively narrow normal biological reference ranges in human serum. METHODS: A chemical analysis study of 275 biobanked second trimester maternal serum from a large Danish pregnancy screening registry. Serum samples were collected between 1985-1995 and stored at -20°C. Ion concentrations were quantified with indirect potentiometry using a Roche Cobas 6000 analyzer and compared according to storage time and normal biological ranges in second trimester. Ion concentrations were also compared with normal biological variation assessed by baseline Na+ and Cl- serum concentrations from a separate cohort of 24,199 non-pregnant women measured before freezing with the same instrument. RESULTS: The overall mean ion concentrations in biobanked serum were 147.5 mmol/L for Na+ and 109.7 for Cl-. No marked linear storage effects were observed according to storage time. Ion concentrations were consistently high across sampling years, especially for specific sampling years, and a relatively large proportion were outside respective normal ranges in second trimester: 38.9% for Na+ and 43.6% for Cl-. Some variation in concentrations was also evident in baseline serum used as quality controls. CONCLUSIONS: Elevated ion concentrations suggest evaporation, but independent of storage duration in the present study (27-37 years). Any evaporation may have occurred prior to freezer storage or during the first 27 years. Other pre-analytical factors such as low serum volume have likely influenced the concentrations, particularly given the high within year variability. Overall, we consider the biobanked serum samples internally comparable to enable their use in epidemiological studies.

External validation of GO-FAR 2 calculator for outcomes after in-hospital cardiac arrest with comparison to GO-FAR and trial of expanded applications.

Aim: Externally validate the GO-FAR 2 tool for predicting survival with good neurologic function after in-hospital cardiac arrest with comparison to the original GO-FAR tool. Additionally, we collected qualitative descriptors and performed exploratory analyses with various levels of neurologic function and discharge destination. Methods: Retrospective chart review of all patients who underwent in-hospital resuscitation after cardiac arrest during the calendar years 2016-2019 in our institution (n = 397). GO-FAR and GO-FAR 2 scores were calculated based on information available in the medical record at the time of hospital admission. Cerebral performance category (CPC) scores at the time of admission and discharge were assessed by chart review. Results: The GO-FAR 2 score accurately predicted outcomes in our study population with a c-statistic of 0.625. The original GO-FAR score also had accurate calibration with a stronger c-statistic of 0.726. The GO-FAR score had decreased predictive value for lesser levels of neurologic function (c-statistic 0.56 for alive at discharge) and discharge destination (0.69). Descriptors of functional status by CPC score were collected. Conclusion: Our findings support the validity of the GO-FAR and GO-FAR 2 tools as published, but the c-statistics suggest modest predictive discrimination. We include functional descriptors of CPC outcomes to aid clinicians in using these tools. We propose that information about expected outcomes could be valuable in shared decision-making conversations.

Skin infiltrating NK cells in cutaneous T-cell lymphoma are increased in number and display phenotypic alterations partially driven by the tumor.

Cutaneous T-cell lymphomas (CTCL) are characterized by focal infiltration of malignant T cell clones in solitary skin lesions. Many CTCL patients experience an indolent disease, but some progress to advanced disease with high fatality. We hypothesized that natural killer (NK) cells participate in local control of tumor growth in CTCL skin. Immunohistochemistry and flow cytometry analysis of the density, localization, phenotype and function of NK cells in twenty-nine fresh or formalin-fixed skin biopsies from twenty-four CTCL patients and twenty-three biopsies from twenty healthy controls highlighted higher numbers of CD56+CD3- NK cells in CTCL skin. A reduced fraction of CTCL skin NK cells expressed the maturation marker CD57, the cytotoxic protein granzyme B and the activation marker CD69, indicating reduced tumor-killing abilities of the NK cells. Retained expression of immune checkpoint proteins or inhibitory proteins including PD1, TIM3, LAG3, CD73 and NKG2A and the activating receptors CD16 and NKp46 indicated maintained effector functions. Indeed, the capacity of NK cells to produce anti-tumor acting IFNγ upon PMA+ionomycin stimulation was similar in cells from CTCL and healthy skin. Co-cultures of primary human NK cells or the NK cell line NKL with CTCL cells resulted in reduced levels of granzyme B and CD69, indicating that close cellular interactions with CTCL cells induced the impaired functional NK cell phenotype. In conclusion, increased numbers of NK cells in CTCL skin exhibit a partially impaired phenotype in terms of activity. Enhancing NK cell activity with NK cell activating cytokines such as IL-15 or immune checkpoint blockade therefore represents a potential immunotherapeutic approach in CTCL.

