HuR-Targeted Inhibition Impairs Th2 Proinflammatory Responses in Asthmatic CD4+ T Cells.

RNA-binding protein HuR (ELAVL1) is a master regulator of gene expression in human pathophysiology. Its dysregulation plays an important role in many diseases. We hypothesized that HuR plays an important role in Th2 inflammation in asthma in both mouse and human. To address this, we used a model of airway inflammation in a T cell-specific knockout mouse model, distal lck-Cre HuRfl/fl, as well as small molecule inhibitors in human peripheral blood-derived CD4+ T cells. Peripheral CD4+ T cells were isolated from 26 healthy control subjects and 45 asthmatics (36 type 2 high and 9 non-type 2 high, determined by blood eosinophil levels and fraction of exhaled NO). Our mouse data showed conditional ablation of HuR in T cell-abrogated Th2 differentiation, cytokine production, and lung inflammation. Studies using human T cells showed that HuR protein levels in CD4+ T cells were significantly higher in asthmatics compared with healthy control subjects. The expression and secretion of Th2 cytokines were significantly higher in asthmatics compared with control subjects. AMP-activated protein kinase activator treatment reduced the expression of several cytokines in both type 2 high and non-type 2 high asthma groups. However, the effects of CMLD-2 (a HuR-specific inhibitor) were more specific to endotype-defining cytokines in type 2 high asthmatics. Taken together, these data suggest that HuR plays a permissive role in both allergen and non-allergen-driven airway inflammation by regulating key genes, and that interfering with its function may be a novel method of asthma treatment.

Procalcitonin and High APACHE (Acute Physiological and Chronic Health Evaluation) Level Are Associated with the Course of Acute Kidney Injury in Patients with SARS-CoV-2.

Background: Acute kidney injury (AKI) is associated with poor outcomes in patients infected with SARS-CoV-2. Sepsis, direct injury to kidney cells by the virus, and severe systemic inflammation are mechanisms implicated in its development. We investigated the association between inflammatory markers (C-reactive protein, procalcitonin, D-dimer, lactate dehydrogenase, and ferritin) in patients infected with SARS-CoV-2 and the development of AKI. Methods: A prospective cohort study performed at the Civil Hospital (Dr. Juan I. Menchaca) Guadalajara, Mexico, included patients aged >18 years with a diagnosis of SARS-CoV-2 pneumonia confirmed by RT-PCR and who did or did not present with AKI (KDIGO) while hospitalized. Biomarkers of inflammation were recorded, and kidney function was estimated using the CKD-EPI formula. Results: 291 patients were included (68% males; average age, 57 years). The incidence of AKI was 40.5% (118 patients); 21% developed stage 1 AKI, 6% developed stage 2 AKI, and 14% developed stage 3 AKI. The development of AKI was associated with higher phosphate (p = 0.002) (RR 1.39, CI 95% 1.13-1.72), high procalcitonin levels at hospital admission (p = 0.005) (RR 2.09, CI 95% 1.26-3.50), and high APACHE scores (p = 0.011) (RR 2.0, CI 95% 1.17-3.40). The survival analysis free of AKI according to procalcitonin levels and APACHE scores demonstrated a lower survival in patients with procalcitonin >0.5 ng/ml (p = 0.001) and APACHE >15 points (p = 0.004). Conclusions: Phosphate, high procalcitonin levels, and APACHE levels >15 were predictors of AKI development in patients hospitalized with COVID-19.

Global Quantum Thermometry.

A paradigm shift in quantum thermometry is proposed. To date, thermometry has relied on local estimation, which is useful to reduce statistical fluctuations once the temperature is very well known. In order to estimate temperatures in cases where few measurement data or no substantial prior knowledge are available, we build instead a method for global quantum thermometry. Based on scaling arguments, a mean logarithmic error is shown here to be the correct figure of merit for thermometry. Its full minimization provides an operational and optimal rule to postprocess measurements into a temperature reading, and it establishes a global precision limit. We apply these results to the simulated outcomes of measurements on a spin gas, finding that the local approach can lead to biased temperature estimates in cases where the global estimator converges to the true temperature. The global framework thus enables a reliable approach to data analysis in thermometry experiments.

DNA Methylation in T-Cell Development and Differentiation.

