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In Saccharomyces cerevisiae, the J-protein Zuo1 and the nonconventional Hsp70 homologue Ssz1 stimulate the ATPase activity of the chaperone proteins Ssb1 and Ssb2 (Ssb1/2), which are associated with the ribosomes. The dephosphorylation of sucrose nonfermenting 1 (Snf1) on Thr210 is required for glucose repression. The Ssb1/2 and 14-3-3 proteins Bmh1 and Bmh2 appear to be responsible for the dephosphorylation of Snf1 on Thr210 and glucose repression. Here, we investigated the role of Zuo1 in glucose repression. The zuo1∆ strain as well as the ssb1∆ssb2∆ strain exhibited a glucose-specific growth defect during logarithmic growth on glucose. Many of the respiratory chain genes examined were statistically significantly upregulated, but less than 2-fold, in the zuo1∆ strain as well as in the ssb1∆ssb2∆ strain on glucose. In addition, excessive phosphorylation of Snf1 on Thr210 was observed in the zuo1∆ strain as well as in the ssb1∆ssb2∆ strain in the presence of glucose. The mRNA levels of SSB1/2 and BMH1 were statistically significantly reduced by approximately 0.5- to 0.8-fold relative to the wild-type level in the zuo1∆ strain on glucose. These results suggest that Zuo1 is responsible for glucose repression, possibly by increasing the mRNA levels of SSB1/2 and BMH1 during growth on glucose., (© The Author(s) 2023. Published by Oxford University Press on behalf of FEMS.)

Background: The macrophage infectivity potentiator (Mip) protein, which belongs to the immunophilin superfamily, is a peptidyl-prolyl cis/trans isomerase (PPIase) enzyme. Mip has been shown to be important for virulence in a wide range of pathogenic microorganisms. It has previously been demonstrated that small-molecule compounds designed to target Mip from the Gram-negative bacterium Burkholderia pseudomallei bind at the site of enzymatic activity of the protein, inhibiting the in vitro activity of Mip., Objectives: In this study, co-crystallography experiments with recombinant B. pseudomallei Mip (BpMip) protein and Mip inhibitors, biochemical analysis and computational modelling were used to predict the efficacy of lead compounds for broad-spectrum activity against other pathogens., Methods: Binding activity of three lead compounds targeting BpMip was verified using surface plasmon resonance spectroscopy. The determination of crystal structures of BpMip in complex with these compounds, together with molecular modelling and in vitro assays, was used to determine whether the compounds have broad-spectrum antimicrobial activity against pathogens., Results: Of the three lead small-molecule compounds, two were effective in inhibiting the PPIase activity of Mip proteins from Neisseria meningitidis, Klebsiella pneumoniae and Leishmania major. The compounds also reduced the intracellular burden of these pathogens using in vitro cell infection assays., Conclusions: These results indicate that Mip is a novel antivirulence target that can be inhibited using small-molecule compounds that prove to be promising broad-spectrum drug candidates in vitro. Further optimization of compounds is required for in vivo evaluation and future clinical applications., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Interferon regulatory factor 5 (IRF5) is a master regulator of macrophage phenotype and a key transcription factor involved in expression of proinflammatory cytokine responses to microbial and viral infection. Here, we show that IRF5 controls cellular and metabolic responses. By integrating ChIP sequencing (ChIP-Seq) and assay for transposase-accessible chromatin using sequencing (ATAC)-seq data sets, we found that IRF5 directly regulates metabolic genes such as hexokinase-2 (Hk2). The interaction of IRF5 and metabolic genes had a functional consequence, as Irf5 -/- airway macrophages but not bone marrow-derived macrophages (BMDMs) were characterized by a quiescent metabolic phenotype at baseline and had reduced ability to utilize oxidative phosphorylation after Toll-like receptor (TLR)-3 activation, in comparison to controls, ex vivo. In a murine model of influenza infection, IRF5 deficiency had no effect on viral load in comparison to wild-type controls but controlled metabolic responses to viral infection, as IRF5 deficiency led to reduced expression of Sirt6 and Hk2. Together, our data indicate that IRF5 is a key component of AM metabolic responses following influenza infection and TLR-3 activation., (© 2021 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology.)