Hydrothermal impacts of water release on early life stages of white sturgeon in the Nechako river, B.C. Canada.

Water temperature plays a crucial role in the physiology of aquatic species, particularly in their survival and development. Thus, resource programs are commonly used to manage water quality conditions for endemic species. In a river system like the Nechako River system, central British Columbia, a water management program was established in the 1980s to alter water release in the summer months to prevent water temperatures from exceeding a 20 °C threshold downstream during the spawning season of Sockeye salmon (Oncorhynchus nerka). Such a management regime could have consequences for other resident species like the white sturgeon (Acipenser transmontanus). Here, we use a hydrothermal model and white sturgeon life stage-specific experimental thermal tolerance data to evaluate water releases and potential hydrothermal impacts based on the Nechako water management plan (1980-2019). Our analysis focused mainly on the warmest five-month period of the year (May to September), which includes the water release management period (July-August). Our results show that the thermal exposure risk, an index that measures temperature impact on species physiology of Nechako white sturgeon across all early life stages (embryo, yolk-sac larvae, larvae, and juvenile) has increased substantially, especially in the 2010s relative to the management program implementations' first decade (the 1980s). The embryonic life stage was the most impacted, with a continuous increase in potential adverse thermal exposure in all months examined in the study. We also recorded major impacts of increased thermal exposure on the critical habitats necessary for Nechako white sturgeon recovery. Our study highlights the importance of a holistic management program with consideration for all species of the Nechako River system and the merit of possibly reviewing the current management plan, particularly with the current concerns about climate change impacts on the Nechako River.

Clinical outcomes and cost of open, laparoscopic, and percutaneous ablation for hepatocellular carcinoma.

BACKGROUND: Open (OA), laparoscopic (LA), and percutaneous (PA) ablation are all ablation approaches for hepatocellular carcinoma (HCC) utilized in the United States today. However, it remains unclear today which approach is (A) most effective, (B) cost-efficient, and (C) nationally practiced. METHODS: In-hospital mortality and cost were collected from the National Inpatient Sample (NIS) database for patients undergoing liver ablation from 2011 to 2018. Secondary outcomes included length of stay, disposition, and perioperative composite complications. We used inverse probability of treatment weighting (IPTW) to adjust for differences in patient and hospital baseline characteristics. RESULTS: One thousand and one hundred and twenty-five LA, 1221 OA, and 1068 PA liver ablations were analyzed. After IPTW, in-hospital mortality risk was significantly lower in PA versus OA cohorts (0.57% vs. 2.90%, p < 0.001) and reduced among PA patients, yet not significantly different from the LA cohort (0.57% vs. 1.64%, p = 0.056). The median length of hospital stay was significantly lower in the PA and LA group compared to OA (2 days vs. 6 days, p < 0.001). The median hospitalization costs were significantly lower for PA ($44,884 vs. $90,187, p < 0.001) and LA ($61,445 vs. $90,187, p < 0.001) compared to OA. Moreover, we found significant regional differences regarding the use of each ablation approach, with the Midwest having the lowest rates of PA and LA. CONCLUSIONS: Among patients hospitalized after ablation for HCC, PA leads to the lowest hospital cost. Both PA and LA result in lower peri-operative morbidity and mortality relative to OA. Despite these reported advantages, there are significant regional differences with respect to ablation availability suggesting the need to promote the standardization of best practices.

Prediction of herpes virus infections after solid organ transplantation: a prospective study of immune function.