T lymphocytes undergo carefully orchestrated programming during development in the thymus and subsequently during differentiation in the periphery. This intricate specification allows for cell-type and context-specific transcriptional programs that regulate immune responses to infection and malignancy. Epigenetic changes, including histone modifications and covalent modification of DNA itself through DNA methylation, are now recognized to play a critical role in these cell-fate decisions. DNA methylation is mediated primarily by the actions of the DNA methyltransferase (DNMT) and ten-eleven-translocation (TET) families of epigenetic enzymes. In this review, we discuss the role of DNA methylation and its enzymatic regulators in directing the development and differentiation of CD4+ and CD8+ T-cells.

Using Polarons for sub-nK Quantum Nondemolition Thermometry in a Bose-Einstein Condensate.

We introduce a novel minimally disturbing method for sub-nK thermometry in a Bose-Einstein condensate (BEC). Our technique is based on the Bose polaron model; namely, an impurity embedded in the BEC acts as the thermometer. We propose to detect temperature fluctuations from measurements of the position and momentum of the impurity. Crucially, these cause minimal backaction on the BEC and hence, realize a nondemolition temperature measurement. Following the paradigm of the emerging field of quantum thermometry, we combine tools from quantum parameter estimation and the theory of open quantum systems to solve the problem in full generality. We thus avoid any simplification, such as demanding thermalization of the impurity atoms, or imposing weak dissipative interactions with the BEC. Our method is illustrated with realistic experimental parameters common in many labs, thus showing that it can compete with state-of-the-art destructive techniques, even when the estimates are built from the outcomes of accessible (suboptimal) quadrature measurements.

Pushing the limits of the reaction-coordinate mapping.

The reaction-coordinate mapping is a useful technique to study complex quantum dissipative dynamics into structured environments. In essence, it aims to mimic the original problem by means of an "augmented system," which includes a suitably chosen collective environmental coordinate-the "reaction coordinate." This composite then couples to a simpler "residual reservoir" with short-lived correlations. If, in addition, the residual coupling is weak, a simple quantum master equation can be rigorously applied to the augmented system, and the solution of the original problem just follows from tracing out the reaction coordinate. But, what if the residual dissipation is strong? Here, we consider an exactly solvable model for heat transport-a two-node linear "quantum wire" connecting two baths at different temperatures. We allow for a structured spectral density at the interface with one of the reservoirs and perform the reaction-coordinate mapping, writing a perturbative master equation for the augmented system. We find that (a) strikingly, the stationary state of the original problem can be reproduced accurately by a weak-coupling treatment even when the residual dissipation on the augmented system is very strong, (b) the agreement holds throughout the entire dynamics under large residual dissipation in the overdamped regime; and (c) such a master equation can grossly overestimate the stationary heat current across the wire, even when its nonequilibrium steady state is captured faithfully. These observations can be crucial when using the reaction-coordinate mapping to study the largely unexplored strong-coupling regime in quantum thermodynamics.

Individual Quantum Probes for Optimal Thermometry.

The unknown temperature of a sample can be estimated with minimal disturbance by putting it in thermal contact with an individual quantum probe. If the interaction time is sufficiently long so that the probe thermalizes, the temperature can be read-out directly from its steady state. Here we prove that the optimal quantum probe, acting as a thermometer with maximal thermal sensitivity, is an effective two-level atom with a maximally degenerate excited state. When the total interaction time is insufficient to produce full thermalization, we optimize the estimation protocol by breaking it down into sequential stages of probe preparation, thermal contact, and measurement. We observe that frequently interrogated probes initialized in the ground state achieve the best performance. For both fully and partly thermalized thermometers, the sensitivity grows significantly with the number of levels, though optimization over their energy spectrum remains always crucial.

Whole-Mount Imaging of Adipose Tissue Macrophages.

