Testis size variation within sneaker males of the dusky frillgoby Bathygobius fuscus (Gobiidae): effects of within-tactic competition

A ‘sneaking tactic’ is an alternative reproductive strategy that usually results in sperm competition among males with different tactics. Relatively large testes are a sneaker-specific trait that has generally been thought to have evolved due to sperm competition between sneaker males and bourgeois (guarding) males. However, here we show that competition among sneaker males can also affect testis enlargement in the dusky frillgoby (Bathygobius fuscus) sneaker males. The competitive advantage of focal sneaker males was experimentally manipulated by placing them in tanks with either relatively smaller or larger males. Testis enlargement was conspicuous in focal males that were cohoused with larger males. Smaller sneaker males may invest more in testicular growth because they are at a competitive disadvantage in physical contests for sneaking opportunities among sneaker males and consequently may be confined to making relatively late intrusions during spawning into nests that have a higher risk of sperm competition. Another possible reason for the relative size-dependent energy investment in testes may be increased investment by large sneaker males in aggressive interactions for sneaking opportunities. This is the first evidence that testis size variation among sneaker males is affected by the competition among sneaker males

A Genetic Variant in the IL-17 Promoter Is Functionally Associated with Acute Graft-Versus-Host Disease after Unrelated Bone Marrow Transplantation

Interleukin IL-17 is a proinflammatory cytokine that has been implicated in the pathogenesis of various autoimmune diseases. The single nucleotide polymorphism (SNP), rs2275913, in the promoter region of the IL-17 gene is associated with susceptibility to ulcerative colitis. When we examined the impact of rs2275913 in a cohort consisting of 438 pairs of patients and their unrelated donors transplanted through the Japan Marrow Donor Program, the donor IL-17 197A allele was found to be associated with a higher risk of acute graft-versus-host disease (GVHD; hazard ratio [HR], 1.46; 95% confidence interval [CI], 1.00 to 2.13; P = 0.05). Next, we investigated the functional relevance of the rs2275913 SNP. In vitro stimulated T cells from healthy individuals possessing the 197A allele produced significantly more IL-17 than those without the 197A allele. In a gene reporter assay, the 197A allele construct induced higher luciferase activity than the 197G allele, and the difference was higher in the presence of T cell receptor activation and was abrogated by cyclosporine treatment. Moreover, the 197A allele displayed a higher affinity for the nuclear factor activated T cells (NFAT), a critical transcription factor involved in IL-17 regulation. These findings substantiate the functional relevance of the rs2275913 polymorphism and indicate that the higher IL-17 secretion by individuals with the 197A allele likely accounts for their increased risk for acute GVHD and certain autoimmune diseases

Hippocampal metabolism of amino acids by L-amino acid oxidase is involved in fear learning and memory

Amino acids participate directly and indirectly in many important biochemical functions in the brain. We focused on one amino acid metabolic enzyme, L-amino acid oxidase (LAO), and investigated the importance of LAO in brain function using LAO1 knockout (KO) mice. Compared to wild-type mice, LAO1 KO mice exhibited impaired fear learning and memory function in a passive avoidance test. This impairment in LAO1 KO mice coincided with significantly reduced hippocampal acetylcholine levels compared to wild-type mice, while treatment with donepezil, a reversible acetylcholine esterase inhibitor, inhibited this reduction. Metabolomic analysis revealed that knocking out LAO1 affected amino acid metabolism (mainly of phenylalanine [Phe]) in the hippocampus. Specifically, Phe levels were elevated in LAO1 KO mice, while phenylpyruvic acid (metabolite of Phe produced largely by LAO) levels were reduced. Moreover, knocking out LAO1 decreased hippocampal mRNA levels of pyruvate kinase, the enzymatic activity of which is known to be inhibited by Phe. Based on our findings, we propose that LAO1 KO mice exhibited impaired fear learning and memory owing to low hippocampal acetylcholine levels. Furthermore, we speculate that hippocampal Phe metabolism is an important physiological mechanism related to glycolysis and may underlie cognitive impairments, including those observed in Alzheimer’s disease

Frequency components of systolic blood pressure variability reflect vasomotor and cardiac sympathetic functions in conscious rats

In this study, after confirming the suppression of autonomic nervous function by isoflurane anesthesia using autonomic antagonists, we pharmacologically investigated the involvement of vasomotor and cardiac sympathetic functions in systolic blood pressure variability (SBPV) frequency components in conscious rats at rest and during exposure to low-ambient temperature (LT-exposure, 9°C for 90 min). Under unanesthesia, phentolamine administration (α-adrenoceptor antagonist, 10 mg/kg) decreased the mid-frequency component (MF 0.33–0.73 Hz) and inversely increased the high-frequency component (HF 1.3–2.5 Hz). The increased HF was suppressed by subsequent treatment with atenolol (β-adrenoceptor antagonist, 10 mg/kg), but not with atropine (muscarinic receptor antagonist, 10 mg/kg). Moreover, phentolamine administration after atenolol decreased MF, but did not increase HF. LT-exposure increased MF and HF; however, phentolamine pretreatment suppressed the increased MF during LT-exposure, and atenolol pretreatment dose-dependently decreased the increased HF. These results suggest that MF and HF of SBPV may reflect α-adrenoceptor-mediated vasomotor function and β-adrenoceptor-mediated cardiac sympathetic function, respectively, in the conscious state

Genetic Variants of Human Granzyme B Predict Transplant Outcomes after HLA Matched Unrelated Bone Marrow Transplantation for Myeloid Malignancies

Serine protease granzyme B plays important roles in infections, autoimmunity, transplant rejection, and antitumor immunity. A triple-mutated granzyme B variant that encodes three amino substitutions (Q48R, P88A, and Y245H) has been reported to have altered biological functions. In the polymorphism rs8192917 (2364A>G), the A and G alleles represent wild type QPY and RAH mutant variants, respectively. In this study, we analyzed the impact of granzyme B polymorphisms on transplant outcomes in recipients undergoing unrelated HLA-fully matched T-cell-replete bone marrow transplantation (BMT) through the Japan Donor Marrow Program. The granzyme B genotypes were retrospectively analyzed in a cohort of 613 pairs of recipients with hematological malignancies and their unrelated donors. In patients with myeloid malignancies consisting of acute myeloid leukemia and myelodysplastic syndrome, the donor G/G or A/G genotype was associated with improved overall survival (OS; adjusted hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.41–0.89; P = 0.01) as well as transplant related mortality (TRM; adjusted HR, 0.48; 95% CI, 0.27–0.86, P = 0.01). The recipient G/G or A/G genotype was associated with a better OS (adjusted HR, 0.68; 95% CI, 0.47–0.99; P = 0.05) and a trend toward a reduced TRM (adjusted HR, 0.61; 95% CI, 0.35–1.06; P = 0.08). Granzyme B polymorphism did not have any effect on the transplant outcomes in patients with lymphoid malignancies consisting of acute lymphoid leukemia and malignant lymphoma. These data suggest that there is an association between the granzyme B genotype and better clinical outcomes in patients with myeloid malignancies after unrelated BMT