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Leigh syndrome (LS) is the most common pediatric presentation of genetic mitochondrial disease and characterized by neurological and metabolic abnormalities. The hallmark of the disease is the presence of progressive, bilateral, symmetric neurodegenerative lesions in the brainstem and/or basal ganglia. Recent studies in the Ndufs4 (-/-) mouse model of LS indicate that disease is causally driven by the immune system. Both microglia and peripherally originating macrophages are enriched in the lesions of Ndufs4 (-/-) mice and pharmacologic elimination of these cell types prevents disease indicating a crucial role for innate immune cells. Here, we investigated the role of the adaptive immune system in Ndufs4 (-/-) disease pathogenesis. We crossed Ndufs4 (-/-) mice with mice expressing a null form of interleukin 2 receptor gamma ( Il2rg ) and monitored disease onset and progression. Il2rg knockout (KO) mice have dramatically depleted numbers of B-, T-, the adaptive immune system’s key cellular actors, and NK-cells. We observed no difference in neurological disease progression or overall survival between Ndufs4 (-/-)/ Il2rg (WT) and Ndufs4 (-/-)/ Il2rg (KO) mice, strongly suggesting that T cells, B cells, and NK cells do not play a significant role in CNS disease pathogenesis in Ndufs4 (-/-) mice. Combined with previous studies indicating a causal role for macrophages, we conclude that LS CNS pathology is primarily driven by the monocyte/macrophage innate immune system.

Elucidating the relationships between a class I peptide antigen, a CD8 T cell receptor (TCR) specific to that antigen, and the T cell phenotype that emerges following antigen stimulation, remains a mostly unsolved problem, largely due to the lack of large data sets that can be mined to resolve such relationships. Here, we describe Antigen-TCR Pairing and Multiomic Analysis of T-cells (APMAT), an integrated experimental-computational framework designed for the high-throughput capture and analysis of CD8 T cells, with paired antigen, TCR sequence, and single-cell transcriptome. Starting with 951 putative antigens representing a comprehensive survey of the SARS-CoV-2 viral proteome, we utilize APMAT for the capture and single cell analysis of CD8 T cells from 62 HLA A*02:01 COVID-19 participants. We leverage this comprehensive dataset to integrate with peptide antigen properties, TCR CDR3 sequences, and T cell phenotypes to show that distinct physicochemical features of the antigen-TCR pairs strongly associate with both T cell phenotype and T cell persistence. This analysis suggests that CD8 T cell phenotype following antigen stimulation is at least partially deterministic, rather than the result of stochastic biological properties. Combinatorial experimental and bioinformatics methods can be used to analyse function and specificity of CD8 T cells. Here the authors propose a multiomic analysis framework Antigen-TCR Pairing and Multiomic Analysis of T cell (APMAT) to relate TCR specificity to transcriptomic phenotype indicating associations with physicochemical features.

Leigh syndrome (LS) is the most common pediatric presentation of genetic mitochondrial disease and characterized by neurological and metabolic abnormalities. The hallmark of the disease is the presence of progressive, bilateral, symmetric neurodegenerative lesions in the brainstem and/or basal ganglia. Recent studies in the Ndufs4(-/-) mouse model of LS indicate that disease is causally driven by the immune system. Both microglia and peripherally originating macrophages are enriched in the lesions of Ndufs4(-/-) mice and pharmacologic elimination of these cell types prevents disease indicating a crucial role for innate immune cells. Here, we investigated the role of the adaptive immune system in Ndufs4(-/-) disease pathogenesis. We crossed Ndufs4(-/-) mice with mice expressing a null form of interleukin 2 receptor gamma (Il2rg) and monitored disease onset and progression. Il2rg knockout (KO) mice have dramatically depleted numbers of B-, T-, the adaptive immune system's key cellular actors, and NK-cells. We observed no difference in neurological disease progression or overall survival between Ndufs4(-/-)/Il2rg(WT) and Ndufs4(-/-)/Il2rg(KO) mice, strongly suggesting that T cells, B cells, and NK cells do not play a significant role in CNS disease pathogenesis in Ndufs4(-/-) mice. Combined with previous studies indicating a causal role for macrophages, we conclude that LS CNS pathology is primarily driven by the monocyte/macrophage innate immune system.