The adipose tissue comprises highly heterogeneous macrophage populations, which play critical roles in the regulation of adipose tissue function and dysfunction during health and disease. Whole-amount staining is a powerful technique for macrophage characterization within the 3D environment of the adipose tissue, enabling the visualization of different macrophage populations and their interaction with other cells within their in vivo niche. Due to the high-fat content and softness, freezing and sectioning of adipose tissue is difficult, and distortion of tissue morphology typically occurs, especially in the case of white adipose tissue. We describe here a whole-mount staining alternative for adipose tissue imaging that preserves all structures and allows high-resolution image acquisition. We address in a step-by-step manner how to perform immunofluorescence staining of different fat pads and how to optimally visualize cellular and acellular (extracellular matrix) constituents of the adipose tissue and its vasculature, as well as resident and infiltrating macrophage populations.

Benign synthesis of terpene-based 1,4-p-menthane diamine.

Terpenes represent a promising renewable feedstock for the substitution of fossil resources in the synthesis of renewable platform chemicals, like diamines. This work describes the synthesis and full characterization of 1,4-p-menthane diamine (1,4-PMD) obtained from α-terpinene (1). A two-step procedure using dibenzyl azodicarboxylate (DBAD) and H2 as rather benign reagents was employed under comparatively mild conditions. Both C-N bonds were formed simultaneously during a visible-light mediated Diels-Alder reaction, which was investigated in batch or flow, avoiding regioselectivity issues during the amination steps that are otherwise typical for terpene chemistry. Heterogeneously catalyzed quadruple hydrogenation of the cycloadduct (2a) yielded 1,4­PMD (3). While the intermediate cycloadduct was shown to be distillable, the target diamine can be sublimed, offering sustainable purification methods.

Synthetic Peptides Elicit Humoral Response against Porcine Reproductive and Respiratory Syndrome Virus in Swine.

The aim of this study was to analyze the immunogenic response elicited in swine by two synthetic peptides derived from GP5 to understand the role of lineal B epitopes in the humoral and B-cell-mediated response against the porcine reproductive and respiratory syndrome virus (PRRSV). For inoculation, twenty-one-day-old pigs were allocated into six groups: control, vehicle, vaccinated (Ingelvac-PRRSV, MLV®), non-vaccinated and naturally infected, GP5-B and GP5-B3. At 2 days post-immunization (dpi), the GP5-B3 peptide increased the serum concentrations of cytokines associated with activate adaptive cellular immunity, IL-1ß (1.15 ± 1.15 to 10.17 ± 0.94 pg/mL) and IL-12 (323.8 ± 23.3 to 778.5 ± 58.11 pg/mL), compared to the control group. The concentration of IgGs anti-GP5-B increased in both cases at 21 and 42 dpi compared to that at 0 days (128.3 ± 8.34 ng/mL to 231.9 ± 17.82 and 331 ± 14.86 ng/mL), while IgGs anti-GP5-B3 increased at 21 dpi (105.1 ± 19.06 to 178 ± 15.09 ng/mL) and remained at the same level until 42 dpi. Also, antibody-forming/Plasma B cells (CD2+/CD21-) increased in both cases (9.85 ± 0.7% to 13.67 ± 0.44 for GP5-B and 15.72 ± 1.27% for GP5-B3). Furthermore, primed B cells (CD2-/CD21+) from immunized pigs showed an increase in both cases (9.62 ± 1.5% to 24.51 ± 1.3 for GP5-B and 34 ± 2.39% for GP5-B3) at 42 dpi. Conversely the naïve B cells from immunized pigs decreased compared with the control group (8.84 ± 0.63% to 6.25 ± 0.66 for GP5-B and 5.78 ± 0.48% for GP5-B3). Importantly, both GP5-B and GP5-B3 peptides exhibited immunoreactivity against serum antibodies from the vaccinated group, as well as the non-vaccinated and naturally infected group. In conclusion, GP5-B and GP5-B3 peptides elicited immunogenicity mediated by antigen-specific IgGs and B cell activation.

An observational study investigating soluble immune checkpoints as indicators of severe COVID-19.