Introduction: Herpes virus infections are a major concern after solid organ transplantation and linked to the immune function of the recipient. We aimed to determine the incidence of positive herpes virus (cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus type 1/2 (HSV-1/2), and varicella zoster virus (VZV)) PCR tests during the first year post-transplantation and assess whether a model including immune function pre-transplantation and three months post-transplantation could predict a subsequent positive herpes virus PCR. Methods: All participants were preemptively screened for CMV, and EBV IgG-negative participants were screened for EBV during the first year post-transplantation. Herpes virus PCR tests for all included herpes viruses (CMV, EBV, HSV-1/2, and VZV) were retrieved from the Danish Microbiology database containing nationwide PCR results from both hospitals and outpatient clinics. Immune function was assessed by whole blood stimulation with A) LPS, B) R848, C) Poly I:C, and D) a blank control. Cytokine concentrations (TNF-α, IL-1ß, IL-6, IL-8, IL-10, IL-12p40, IL-17A, IFN-α, and IFN-γ) were measured using Luminex. Results: We included 123 liver (54%), kidney (26%), and lung (20%) transplant recipients. The cumulative incidence of positive herpes virus PCR tests was 36.6% (95% CI: 28.1-45.1) during the first year post-transplantation. The final prediction model included recipient age, type of transplantation, CMV serostatus, and change in Poly I:C-induced IL-12p40 from pre-transplantation to three months post-transplantation. The prediction model had an AUC of 77% (95% CI: 61-92). Risk scores were extracted from the prediction model, and the participants were divided into three risk groups. Participants with a risk score <5 (28% of the cohort), 5-10 (45% of the cohort), and >10 (27% of the cohort) had a cumulative incidence of having a positive herpes virus PCR test at 5.8%, 25%, and 73%, respectively (p < 0.001). Conclusion: In conclusion, the incidence of positive herpes virus PCR tests was high, and a risk model including immune function allowed the prediction of positive herpes virus PCR and may be used to identify recipients at higher risk.

Slow heating rates increase thermal tolerance and alter mRNA HSP expression in juvenile white sturgeon (Acipenser transmontanus).

Freshwater fish such as white sturgeon (Acipenser transmontanus) are particularly vulnerable to the effects of anthropogenically induced global warming. Critical thermal maximum tests (CTmax) are often conducted to provide insight into the impacts of changing temperatures; however, little is known about how the rate of temperature increase in these assays affects thermal tolerance. To assess the effect of heating rate (0.3 °C/min, 0.03 °C/min, 0.003 °C/min) we measured thermal tolerance, somatic indices, and gill Hsp mRNA expression. Contrary to what has been observed in most other fish species, white sturgeon thermal tolerance was highest at the slowest heating rate of 0.003 °C/min (34.2 °C, and CTmax of 31.3 and 29.2 °C, for rates 0.03 and 0.3 °C/min, respectively) suggesting an ability to rapidly acclimate to slowly increasing temperatures. Hepatosomatic index decreased in all heating rates relative to control fish, indicative of the metabolic costs of thermal stress. At the transcriptional level, slower heating rates resulted in higher gill mRNA expression of Hsp90a, Hsp90b, and Hsp70. Hsp70 mRNA expression was increased in all heating rates relative to controls, whereas expression of Hsp90a and Hsp90b mRNA only increased in the two slower trials. Together these data indicate that white sturgeon have a very plastic thermal response, which is likely energetically costly to induce. Acute temperature changes may be more detrimental to sturgeon as they struggle to acclimate to rapid changes in their environment, however under slower warming rates they demonstrate strong thermal plasticity to warming.

Identification of upper thermal thresholds during development in the endangered Nechako white sturgeon with management implications for a regulated river.

Climate change-induced warming effects are already evident in river ecosystems, and projected increases in temperature will continue to amplify stress on fish communities. In addition, many rivers globally are impacted by dams, which have many negative effects on fishes by altering flow, blocking fish passage, and changing sediment composition. However, in some systems, dams present an opportunity to manage river temperature through regulated releases of cooler water. For example, there is a government mandate for Kenney dam operators in the Nechako river, British Columbia, Canada, to maintain river temperature <20°C in July and August to protect migrating sockeye salmon (Oncorhynchus nerka). However, there is another endangered fish species inhabiting the same river, Nechako white sturgeon (Acipenser transmontanus), and it is unclear if these current temperature regulations, or timing of the regulations, are suitable for spawning and developing sturgeon. In this study, we aimed to identify upper thermal thresholds in white sturgeon embryos and larvae to investigate if exposure to current river temperatures are playing a role in recruitment failure. We incubated embryos and yolk-sac larvae in three environmentally relevant temperatures (14, 18 and 21°C) throughout development to identify thermal thresholds across different levels of biological organization. Our results demonstrate upper thermal thresholds at 21°C across physiological measurements in embryo and yolk-sac larvae white sturgeon. Before hatch, both embryo survival and metabolic rate were reduced at 21°C. After hatch, sublethal consequences continued at 21°C because larval sturgeon had decreased thermal plasticity and a dampened transcriptional response during development. In recent years, the Nechako river has reached 21°C by the end of June, and at this temperature, a decrease in sturgeon performance is evident in most of the traits measured. As such, the thermal thresholds identified here suggest current temperature regulations may not be suitable for developing white sturgeon and future recruitment.