Primary genetic mitochondrial diseases (GMDs) are a clinically and genetically diverse group of diseases estimated to impact over 1 in 4,000 individuals. Leigh syndrome (LS) is the most common pediatric presentation of GMD. LS typically presents within the first years of life and is a severe progressive multi-system disorder. Symmetric progressive inflammatory brain lesions are a defining feature of the disease. Patients can also present with seizures, metabolic dysfunction, muscle weakness, and other symptoms. No effective clinical treatments currently exist. Recent data from the (-/-) mouse model shows that peripheral macrophages contribute to brain lesions in LS, that disease is causally driven by innate immune populations, and that depletion of innate immune cells prevents LS disease. However, the precise mechanisms underlying immune activation remain unknown. Certain mitochondrial macromolecules retain bacterial signatures and can act as potent agonists for innate immune pathways. For example, cytoplasmic mitochondrial RNA and mitochondrial DNA are detected by Toll-like receptors (TLRs) 7 and 9, respectively, at the endosome. Accordingly, these are considered strong candidates for mediating innate immune activation in LS. Here, we generated TLR signaling deficient (-/-)/ (-/-) animals to assess whether TLR signaling plays a role in disease onset or progression in LS. Loss of in (-/-) animals statistically significantly increased survival and delayed the onset of some symptoms, but the benefits were modest compared to CSF1R inhibition from prior work. We conclude that -mediated immune signaling is not a primary driver of LS. Notably, prophylactic enrofloxacin treatment, which was necessary for production of innate immune deficient (-/-) animals, modestly decreased survival and accelerated disease. The impact of enrofloxacin and similar drugs in the context of mitochondrial disease warrants further investigation.

Elucidating the relationships between a class I peptide antigen, a CD8 T cell receptor (TCR) specific to that antigen, and the T cell phenotype that emerges following antigen stimulation, remains a mostly unsolved problem, largely due to the lack of large data sets that can be mined to resolve such relationships. Here, we describe Antigen-TCR Pairing and Multiomic Analysis of T-cells (APMAT), an integrated experimental-computational framework designed for the high-throughput capture and analysis of CD8 T cells, with paired antigen, TCR sequence, and single-cell transcriptome. Starting with 951 putative antigens representing a comprehensive survey of the SARS-CoV-2 viral proteome, we utilize APMAT for the capture and single cell analysis of CD8 T cells from 62 HLA A*02:01 COVID-19 participants. We leverage this unique, comprehensive dataset to integrate with peptide antigen properties, TCR CDR3 sequences, and T cell phenotypes to show that distinct physicochemical features of the antigen-TCR pairs strongly associate with both T cell phenotype and T cell persistence. This analysis suggests that CD8+ T cell phenotype following antigen stimulation is at least partially deterministic, rather than the result of stochastic biological properties.

This study examined the effects of contrast water therapy (CWT) on physiological, perceptual, and performance-related recovery in collegiate male swimmers following high-intensity interval training. Fifteen freestyle swimmers (19.3 ± 1.1 years) completed two sessions of five 100 m maximal-effort intervals under two recovery conditions, CWT and passive rest (PAS), in a crossover design. The CWT protocol consisted of 10 alternating immersions in hot (40–41 °C, 60 s) and cold (20–21 °C, 30 s) water. Blood lactate (LA), blood pressure (BP), and subjective fatigue (VAS-FAS) were assessed at multiple time points. Compared with PAS, CWT resulted in significantly lower post-recovery blood LA (7.75 ± 2.08 vs. 10.86 ± 2.86 mmol/L, p = 0.002) and reduced subjective fatigue (6.60 ± 1.30 vs. 7.60 ± 0.91 cm, p = 0.021), whereas no significant differences were observed in BP or 100-m swimming performance. Individual-level analyses revealed heterogeneous responses, with most swimmers demonstrating improved lactate clearance and reduced fatigue following CWT, although performance responses varied among participants. These findings indicate that CWT facilitates physiological and perceptual recovery without producing immediate performance enhancement. CWT may be considered a practical short-term recovery option for competitive swimmers, although its effectiveness likely depends on individual response characteristics. Further research involving larger and more diverse samples is warranted to clarify optimal application parameters and individual recovery profiles.