This study aimed to investigate the immunomodulatory behavior of soluble immune checkpoints (sICPs) and other biomarkers in the pathophysiology of SARS-CoV-2 infection. The study included 59 adult participants, 43 of whom tested positive for SARS-CoV-2. Patients were divided into three cohorts: those with moderate disease (n = 16), recovered patients with severe disease (n = 13), and deceased patients with severe disease (n = 16). In addition, 16 participants were pre-pandemic subjects negative for SARS-CoV-2. The relative activity of neutralizing antibodies (rNAbs) against SARS-CoV-2 and the values of 14 sICPs in peripheral blood were compared between the four groups. Because the increase of markers values of inflammation [NLR > 12; CRP > 150 mg/L] and venous thromboembolism [D-dimer > 0.5 mg/L] has been associated with mortality from COVID-19, the total and differential leukocyte counts, the NLR, and CRP and D-dimer values were obtained in patients with severe disease. No differences in rNAbs were observed between the cohorts. Only the levels of five sICPs, sCD27, sHVEM sTIM-3, sPD-1, and sPDL-1, were significantly higher in patients with severe rather than moderate disease. The sPDL-2 level and NLR were higher in deceased patients than in recovered patients. However, there was no difference in CRP and D-dimer values between the two groups. Of the five soluble biomarkers compared among patients with severe disease, only sPDL-2 was higher in deceased patients than in recovered patients. This suggests that immuno-inhibitory sICPs might be used as indicators for severe COVID-19, with sPDL-2 used to assess individual risk for fatality.IMPORTANCECOVID-19, the disease caused by a SARS-CoV-2 infection, generates a broad spectrum of clinical symptoms, progressing to multiorgan failure in the most severe cases. As activation of the immune system is pivotal to eradicating the virus, future research should focus on identifying reliable biomarkers to efficiently predict the outcome in severe COVID-19 cases. Soluble immune checkpoints represent the function of the immune system and are easily determined in peripheral blood. This research could lead to implementing more effective severity biomarkers for COVID-19, which could increase patients' survival rate and quality of life.

An Unusual Finding of a Neurogenic Tumor of the Trachea: A Tracheal Schwannoma.

We report a rare case of a 57-year-old female patient with intraluminal tracheal obstruction caused by a benign schwannoma. She underwent successful bronchoscopic resection under general anesthesia, with no complications observed during the post-procedure follow-up. Tracheal schwannomas are exceedingly uncommon, and while conventional treatment involves surgical resection, bronchoscopic techniques, such as laser ablation, can be a valuable alternative, particularly for high-risk patients. Further studies are needed to explore the full potential of bronchoscopic interventions in managing tracheal schwannomas.

Selection of Strains of Trichogramma foersteri and Trichogramma pretiosum (Hymenoptera: Trichogrammatidae) for the Control of Palpita forficifera (Lepidoptera: Crambidae).

Palpita forficifera Munroe 1959 is a lepidopteran pest native to the Neotropical region and has been causing damage to olive tree crops in Brazil and Uruguay. The use of egg parasitoids of the genus Trichogramma may be a viable and sustainable alternative to pest management. The objective of the present work was to select species and/or strains of Trichogramma as possible agents of control for P. forficifera. Selections were made from five strains of Trichogramma foersteri Takahashi (R1, R2, R3, R4, and R5) collected in olive orchards of southern Brazil and four strains of Trichogramma pretiosum Riley (AC, PR, MJU, and RVI) from laboratory rearings. The strains of T. foersteri presented the longest periods from egg to adult (≈ 11.5 days) when compared to T. pretiosum (≈ 9.5 days). However, T. foersteri provided, in general, the highest daily percentage of parasitized P. forficifera eggs and, consequently, a higher rate of parasitism (between 50 and 69%) in relation to those of T. pretiosum (variation from 7 to 20%). In addition, T. foersteri provided a higher emergence rate (above 90%), with a sex ratio close to 1.0. However, all strains of T. pretiosum were longer-lived compared to adults of T. foersteri. From the biological parameters evaluated, two distinct groups were formed between T. foersteri and T. pretiosum. In general, T. foersteri has better potential for controlling P. forficifera, demonstrating its potential for use in field multiplication and release programs for the management of the olive larvae.

Efficacy of omecamtiv mecarbil in heart failure with reduced ejection fraction according to N-terminal pro-B-type natriuretic peptide level: insights from the GALACTIC-HF trial.