Endocytic proteins mediating GPR15 receptor internalization provide insight into the underlying mechanisms.

GPR15 is a G protein-coupled receptor involved in immune disorders such as human immunodeficiency virus-induced enteropathy, multiple sclerosis, and colitis. Yet, the important endocytosis mechanism of GPR15 remained unclear. This study determined the participation of endocytic machinery proteins, including Gα proteins, G protein-coupled receptor kinases (GRKs), protein kinase C, arrestins, clathrin, caveolin, and dynamin in GPR15 internalization. The results demonstrate that GPR15 internalization is moderately dependent on GRKs and clathrin, and highly dependent on caveolin and dynamin. Moreover, a bystander arrestin recruitment assay showed that GPR15 recruits arrestin-3 to the cell membrane upon agonist stimulation, although GPR15 internalizes in an arrestin-independent manner. Overall, our study provides novel insights into ß-arrestin recruitment and receptor internalization mechanisms for the recently deorphanized GPR15.

Structure-activity relationship of GPR15L peptide analogues and investigation of their interaction with the GPR15 receptor.

The 57-mer full-length GPR15L(25-81) peptide has been identified as the principal endogenous agonist of the G protein-coupled receptor GPR15. Its main activity resides in the C-terminal 11-mer GPR15L(71-81), which has full efficacy but ~40-fold lower potency than the full-length peptide. Here, we systematically investigated the structure-activity relationship of GPR15L(71-81) by truncations/extensions, alanine-scanning, and N- and C-terminal capping. The synthesized peptide analogues were tested at GPR15 stably expressed in HEK293A cells using a homogenous time-resolved Förster resonance energy transfer-based Gi cAMP functional assay. We show that the C-terminal α carboxyl group and the residues Leu78 , Pro75 , Val74 , and Trp72 are critical for receptor interaction and contribute significantly to the peptide potency. Furthermore, we tested the ability of GPR15L(71-81), C-terminally amidated GPR15L(71-81), and GPR15L(25-81) to activate the three GPR15 receptor mutants in a bioluminescence resonance energy transfer-based G protein activation assay. The results demonstrate that the Lys192 and Glu272 residues in GPR15 are important for the potency of the GPR15L peptide. Overall, our study identifies critical residues in the peptide and receptor sequences for future drug design.

Identification of proteinase 3 autoreactive CD4+T cells and their T-cell receptor repertoires in antineutrophil cytoplasmic antibody-associated vasculitis.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune disease involving autoreactivity to proteinase 3 (PR3) as demonstrated by presence of ANCAs. While autoantibodies are screened for diagnosis, autoreactive T cells and their features are less well-studied. Here, we investigated PR3-specific CD4+T cell responses and features of autoreactive T cells in patients with PR3-AAV, using a cohort of 72 patients with either active or inactive disease. Autoreactive PR3-specific CD4+T cells producing interferon γ in response to protein stimulation were found to express the G-protein coupled receptor 56 (GPR56), a cell surface marker that distinguishes T cells with cytotoxic capacity. GPR56+CD4+T cells were significantly more prominent in the blood of patients with inactive as compared to active disease, suggesting that these cells were affected by immunosuppression and/or that they migrated from the circulation to sites of organ involvement. Indeed, GPR56+CD4+T cells were identified in T-cell infiltrates of affected kidneys and an association with immunosuppressive therapy was found. Moreover, distinct TCR gene segment usage and shared (public) T cell clones were found for the PR3-reactive TCRs. Shared T cell clones were found in different patients with AAV carrying the disease-associated HLA-DP allele, demonstrating convergence of the autoreactive T cell repertoire. Thus, we identified a CD4+T cell signature in blood and in affected kidneys that display PR3 autoreactivity and associates with T cell cytotoxicity. Our data provide a basis for novel rationales for both immune monitoring and future therapeutic intervention in PR3-AAV.

Microscopic alterations in Fasciola hepatica treated with the essential oils of Pelargonium graveolens and Citrus aurantium.

