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Objective: To explore the mechanism of electroacupuncture (EA) in promoting recovery of the facial function with the involvement of autophagy, glial cell line-derived neurotrophic factor (GDNF), and phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway. Methods: Seventy-two male Sprague-Dawley rats were randomly allocated into the control, sham-operated, facial nerve injury (FNI), EA, EA+3-methyladenine (3-MA), and EA+GDNF antagonist groups using a random number table, with 12 rats in each group. An FNI rat model was established with facial nerve crushing method. EA intervention was conducted at Dicang (ST 4), Jiache (ST 6), Yifeng (SJ 17), and Hegu (LI 4) acupoints for 2 weeks. The Simone's 10-Point Scale was utilized to monitor the recovery of facial function. The histopathological evaluation of facial nerves was performed using hematoxylin-eosin (HE) staining. The levels of Beclin-1, light chain 3 (LC3), and P62 were detected by immunohistochemistry (IHC), immunofluorescence, and reverse transcription-polymerase chain reaction, respectively. Additionally, IHC was also used to detect the levels of GDNF, Rai, PI3K, and mTOR. Results: The facial functional scores were significantly increased in the EA group than the FNI group (P<0.05 or P<0.01). HE staining showed nerve axons and myelin sheaths, which were destroyed immediately after the injury, were recovered with EA treatment. The expressions of Beclin-1 and LC3 were significantly elevated and the expression of P62 was markedly reduced in FNI rats (P<0.01); however, EA treatment reversed these abnormal changes (P<0.01). Meanwhile, EA stimulation significantly increased the levels of GDNF, Rai, PI3K, and mTOR (P<0.01). After exogenous administration with autophagy inhibitor 3-MA or GDNF antagonist, the repair effect of EA on facial function was attenuated (P<0.05 or P<0.01). Conclusions: EA could promote the recovery of facial function and repair the facial nerve damages in a rat model of FNI. EA may exert this neuroreparative effect through mediating the release of GDNF, activating the PI3K/mTOR signaling pathway, and further regulating the autophagy of facial nerves. [ABSTRACT FROM AUTHOR]

Vancomycin (VCM)'s nephrotoxicity limits its application and therapeutic efficiency. The aim of this study was to determine the protective effect of rhein against VCM-induced nephrotoxicity (VIN). VIN models were established in rats and NRK-52E cells. Rhein up-regulated the expressions of renal organic anion transporter (Oat) 1, Oat3, organic cation transporter 2 (Oct2), multidrug resistance-associated protein 2 (Mrp2), mammal multidrug and toxin extrusion proteins 1 (Mate 1) and P-glycoprotein (P-gp) to facilitate the efflux of plasma creatinine, blood urea nitrogen (BUN), and plasma indoxyl sulfate. Rhein increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) to regulate the expression of Mrp2, P-gp, and Mate 1. The increased level of superoxide dismutase (SOD), decreased level of malondialdehyde (MDA) and reduced number of apoptosis cells were observed after treatment of rhein. Rhein decreased the number of apoptosis cells as well as increased the expression of B-cell lymphoma-2 (Bcl-2) and decreased expressions of Bcl-2-like protein 4 (Bax). ML385, as a typical inhibitor of Nrf2, reversed the protective effects of rhein in cells. Rhein oriented itself in the site of Keap1, inhibiting the Keap1-Nrf2 interaction. Rhein ameliorated VIN mainly through regulating the expressions of renal transporters and acting on Nrf2 pathway. [ABSTRACT FROM AUTHOR]