PurposeSilent corticotroph pituitary adenomas (SCAs)/pituitary neuroendocrine tumors (PitNETs) are common non-functioning pituitary adenomas (NFAs)/PitNETs with a clinically aggressive course. This study aimed to investigate the ability of time-intensity analysis of dynamic magnetic resonance imaging (MRI) for distinguishing adrenocorticotropic hormone (ACTH)-positive SCAs and ACTH-negative SCAs from other NFAs.Materials and methodsWe retrospectively evaluated the dynamic MRI findings of patients with NFAs. The initial slope of the kinetic curve (slopeini) obtained by dynamic MRI for each tumor was analyzed using a modified empirical mathematical model. The maximum slope of the kinetic curve (slopemax) was obtained by geometric calculation.ResultsA total of 106 patients with NFAs (11 ACTH-positive SCAs, 5 ACTH-negative SCAs, and 90 other NFAs) were evaluated. The kinetic curves of ACTH-positive SCAs had significantly lesser slopeini and slopemax compared with ACTH-negative SCAs (P = 0.040 and P = 0.001, respectively) and other NFAs (P = 0.018 and P = 0.035, respectively). Conversely, the slopeini and slopemax were significantly greater in ACTH-negative SCAs than in NFAs other than ACTH-negative SCAs (P = 0.033 and P = 0.044, respectively). In receiver operating characteristic analysis of ACTH-positive SCAs and other NFAs, the area under the curve (AUC) values for slopeini and slopemax were 0.762 and 0748, respectively. In predicting ACTH-negative SCAs, the AUC values for slopeini and slopemax were 0.784 and 0.846, respectively.ConclusionsDynamic MRI can distinguish ACTH-positive SCAs and ACTH-negative SCAs from other NFAs.

All superheavy elements (SHEs), with atomic numbers (Z) ≥104, have been artificially synthesized one atom at a time and their chemical properties are largely unknown. Because these heavy nuclei have short lifetimes as well as extremely low production rates, chemical experiments need to be carried out on single atoms and have mostly been limited to adsorption and extraction. We have now investigated the precipitation properties of the SHE Rf (Z = 104). A co-precipitation method with samarium hydroxide had previously established that the co-precipitation behaviour of a range of elements reflected these elements’ tendency to form hydroxide precipitates and/or ammine complex ions. Here we investigated co-precipitation of Rf in basic solutions containing NH3 or NaOH. Comparisons between the behaviour of Rf with that of Zr and Hf (lighter homologues of Rf) and actinide Th (a pseudo-homologue of Rf) showed that Rf does not coordinate strongly with NH3, but forms a hydroxide (co)precipitate that is expected to be Rf(OH)4.It is difficult to investigate the chemical properties of superheavy elements, which are only available an atom at a time and rapidly decay. A co-precipitation method with samarium has now been developed that suggests rutherfordium would form hydroxide precipitates—but not ammine ones—if it were possible to perform these experiments on macroscopic quantities.

Glacial cycles during the early Pleistocene are characterised by a dominant 41,000-year periodicity and amplitudes smaller than those of glacial cycles with ~100,000-year periodicity during the late Pleistocene. However, it remains unclear how the 41,000-year glacial cycles during the early Pleistocene respond to Earth’s astronomical forcings. Here we employ a three-dimensional ice-sheet model to simulate the glacial cycles at ~1.6–1.2 million years before present and analyse the phase angle of precession and obliquity at deglaciations. We show that each deglaciation occurs at every other precession minimum, and when obliquity is large. The lead-lag relationship between precession and obliquity controls the length of interglacial periods, the shape of the glacial cycle, and the glacial ice-sheet geometry. The large amplitudes of obliquity and eccentricity during this period helped to establish robust 41,000-year glacial cycles. This behaviour is explained by the threshold mechanism determined by ice-sheet size and astronomical forcings.