Fasciolosis is one of the most important parasitic diseases in animal health, affecting mainly ruminants, causing economic and productivity losses. This study aimed to evaluate the in vitro ovicidal and adulticidal activity of essential oils (EOs) from Pelargonium graveolens (geranium) and Citrus aurantium (sour orange) on Fasciola hepatica. Performed Gas Chromatography of EOs P. graveolens and C. aurantium, with major compound, citronellol (31.37 %) and limonene (93.89 %), respectively. For the cytotoxicity assay, the sour orange EO showed to be promising when used in lower concentrations. For the ovicidal tests, the eggs were incubated with geranium EOs at concentrations from 4.5 to 0.03375 mg/mL and sour orange at concentrations from 4.25 to 0.031875 mg/mL, along with controls. The viable eggs were counted on the 14th day post-incubation. Adult forms of F. hepatica were incubated containing the EOs and observed for 24 h after treatment, as well as the control groups. Later the specimens were fixed for histological analysis. Geranium and sour orange EOs in trematode eggs at the concentrations tested were 100 % effective in inactivating hatching (p < 0.05) when compared to the untreated control. In the adulticidal test, the essential oil of P. graveolens at both concentrations tested (0.0675 and 0.03375) within 15 h, promoted the death of flukes. For C. aurantium, 18 h was enough to inactivate all specimens, up to a concentration of 0.06375. The histological analysis, observed the accumulation of liquid in the tegument in the specimens incubated in C. aurantium and P. graveolens, with vacuolization in the tegument and spines, preventing externalization. The results of the study present OEs with efficient ovicidal and adulticidal activity.

Despite Good Correlations, There Is No Exact Coincidence between Isometric and Dynamic Strength Measurements in Elite Youth Soccer Players.

Speed strength performances are substantially dependent on maximum strength. Due to their importance, various methods have been utilized to measure maximum strength (e.g., isometric or dynamic) with discussed differences regarding transferability to sport-specific movements dependent upon the testing procedure. The aim of this study was to analyze whether maximum isometric force (MIF) during isometric back squats correlates with maximum strength measurements of the one repetition maximum (1RM) in the squat, with countermovement jump (CMJ) performance, and with drop jump (DJ) performances in elite youth soccer players (n = 16, 18.4 ± 1.5 [range: 17-23] years old). Additionally, concordance correlation coefficients (CCC, [ρc]) between isometric and dynamic measurements were calculated to verify whether one measurement can actually reproduce the results of the other. To improve comprehension, differences between isometric and dynamic testing values were illustrated by providing differences between both testing conditions. For this, the mean absolute error (MAE) and the mean absolute percentage error (MAPE) were calculated. To reach equality in scale, the 1RM measures were multiplicated by 9.81 to obtain a value of N. The 1RM demonstrated correlations of τ = |0.38| to |0.52| with SJ and CMJ performances, while MIF demonstrated correlations of τ = |0.21| to |0.32|. However, the correlations of both 1RM and MIF with the DJ reactive strength index (RSI = jump height /contact time) from different falling heights were of no statistical significance. The data showed significant correlations between both the absolute (τ = |0.54|) and the relative (τ = |0.40|) performances of 1RM and MIF, which were confirmed by CCC of ρc= |0.56| to |0.66|, respectively. Furthermore, the MAE and MAPE showed values of 2080.87 N and 67.4%, respectively. The data in this study show that, despite good correlations, there is no exact coincidence between isometric and dynamic strength measurements. Accordingly, both measurements may only represent an estimation of maximal strength capacity and cannot be substituted for each other. Therefore, maximal strength should be tested by using high similarity in the contraction condition, as it is used in the training process to counteract underestimation in strength because of unfamiliarity with the testing condition.

A Manufacturing Process Simulation of Toughened Cyanate-Ester-Based Composite Structures with Respect to Stress Relaxation.

The objectives of this study were to experimentally determine the effects of the stress relaxation of a cyanate-ester-based composite, derive and integrate constitutive equations into commercial FEM software, and apply this approach to understand the formation of residual stress in a typical aerospace structure-namely, a stiffened panel. In preliminary studies, a cyanate-ester-based composite with increased fracture toughness for high-temperature applications was developed. High curing temperatures up to 260 °C will inevitably lead to high process-induced stresses. To assess the magnitude of impact on the development of internal stresses, the relaxation behavior of the neat resin was measured and characterized. The system was toughened, and the effect of stress relaxation increased as the temperature got closer to the glass transition temperature of the toughener, which was approximately 240 °C. With the use of an incremental linear viscoelastic model, the relaxation behavior was integrated into a process model with a holistic approach. A stiffened panel was manufactured and used as the validation use case. The displacement field was validated with an optical 3D measuring system, and good agreement was found between the simulated and experimental results. The maximum difference between the elastic and the viscoelastic solution was found to be 15%. Furthermore, the stress magnitude in the transverse material direction resulted in a more critical value higher than the material strength.