The dynamics of predator-prey interactions vary enormously, due both to the heterogeneity of natural environments and to wide variability in the sensorimotor systems of predator and prey. In addition, most predators pursue a range of different types of prey, and most organisms are preyed upon by a variety of predators. We do not yet know whether predators employ a general kinematic and behavioral strategy, or whether they tailor their pursuits to each type of prey; nor do we know how widely prey differ in their survival strategies and sensorimotor capabilities. To gain insight into these questions, we compared aerial predation in 4 species of libelluid dragonflies pursuing 4 types of dipteran prey, spanning a range of sizes. We quantified the proportion of predation attempts that were successful (capture success), as well as the total time spent and the distance flown in pursuit of prey (capture efficiency). Our results show that dragonfly prey-capture success and efficiency both decrease with increasing size of prey, and that average prey velocity generally increases with size. However, it is not clear that the greater distances and times required for capturing larger prey are due solely to the flight performance (e.g., speed or evasiveness) of the prey, as predicted. Dragonflies initiated pursuits of large prey when they were located farther away, on average, as compared to small prey, and the total distance flown in pursuit was correlated with initial distance to the prey. The greater initial distances observed during pursuits of larger prey may arise from constraints on dragonflies' visual perception; dragonflies typically pursued prey subtending a visual angle of 1°, and rarely pursued prey at visual angles greater than 3°. Thus, dragonflies may be unable to perceive large prey flying very close to their perch (subtending a visual angle greater than 3-4°) as a distinct target. In comparing the performance of different dragonfly species that co-occur in the same habitat, we found significant differences that are not explained by body size, suggesting that some dragonflies may be specialized for pursuing particular types of prey. Our results underscore the importance of performing comparative studies of predator-prey interactions with freely behaving subjects in natural settings, to provide insight into how the behavior of both participants influences the dynamics of the interaction. In addition, it is clear that gaining a full understanding of predator-prey interactions requires detailed knowledge not only of locomotory mechanics and behavior, but also of the sensory capabilities and constraints of both predator and prey.

Gastrointestinal tract cancers constitute a group of highest morbidity both in and outside Japan, and the prognosis still remains unfavorable when the disease has progressed to the unresectable stage. Since the late 1990s, a novel category of anti-cancer drugs, 'molecular-targeted drugs', has become available, and angiogenesis has been considered as one of the most important molecular targets for antitumor therapy since it is essential for tumor growth. Anti-angiogenic therapy inhibits tumor angiogenesis and promotes apoptosis of existing tumor blood vessels, thereby intercepting the supply of oxygen and nutrition essential for tumor growth and metastasis. It was also suggested that anti-angiogenic therapy effectively normalizes abnormal vascular permeability, and thereby decreases the interstitial pressure, which may improve delivery of concomitantly used chemotherapeutic agents to tumor cells. Vascular endothelial growth factor (VEGF) acts as one of the most potent stimulating agents of angiogenesis, and several strategies targeting the VEGF signaling pathway have been developed, including anti-VEGF antibodies, soluble receptors binding directly to VEGF ligand, anti-VEGF receptor (VEGFR) antibodies and VEGFR tyrosine kinase inhibitors. The breakthrough in the clinical development of anti-angiogenic therapy against colorectal cancer came in 2003 with a large prospective, randomized clinical trial of bevacizumab, a monoclonal antibody directed against VEGF. Anti-angiogenic therapy has introduced a highly effective, completely new mode of action in this area and is the new standard of care in advanced colorectal cancer, while still being tested in gastric cancer due to its convincing clinical benefit and its tolerability and combinability with multiple chemotherapeutic agents.