Initiation and maintenance of transcriptional states are critical for controlling normal tissue homeostasis and differentiation. The cyclin dependent kinases CDK8 and CDK19 (Mediator kinases) are regulatory components of Mediator, a highly conserved complex that orchestrates enhancer-mediated transcriptional output. While Mediator kinases have been implicated in the transcription of genes necessary for development and growth, its function in mammals has not been well defined. Using genetically defined models and pharmacological inhibitors, we showed that CDK8 and CDK19 function in a redundant manner to regulate intestinal lineage specification in humans and mice. The Mediator kinase module bound and phosphorylated key components of the chromatin remodeling complex switch/sucrose non-fermentable (SWI/SNF) in intestinal epithelial cells. Concomitantly, SWI/SNF and MED12-Mediator colocalized at distinct lineage-specifying enhancers in a CDK8/19-dependent manner. Thus, these studies reveal a transcriptional mechanism of intestinal cell specification, coordinated by the interaction between the chromatin remodeling complex SWI/SNF and Mediator kinase. [ABSTRACT FROM AUTHOR]

Leigh disease, or subacute necrotizing encephalomyelopathy, a genetically heterogeneous condition consistently characterized by defective mitochondrial bioenergetics, is the most common oxidative-phosphorylation related disease in infancy. Both neurological signs and pathological lesions of Leigh disease are mimicked by the ablation of the mouse mitochondrial respiratory chain subunit Ndufs4-/-, which is part of, and crucial for, normal Complex I activity and assembly, particularly in the brains of both children and mice. We previously conveyed the human NDUFS4 gene to the mouse brain using either single-stranded adeno-associated viral 9 recombinant vectors or the PHP.B adeno-associated viral vector. Both these approaches significantly prolonged the lifespan of the Ndufs4-/- mouse model but the extension of the survival was limited to a few weeks by the former approach, whereas the latter was applicable to a limited number of mouse strains, but not to primates. Here, we exploited the recent development of new, self-complementary adeno-associated viral 9 vectors, in which the transcription rate of the recombinant gene is markedly increased compared with the single-stranded adeno-associated viral 9 and can be applied to all mammals, including humans. Either single intra-vascular or double intra-vascular and intra-cerebro-ventricular injections were performed at post-natal Day 1. The first strategy ubiquitously conveyed the human NDUFS4 gene product in Ndufs4-/- mice, doubling the lifespan from 45 to ≈100 days after birth, when the mice developed rapidly progressive neurological failure. However, the double, contemporary intra-vascular and intra-cerebroventricular administration of self-complementary-adeno-associated viral NDUFS4 prolonged healthy lifespan up to 9 months of age. These mice were well and active at euthanization, at 6, 7, 8 and 9 months of age, to investigate the brain and other organs post-mortem. Robust expression of hNDUFS4 was detected in different cerebral areas preserving normal morphology and restoring Complex I activity and assembly. Our results warrant further investigation on the translatability of self-complementary-adeno-associated viral 9 NDUFS4-based therapy in the prodromal phase of the disease in mice and eventually humans. [ABSTRACT FROM AUTHOR]

Background: General anaesthesia in the neonatal period has detrimental effects on the developing mammalian brain. The impact of underlying inflammation on anaesthesia-induced developmental neurotoxicity remains largely unknown.Methods: Postnatal day 7 (PND7) rats were randomly assigned to receive sevoflurane (3 vol% for 3 h) or carrier gas 12 h after bacterial lipopolysaccharide (LPS; 1 μg g-1) or vehicle injection. Pharmacological inhibition of caspase-1 by Vx-765 (two doses of 50 μg g-1 body weight) was used to investigate mechanistic pathways of neuronal injury. Histomorphological injury and molecular changes were quantified 2 h after the end of anaesthesia. Long-term functional deficits were tested at 5-8 weeks of age using a battery of behavioural tests in the memory and anxiety domains.Results: Sevoflurane or LPS treatment increased activated caspase-3 and caspase-9 expression in the hippocampal subiculum and CA1, which was greater when sevoflurane was administered in the setting of LPS-induced inflammation. Neuronal injury induced by LPS+sevoflurane treatment resulted in sex-specific behavioural outcomes when rats were tested at 5-8 weeks of age, including learning and memory deficits in males and heightened anxiety-related behaviour in females. Hippocampal caspase-1 and NLRP1 (NLR family pyrin domain containing 1), but not NLRP3, were upregulated by LPS or LPS+sevoflurane treatment, along with related proinflammatory cytokines, interleukin (IL)-1β, and IL-18. Pretreatment with Vx-765, a selective caspase-1 inhibitor, led to reduced IL-1β in LPS and LPS+sevoflurane groups. Caspase-1 inhibition by Vx-765 significantly decreased activated caspase-3 and caspase-9 immunoreactivity in the subiculum.Conclusions: Systemic inflammation promotes developmental neurotoxicity by worsening anaesthesia-induced neuronal damage with sex-specific behavioural outcomes. This highlights the importance of studying anaesthesia-induced neurotoxicity in more clinically relevant settings. [ABSTRACT FROM AUTHOR]