Incremental Numerical Approach for Modeling the Macroscopic Viscoelastic Behavior of Fiber-Reinforced Composites Using a Representative Volume Element.

The objective of this study is to describe the stress relaxation behavior of an epoxy-based fiber-reinforced material. An existing incremental formulation of an orthotropic linear viscoelastic material behavior was adapted to Voigt notation and to the special case of an isotropic material. Virtual relaxation tests on a representative volume element were performed, and the behavior of individual components of the relaxation tensor of the transversely isotropic composite material was determined. The study demonstrated that in the case of only one viscoelastic material, each component of the relaxation tensor can be described in terms of a scalar form factor and the behavior of the neat resin. The developed method was implemented in an incremental finite element model (FEM) analysis to calculate the stress relaxation on the macroscopic ply level. A validation of the approach has shown a promising agreement up to a limit below the glass transition temperature of 15 °C in longitudinal and 35 °C in transverse direction. This study therefore demonstrates a novel way to incrementally describe the macroscopic viscoelastic behavior of materials with a single viscoelastic component with good controllability for engineering purposes.

Multi-Omic analyses characterize the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer's disease.

Dysregulation of sphingomyelin and ceramide metabolism have been implicated in Alzheimer's disease. Genome-wide and transcriptome-wide association studies have identified various genes and genetic variants in lipid metabolism that are associated with Alzheimer's disease. However, the molecular mechanisms of sphingomyelin and ceramide disruption remain to be determined. We focus on the sphingolipid pathway and carry out multi-omics analyses to identify central and peripheral metabolic changes in Alzheimer's patients, correlating them to imaging features. Our multi-omics approach is based on (a) 2114 human post-mortem brain transcriptomics to identify differentially expressed genes; (b) in silico metabolic flux analysis on context-specific metabolic networks identified differential reaction fluxes; (c) multimodal neuroimaging analysis on 1576 participants to associate genetic variants in sphingomyelin pathway with Alzheimer's disease pathogenesis; (d) plasma metabolomic and lipidomic analysis to identify associations of lipid species with dysregulation in Alzheimer's; and (e) metabolite genome-wide association studies to define receptors within the pathway as a potential drug target. We validate our hypothesis in amyloidogenic APP/PS1 mice and show prolonged exposure to fingolimod alleviated synaptic plasticity and cognitive impairment in mice. Our integrative multi-omics approach identifies potential targets in the sphingomyelin pathway and suggests modulators of S1P metabolism as possible candidates for Alzheimer's disease treatment.

Temperature independence of haemoglobin-oxygen affinity in smalleye Pacific opah (Lampris incognitus) and swordfish (Xiphias gladius).

Smalleye Pacific opah and swordfish can conserve metabolic heat and maintain specific body regions warmer than ambient water temperature (i.e. regional heterothermy). Consequently, blood O2 uptake at the gills occurs at the environmental temperature at which the individual is found, but O2 offloading will occur at different temperatures in different tissues. While several regionally heterothermic fishes (e.g. billfishes, tunas and sharks) show a reduced temperature effect on haemoglobin (Hb)-O2 affinity, the temperature dependence of Hb-O2 affinity in opah and swordfish is unknown. We hypothesized that the Hb of opah and swordfish would also show a reduced temperature dependence. Opah whole-blood-O2 affinity exhibited a reverse temperature dependence above 50% Hb-O2 saturation (10-20°C, pH 7.2-8.0), while the temperature dependence of swordfish blood-O2 affinity (10-25°C) was saturation and pH dependent, becoming temperature independent below 50% Hb-O2 saturation and pH 7.4. Experiments on stripped haemolysates showed that adding ATP ([ATP]/[Hb]=30) decreased the temperature sensitivity of Hb-O2 affinity, changing the overall oxygenation enthalpy (ΔH') values of opah (10-20°C) and swordfish (10-25°C) Hbs at pH 7.4 from -15 and -42 kJ mol-1 O2, respectively, to +84 and -9 kJ mol-1 O2. Swordfish blood-O2 affinity was high compared with that of other large, pelagic, marine teleosts, which may be the result of unusually low ATP/Hb levels, but might also enable swordfish to forage in the potentially low-oxygenated water of the upper reaches of the oxygen minimum layer. The existence of Hbs with reduced temperature sensitivity in regionally heterothermic fishes may prevent marked changes in Hb-O2 affinity between the cold and warm tissues.