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Background: Fatigue and related injuries to the musculoskeletal system are among the most frequent reasons for the withdrawal of high-level eventing horses from the sport. The safety of both horse and rider is very important, and early detection of fatigue is crucial., Objectives: To investigate elite eventing horses in competitive events focusing on biomechanical, cardiovascular and metabolic variables across the cross-country test and to identify their potential associations with fatigue., Study Design: Prospective observational exploratory field study., Methods: Observations on 54 cross-country tests of 33 horses at five competitive, high-level events were evaluated using sternal accelerometric analysis of stride parameters between and at the jumps. Blood lactate concentration and heart rate were determined 10 min after finishing. The differences in kinematic parameters between the course start and end were analysed with mixed models for repeated measures. Associations between blood lactate and heart rate recovery with the kinematic variables were quantified with Pearson correlation coefficients., Results: We observed numerous stride characteristics between the jumps and the jumps changing over time during the courses. Blood lactate concentrations were positively correlated with the mean maximal strike power at the jumps in the last minute of the course (r = 0.41; p < 0.001), and the latter was negatively correlated with the mean stride height over the jumps (r = -0.41; p = 0.003)., Main Limitations: The sample contained horses of varying breeds, sexes and ages, and different horses participated in different events., Conclusions: We identified several kinematic changes during a cross-country test depending on event, speed and fatigue., (© 2023 The Authors. Equine Veterinary Journal published by John Wiley & Sons Ltd on behalf of EVJ Ltd.)

Nonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liver disease and cancer 1,2 . The accumulation of metabolites leads to cell stress and inflammation in the liver 3 , but mechanistic understandings of liver damage in NASH are incomplete. Here, using a preclinical mouse model that displays key features of human NASH (hereafter, NASH mice), we found an indispensable role for T cells in liver immunopathology. We detected the hepatic accumulation of CD8 T cells with phenotypes that combined tissue residency (CXCR6) with effector (granzyme) and exhaustion (PD1) characteristics. Liver CXCR6 + CD8 T cells were characterized by low activity of the FOXO1 transcription factor, and were abundant in NASH mice and in patients with NASH. Mechanistically, IL-15 induced FOXO1 downregulation and CXCR6 upregulation, which together rendered liver-resident CXCR6 + CD8 T cells susceptible to metabolic stimuli (including acetate and extracellular ATP) and collectively triggered auto-aggression. CXCR6 + CD8 T cells from the livers of NASH mice or of patients with NASH had similar transcriptional signatures, and showed auto-aggressive killing of cells in an MHC-class-I-independent fashion after signalling through P2X7 purinergic receptors. This killing by auto-aggressive CD8 T cells fundamentally differed from that by antigen-specific cells, which mechanistically distinguishes auto-aggressive and protective T cell immunity.

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are rare, autoimmune mediated cholestatic liver diseases. Other auto-immune diseases are often associated with PBC and PSC, and inflammatory bowel disease is present in the majority of PSC patients. In the course of disease, chronic inflammation in the liver leads to fibrotic restructuring and ultimately cirrhosis. The diagnosis of PBC is confirmed serologically and PSC is diagnosed via cholangiography, whereas MRCP is preferred over ERCP. For PBC, the first line therapy is ursodeoxycholic acid (UDCA). Prognosis is strongly dependent on the response to UDCA. The only approved second line therapy is obeticholic acid (OCA). Alternatively, Budesonide or Fibrates are often used off-label. In the management of PSC, prevention and adequate treatment of bacterial cholangitis play a major role. For both PBC and PSC novel treatments are currently being tested in clinical trials. Disease management should address compromising symptoms like pruritus and sicca as well as complications due to maldigestion and concomitant autoimmune diseases. The only curative treatment available is liver transplantation and should be considered at a MELD score of 15., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.Tobias Böttler erhielt Vortragshonorare von der Falk Foundation und ist an der Durchführung klinischer Studien von Dr. Falk Pharma beteiligt.Die andere Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)

We report a mild approach to the synthesis of difluoro(aryl)-λ 3 -iodanes (aryl-IF 2 compounds) and tetrafluoro(aryl)-λ 5 -iodanes (aryl-IF 4 compounds) using trichloroisocyanuric acid (TCICA) and potassium fluoride (KF). Under these reaction conditions, selective access to either the I(iii)- or I(v)-derivatives is predictable based solely on the substitution pattern of the iodoarene starting material. Moreover, the discovery of this TCICA/KF approach prompted detailed dynamic NMR, kinetic, computational, and crystallographic studies on the relationship between the IF 2 group and the ortho -substituents on carefully designed probe molecules. It was during these experiments that the role of the ortho -substituent in inhibiting further oxidative fluorination of I(iii)-compounds to I(v)-compounds during the reaction with TCICA and KF was revealed. Additionally, a notable exception to this empirical trend is discussed herein., (This journal is © The Royal Society of Chemistry 2019.)

The hspArpoH1 and hspBCdegP heat shock operons of Bradyrhizobium japonicum are preceded by a novel, conserved DNA element of approximately 100 bp, which is responsible for the temperature-regulated transcription of their sigma70-type promoters. We designated this motif ROSE for repression of heat shock gene expression and found additional ROSE elements upstream of two newly identified heat shock operons. A critical core region in the hspA-associated ROSE1 was defined by introducing insertions or deletions. While four mutants retained the ability to repress transcription of the hspArpoH1 operon, five deletion mutants produced elevated hspA mRNA levels under low-temperature growth conditions. Derepression was confirmed by increased RpoH1 levels in non-heat-shocked cells from one of these mutants and by strains that contained a translational hspA-lacZ fusion associated with mutated ROSE1 elements. The hspArpoH1 operon was efficiently transcribed in vitro, and a deletion of ROSE1 did not impair this activity. Gel retardation experiments demonstrated that a protein in non-heat-shocked cells specifically binds to the intact ROSE1 element but not to a mutated element lacking the core region. Taken together, these results indicate that a central region of ROSE serves as a binding site for a repressor protein under standard growth conditions in order to prevent the undesired transcription of heat shock genes.