Chronic wasting disease (CWD) is the transmissible spongiform encephalopathy or prion disease affecting cervids. In 2016, the first cases of CWD were reported in Europe in Norwegian wild reindeer and moose. The origin and zoonotic potential of these new prion isolates remain unknown. In this study to investigate zoonotic potential we inoculated brain tissue from CWD-infected Norwegian reindeer and moose into transgenic mice overexpressing human prion protein. After prolonged postinoculation survival periods no evidence for prion transmission was seen, suggesting that the zoonotic potential of these isolates is low. [ABSTRACT FROM AUTHOR]

In mammalian cells, DNA damage response initiates repair by error-free homologous recombination (HRR) or by error-prone non-homologous end joining (NHEJ). DNA damage is detected by PARP proteins that facilitate this repair, both in normal cells and in cancer cells. Cells containing BRCA1/2 mutations have an HRR-deficient repair mechanism which may result in unrepaired one-ended double-strand breaks and stalled replication forks, considered as the most lethal cell damage. Here, we review the state of the art of the role of Poly (ADP-ribose) polymerase (PARP) inhibitors as a precision-targeted anticancer drug in BRCA1/2-mutated female breast cancer. Although knowledge is incomplete, it is assumed that the main role of the archetype PARP1 in the cell nucleus is to detect and adhere to single-strand breaks. This mediates possible damage repair, after which cells may continue replication; this process is called synthetic lethality. As for PARP clinical monotherapy, progression-free survival has been observed using the FDA- and EMA-approved drugs olaparib and talazoparib. In the case of combined drug therapy, a synergy has been demonstrated between veliparib and platinum drugs. Information regarding adverse effects is limited, but hematological effects have been described. However, there is need for multicenter trials, preferably conducted without commercial guidance and funding. Some of the available trials reported resistance to PARP inhibitors. In this review, we also describe the various causes of resistance to PARP inhibitors and research indicating how resistance can be overcome. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction plays a central role in type 2 diabetes (T2D); however, the pathogenic mechanisms in pancreatic β-cells are incompletely elucidated. Succinate dehydrogenase (SDH) is a key mitochondrial enzyme with dual functions in the tricarboxylic acid cycle and electron transport chain. Using samples from human with diabetes and a mouse model of β-cell-specific SDH ablation (SDHBβKO), we define SDH deficiency as a driver of mitochondrial dysfunction in β-cell failure and insulinopenic diabetes. β-Cell SDH deficiency impairs glucose-induced respiratory oxidative phosphorylation and mitochondrial membrane potential collapse, thereby compromising glucose-stimulated ATP production, insulin secretion, and β-cell growth. Mechanistically, metabolomic and transcriptomic studies reveal that the loss of SDH causes excess succinate accumulation, which inappropriately activates mammalian target of rapamycin (mTOR) complex 1-regulated metabolic anabolism, including increased SREBP-regulated lipid synthesis. These alterations, which mirror diabetes-associated human β-cell dysfunction, are partially reversed by acute mTOR inhibition with rapamycin. We propose SDH deficiency as a contributing mechanism to the progressive β-cell failure of diabetes and identify mTOR complex 1 inhibition as a potential mitigation strategy. [ABSTRACT FROM AUTHOR]