Background: Sleep apnoea (SA) is often observed in haemodialysis patients, but there have been few studies on types of SA and their predictors. We therefore investigated the prevalence and types of SA and the associations between types of SA and clinical factors in haemodialysis patients., Methods: We initially examined nocturnal oxygen desaturation index (ODI) (desaturation of >4%/events per hour) in 119 haemodialysis patients (68 males, mean age of 61.4 years). Patients with ODI of more than five were diagnosed as having SA. Then, 30 patients underwent polysomnography and we measured Apnoea-hypopnoea index (AHI), which was calculated as the number of apnoeas plus hypopnoeas per hour of sleep. Clinical characteristics were examined in all patients., Results: Forty-one (34.5%) of the 119 patients had SA. Twenty-seven (22.7%) of the 119 patients had SA with subjective symptoms such as daytime somnolence and snoring. There was a significant difference between body mass index (BMI) in patients with SA and that in patients without SA (22.5 vs 19.8 kg/m2, P<0.001). There were significantly higher prevalences of hypertension (85.4 vs 66.7%, P<0.05) and diabetes mellitus (36.6 vs 10.3%, P<0.01) in patients with SA than those in patients without SA. Multivariable analysis showed that BMI was independently associated with the occurrence of SA (OR 1.20, 95% CI 1.05-1.38). Mean AHI of 30 patients who underwent polysomnography was 53.2+/-28.9 [central apnoea, 4.1+/-5.6 (8%); obstructive apnoea, 21.7+/-21.5 (42%); mixed apnoea, 4.9+/-8.0 (9%); hypopnoea, 21.4+/-15.5 (41%)]. The number of obstructive apnoea events per hour was significantly correlated with BUN (r=0.490, P<0.01), Cr (r=0.418, P<0.05) and BMI (r=0.489, P<0.01) and was inversely correlated with serum bicarbonate (r=-0.646, P<0.01) and brain natriuretic peptide (BNP) (r=-0.481, P<0.01). The number of central apnoea events per hour was correlated inversely with PaO2 (r=-0.393, P<0.05) and PaCO2 (r=-0.388, P<0.05) and tended to be correlated with cardiothoracic ratio (CTR) (r=0.347, P=0.060)., Conclusions: There is a high prevalence of SA in haemodialysis patients. The dominant type of SA in haemodialysis patients is obstructive sleep apnoea (OSA). Uraemia (BUN, Cr), metabolic acidosis (serum bicarbonate) and BMI are good predictors of OSA. PaO2, PaCO2 and CTR are good predictors of central sleep apnoea (CSA). Good management of these factors might improve SA in haemodialysis patients.

The effects of vasoactive intestinal polypeptide (VIP), dopamine, and somatostatin (SRIF) on GH secretion were examined in vitro in perifused pituitary adenoma tissues obtained at surgery from seven patients with acromegaly. The perifusion of VIP at 5 x 10(-8) M resulted in a significant increase in effluent GH levels in five of the seven adenomas. A dose-related GH response was observed from 5 x 10(-9) to 5 x 10(-7) M VIP in two adenomas examined. SRIF at 5 x 10(-8) to 10(-7) M suppressed not only baseline secretion of GH but also inhibited GH rises elicited by VIP in six of the seven adenomas. Dopamine at 5 x 10(-7) to 5 x 10(-6) M decreased the baseline secretion of GH in six of the seven adenomas. In four of the six adenomas responsive to dopamine, dopamine suppressed VIP-induced GH release when perifused simultaneously. In the remaining two dopamine-sensitive adenomas in which VIP alone failed to affect GH release, the inhibition by dopamine of GH release was blocked by VIP perifused concomitantly with dopamine. Synthetic TRH or theophylline perifused at the end of the experiment stimulated GH release in all of the adenomas, indicating the viability of tumor cells throughout the study. These results suggest that VIP stimulates GH release by its direct action on pituitary adenoma cells of acromegalic patients and that VIP, SRIF, and dopamine interact at the pituitary level in modulating GH secretion from these adenomas.