AIM: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is predictive of both outcomes and response to treatment in patients with heart failure with reduced ejection fraction (HFrEF). The aim of this study was to examine the effect of the cardiac myosin activator omecamtiv mecarbil according to baseline NT-proBNP level in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure trial (GALACTIC-HF). METHODS AND RESULTS: The primary outcome was the composite of a worsening heart failure event (urgent clinic visit, emergency department visit, or hospitalization) or cardiovascular death. We prespecified analysis of the effect of treatment according to baseline NT-proBNP (≤ median, > median), excluding individuals with atrial fibrillation/flutter (AF/AFL). Of the 8232 patients analysed, 8206 had an available baseline NT-proBNP measurement. Among the 5971 patients not in AF/AFL, the median (Q1-Q3) NT-proBNP level was 1675 (812-3579) pg/ml. Hazard ratios (HR) for the effect of omecamtiv mecarbil, compared with placebo, for the primary endpoint in patients without AF/AFL were: ≤ median 0.94 (95% confidence interval [CI] 0.80-1.09), > median 0.81 (0.73-0.90) (p-interaction = 0.095); for the overall population (including patients with AF/AFL) the HRs were ≤ median 1.01 (0.90-1.15) and > median 0.88 (0.80-0.96) (p-interaction = 0.035). There was an interaction between treatment and NT-proBNP, examined as a continuous variable, with greater effect of omecamtiv mecarbil on the primary outcome in patients with a higher baseline NT-proBNP (p-interaction = 0.086). CONCLUSIONS: In GALACTIC-HF, the benefit of omecamtiv mecarbil appeared to be larger in patients with higher baseline NT-proBNP levels, especially in patients without AF/AFL. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02929329; EudraCT number, 2016-002299-28.

Response of lymphocytes from pigs naturally infected with porcine respiratory disease complex at 3 different stages of development.

The objective of this study was to analyze the response of lymphocytes from pigs naturally infected with porcine respiratory disease complex (PRDC) at 3 different stages of development. Porcine respiratory disease complexes were isolated from 2 groups: The infected group, consisting of pigs with PRDC and no vaccination against any virus (n = 24), and the control group, consisting of vaccinated and noninfected piglets (n = 24). Both groups were sampled at 3 stages of development: Weaning (WEA) (n = 8), initiation (INI) (n = 8), and growth (GRO) (n = 8). The PRDC status was confirmed by serological testing against porcine circovirus type 2 (PCV-2), porcine reproductive and respiratory syndrome virus (PRRSV), swine influenza virus (H1N1), and Mycoplasma hyopneumoniae. PCV-2+ cells were quantified by flow cytometry. Weight gain was registered at each stage. PCV-2+ cells, CD4+ cells, monocytes and lymphocytes populations were measured. Gene expression in CD4+ cells was quantified for interferon-γ (IFN-γ), GATA binding protein 3 (GATA3), T-box transcription factor (T-bet), interleukin-10 (IL-10), and IL-4. Control piglets gained approximately 35% more weight than those infected with PRDC. Specifically, PCV-2+ cells were detected in piglets from the infected group in the following proportions: WEA ≤ INI ≤ GRO. In infected piglets, the CD4+ count increased at WEA and decreased at GRO, CD4+ expression profile showed an overexpression of T-bet at INI and GRO, and the expression of IFN-γ was lower at WEA and GRO. In contrast, IL-4 was overexpressed at all 3 stages. GATA3 was overexpressed at INI and GRO. The infected piglets showed lymphopenia and less CD4+ cells. CD4+ cells showed a different expression profile than the control group, in which IFN-γ was less expressed, whereas IL-4 and T-bet were overexpressed.