Immunoreactive human growth hormone-releasing factor (I-hGRF) in human cerebrospinal fluid (CSF) was measured by radioimmunoassay using antiserum specific to the C-terminal portion of hGRF(1-44)NH2. Dilution curves of I-hGRF in the CSF were completely parallel to that of synthetic hGRF(1-44)NH2 standard. On Sephadex G-50 column chromatography a single peak of I-hGRF in the CSF was eluted at the position of synthetic hGRF(1-44)NH2. I-hGRF was present in the CSF of all control patients without any endocrine disease (mean +/- SE, 29.3 +/- 2.0 pg/ml) whereas I-hGRF in the CSF was not detectable (less than 5.8 pg/ml) in any of the patients with hypothalamic germinoma. In all patients with idiopathic GH deficiency, I-hGRF in the CSF was measurable but its concentration (15.1 +/- 1.0 pg/ml) was significantly (p less than 0.05) lower than that in the control subjects. No difference in I-hGRF levels of the CSF was observed between patients with acromegaly and control subjects. These findings demonstrate for the first time that I-hGRF is present in human CSF. Measurement of I-hGRF in the CSF may be useful for understanding the pathophysiology of hypothalamo-pituitary diseases.

Synthetic vasoactive intestinal polypeptide (VIP) administered either intraventricularly or iv caused a significant and dose-related increase in plasma PRL levels in urethane-anesthetized rats. The administration of naloxone, an opiate receptor antagonist, significantly blunted the plasma PRL response to VIP. Increases in plasma PRL induced by VIP were also significantly suppressed by L-dopa, a precursor of dopamine, whereas pilocarpine, a cholinergic agonist, diphenhydramine, a histamine antagonist, and cyproheptadine, an antiserotoninergic agent, did not affect the plasma PRL response to VIP. In in vitro experiments, VIP alone did not stimulate PRL release from cultured pituitary cells, but it significantly attenuated the inhibitory action of dopamine, which was not blocked by naloxone. These results suggest that VIP stimulates rat PRL secretion, at least in part, through activation of an opiate receptor in the central nervous system and by blocking the inhibitory action of a dopaminergic mechanism at the pituitary level.

Bombesin was injected into the cerebral ventricle of male rats anesthetized with urethane to study its effect on plasma levels of immunoreactive somatostatin (IRS) in hypophysial portal and jugular blood. An intraventricular injection of bombesin (0.2 and 2 micrograms/rat) caused a significant and dose-related increase in plasma IRS in hypophysial portal blood but not in jugular blood. Although bombesin placed into the cerebral ventricle is known to stimulate glucagon and epinephrine release, an iv injection of glucagon (100 micrograms/100 g BW) or epinephrine (2.5 micrograms/100 g BW) did not cause any significant changes in plasma IRS levels in hypophysial portal and jugular blood, suggesting that these substances do not mediate bombesin stimulation of portal IRS release. Pretreatment with naloxone (75 micrograms/100 g BW, iv) failed to affect the portal IRS release induced by bombesin (2 micrograms/rat), indicating that the opiate receptor is not likely to be involved in this reaction. To ascertain whether IRS released by bombesin into hypophysial portal blood is biologically active, the effect of bombesin on the plasma GH level was then examined. Bombesin (2 micrograms/rat) injected intraventricularly completely suppressed the rise of plasma GH after the intraventricular injection of beta-endorphin (1 microgram/rat) or the iv injection of prostaglandin E1 (5 micrograms/100 g BW). Bombesin thus appears to stimulate the secretion of IRS, and probably biologically active somatostatin as well, from the hypothalamus into hypophysial portal blood, thereby inhibiting GH release from the anterior pituitary.