L'objectif de cette étude était d'analyser la réponse des lymphocytes de porcs naturellement infectés par le complexe respiratoire porcin (PRDC) à trois stades de développement différents. Des PRDC ont été isolés à partir de deux groupes : le groupe infecté, composé de porcs atteints de PRDC et non vaccinés contre un virus (n = 24), et le groupe témoin, composé de porcelets vaccinés et non infectés (n = 24). Les deux groupes ont été échantillonnés à trois stades de développement : sevrage (WEA) (n = 8), initiation (INI) (n = 8) et croissance (GRO) (n = 8). Le statut de PRDC a été confirmé par des tests sérologiques contre le circovirus porcin de type 2 (PCV-2), le virus du syndrome reproducteur et respiratoire porcin (PRRSV), le virus de la grippe porcine (H1N1) et Mycoplasma hyopneumoniae. Les cellules PCV-2+ ont été quantifiées par cytométrie en flux. Un gain de poids a été enregistré à chaque étape. Les populations de cellules PCV-2+, de cellules CD4+, de monocytes et de lymphocytes ont été mesurées. L'expression génique dans les cellules CD4+ a été quantifiée pour l'interféron-γ (IFN-γ), la protéine de liaison GATA 3 (GATA3), le facteur de transcription T-box (T-bet), l'interleukine-10 (IL-10) et l'IL-4. Les porcelets témoins ont pris environ 35 % de poids en plus que ceux infectés par le PRDC. Plus précisément, des cellules PCV-2+ ont été détectées chez les porcelets du groupe infecté dans les proportions suivantes : WEA ≤ INI ≤ GRO. Chez les porcelets infectés, le nombre de CD4+ a augmenté à WEA et diminué à GRO, le profil d'expression de CD4+ a montré une surexpression de T-bet à INI et GRO, et l'expression d'IFN-γ était plus faible à WEA et GRO. En revanche, l'IL-4 était surexprimée aux trois stades. GATA3 était surexprimé à INI et GRO. Les porcelets infectés présentaient une lymphopénie et moins de cellules CD4+. Les cellules CD4+ ont montré un profil d'expression différent de celui du groupe témoin, dans lequel l'IFN-γ était moins exprimé, tandis que l'IL-4 et le T-bet étaient surexprimés.(Traduit par Docteur Serge Messier).

Glycoprotein 5-Derived Peptides Induce a Protective T-Cell Response in Swine against the Porcine Reproductive and Respiratory Syndrome Virus.

We analyzed the T-cell responses induced by lineal epitopes of glycoprotein 5 (GP5) from PRRSV to explore the role of this protein in the immunological protection mediated by T-cells. The GP5 peptides were conjugated with a carrier protein for primary immunization and booster doses. Twenty-one-day-old pigs were allocated into four groups (seven pigs per group): control (PBS), vehicle (carrier), PTC1, and PTC2. Cytokine levels were measured at 2 days post-immunization (DPI) from serum samples. Cytotoxic T-lymphocytes (CTLs, CD8+) from peripheral blood were quantified via flow cytometry at 42 DPI. The cytotoxicity was evaluated by co-culturing primed lymphocytes with PRRSV derived from an infectious clone. The PTC2 peptide increased the serum concentrations of pro-inflammatory cytokines (i.e., TNF-α, IL-1ß, IL-8) and cytokines that activate the adaptive cellular immunity associated with T-lymphocytes (i.e., IL-4, IL-6, IL-10, and IL-12). The concentration of CTLs (CD8+) was significantly higher in groups immunized with the peptides, which suggests a proliferative response in this cell population. Primed CTLs from immunized pigs showed cytolytic activity in PRRSV-infected cells in vitro. PTC1 and PTC2 peptides induced a protective T-cell-mediated response in pigs immunized against PRRSV, due to the presence of T epitopes in their sequences.

Metabolomic Profiles of Human Glioma Inform Patient Survival.

Aims: Targeting tumor metabolism may improve the outcomes for patients with glioblastoma (GBM). To further preclinical efforts targeting metabolism in GBM, we tested the hypothesis that brain tumors can be stratified into distinct metabolic groups with different patient outcomes. Therefore, to determine if tumor metabolites relate to patient survival, we profiled the metabolomes of human gliomas and correlated metabolic information with clinical data. Results: We found that isocitrate dehydrogenase-wildtype (IDHwt) GBMs are metabolically distinguishable from IDH mutated (IDHmut) astrocytomas and oligodendrogliomas. Survival of patients with IDHmut gliomas was expectedly more favorable than those with IDHwt GBM, and metabolic signatures can stratify IDHwt GBMs subtypes with varying prognoses. Patients whose GBMs were enriched in amino acids had improved survival, while those whose tumors were enriched for nucleotides, redox molecules, and lipid metabolites fared more poorly. These findings were recapitulated in validation cohorts using both metabolomic and transcriptomic data. Innovation: Our results suggest the existence of metabolic subtypes of GBM with differing prognoses, and further support the concept that metabolism may drive the aggressiveness of human gliomas. Conclusions: Our data show that metabolic signatures of human gliomas can inform patient survival. These findings may be used clinically to tailor novel metabolically targeted agents for GBM patients with different metabolic phenotypes. Antioxid. Redox Signal. 39, 942-956.

Retrospective assessment of the relationship between intraoperative nociception and postoperative analgesia requirements in dogs undergoing thoracic surgery.

BACKGROUND: The analgesia management of thoracic surgery can be challenging and debate exists regarding the efficacy of pre-emptive analgesia and its relationship with postoperative pain. The aim of this study was to assess the relationship between intraoperative nociception and postoperative pain in dogs undergoing thoracic surgery. If proven, effective prevention of intraoperative nociception could imply prospective lower postoperative analgesia requirements. METHODS: The study was retrospective and observational. Clinical records from dogs undergoing thoracic surgery (2015-2019) were reviewed and cases were allocated to one of two groups: NOCI-FREE - dogs with no evidence of intraoperative nociception; NOCI - dogs that required intraoperative rescue analgesia to address a nociceptive response. Pre-anaesthetic medication, locoregional analgesia, intraoperative infusions and rescue analgesia were used. Additionally, postoperative pain scores and analgesia plans were registered and compared between groups. RESULTS: Our study failed to identify a difference in the postoperative pain scores and analgesia requirements between dogs having signs of intraoperative nociception and those without. Additionally, the use of postoperative analgesic preventive infusions and rescue analgesia was similar for both NOCI and NOCI-FREE. Being on an intraoperative infusion of opioids, dexmedetomidine or lidocaine was identified as a protective factor for nociception [OR = 11; (4.15-29.7)]. CONCLUSIONS: In the population studied, it appears that dogs showing signs of nociception intraoperatively do not necessarily show higher pain scores nor do they need additionally pain relief in the postoperative period.

Investigation of the Coordination Chemistry of a Bisamidinate Ferrocene Ligand with Cu, Ag, and Au.

The coordination chemistry of a ferrocene ligand with one bulky amidinate function attached to each ring toward two different coinage metal precursors was investigated. In dependence of the metal and the co-ligands, "ansa" type structures and non-bridged structures were obtained. Six different compounds are reported. In the "ansa" type structures, short Fe-M (M = Cu, Ag) distances were observed in the molecular structures in the solid state. However, theoretical calculations (DFT) did not reveal a stabilizing metal-metal interaction. Instead, dispersion interactions within the ligand and between the ligand and metal seem to represent the main stabilization forces.

OXPHOS promotes apoptotic resistance and cellular persistence in TH17 cells in the periphery and tumor microenvironment.

T cell proliferation and cytokine production are bioenergetically and biosynthetically costly. The inability to meet these metabolic demands results in altered differentiation, accompanied by impaired effector function, and attrition of the immune response. Interleukin-17-producing CD4 T cells (TH17s) are mediators of host defense, autoimmunity, and antitumor immunity in the setting of adoptive T cell therapy. TH17s are long-lived cells that require mitochondrial oxidative phosphorylation (OXPHOS) for effector function in vivo. Considering that TH17s polarized under standardized culture conditions are predominately glycolytic, little is known about how OXPHOS regulates TH17 processes, such as their ability to persist and thus contribute to protracted immune responses. Here, we modified standardized culture medium and identified a culture system that reliably induces OXPHOS dependence in TH17s. We found that TH17s cultured under OXPHOS conditions metabolically resembled their in vivo counterparts, whereas glycolytic cultures were dissimilar. OXPHOS TH17s exhibited increased mitochondrial fitness, glutamine anaplerosis, and an antiapoptotic phenotype marked by high BCL-XL and low BIM. Limited mitophagy, mediated by mitochondrial fusion regulator OPA-1, was critical to apoptotic resistance in OXPHOS TH17s. By contrast, glycolytic TH17s exhibited more mitophagy and an imbalance in BCL-XL to BIM, thereby priming them for apoptosis. In addition, through adoptive transfer experiments, we demonstrated that OXPHOS protected TH17s from apoptosis while enhancing their persistence in the periphery and tumor microenvironment in a murine model of melanoma. Together, our work demonstrates how metabolism regulates TH17 cell fate and highlights the potential for therapies that target OXPHOS in TH17-driven diseases.