Although the genetic basis of many kidney diseases is being rapidly elucidated, their experimental study remains problematic owing to the lack of suitable models. The fruitfly Drosophila melanogaster provides a rapid, ethical and cost-effective model system of the kidney. The unique advantages of D. melanogaster include ease and low cost of maintenance, comprehensive availability of genetic mutants and powerful transgenic technologies, and less onerous regulation, as compared with mammalian systems. Renal and excretory functions in D. melanogaster reside in three main tissues - the transporting renal (Malpighian) tubules, the reabsorptive hindgut and the endocytic nephrocytes. Tubules contain multiple cell types and regions and generate a primary urine by transcellular transport rather than filtration, which is then subjected to selective reabsorption in the hindgut. By contrast, the nephrocytes are specialized for uptake of macromolecules and equipped with a filtering slit diaphragm resembling that of podocytes. Many genes with key roles in the human kidney have D. melanogaster orthologues that are enriched and functionally relevant in fly renal tissues. This similarity has allowed investigations of epithelial transport, kidney stone formation and podocyte and proximal tubule function. Furthermore, a range of unique quantitative phenotypes are available to measure function in both wild type and disease-modelling flies. [ABSTRACT FROM AUTHOR]

Introduction: Little is known about the glycosylation of placental villi and areolae of cetaceans. Term tissue from the delivered placenta of an Indo-Pacific Bottlenose Dolphin (Tursiops aduncus) was examined using lectin histochemistry to compare trophoblast glycosylation in these two locations.Methods: Placental blocks fixed in 10% formalin were resin-embedded before semithin sections were stained with 24 biotinylated lectins and an avidin-biotin revealing system.Results: Areolar trophoblast was composed of large, bulbous cells packed with numerous granules compared to the smaller, cuboidal cells clothing the chorionic villi, which had a sparser, mainly subapical granule population. Both were richly glycosylated; generally areolar cells were more heavily stained apart from poor binding to some N-acetylgalactosamine and N-acetylglucosamine termini. Most striking was the distribution of α1,2-linked fucosyl residues, weakly expressed in villous trophoblast but intensely stained in some areolar cells, also terminal sialic acids. Some lectins bound in a variable fashion. Staining of terminal α-d-mannose, which locates mainly to lysosomes, was heavy in areolar cells compared to scattered irregular foci in villous cells.Discussion and Conclusion: The many intracellular inclusions reflect ongoing lysosomal breakdown of histotroph in areolar cells which often show heterogeneous glycosylation staining unlike the uniformly stained villous cells, possibly reflecting partial breakdown of ingested sialoglycoprotein, cell turnover or regional variation in uptake of histotroph. Our results indicate that Dolphin areolae are functionally distinct from villous trophoblast, performing absorptive and phagocytic functions similar to other Artiodactyla. [ABSTRACT FROM AUTHOR]

Background: Triosephosphate isomerase 1 (TPI1), as a key glycolytic enzyme, is upregulated in multiple cancers. However, expression profile and regulatory mechanism of TPI1 in breast cancer (BRCA) remain mysterious.Methods: Western blotting and immunohistochemistry (IHC) assays were used to investigate the expression of TPI1 in BRCA specimens and cell lines. TPI1 correlation with the clinicopathological characteristics and prognosis of 362 BRCA patients was analyzed using a tissue microarray. Overexpression and knockdown function experiments in cells and mice models were performed to elucidate the function and mechanisms of TPI1-induced BRCA progression. Related molecular mechanisms were clarified using co-IP, IF, mass spectrometric analysis, and ubiquitination assay.Results: We have found TPI1 is highly expressed in BRCA tissue and cell lines, acting as an independent indicator for prognosis in BRCA patients. TPI1 promotes BRCA cell glycolysis, proliferation and metastasis in vitro and in vivo. Mechanistically, TPI1 activates phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway to regulate epithelial-mesenchymal transformation (EMT) and aerobic glycolysis, which is positively mediated by cell division cycle associated 5 (CDCA5). Moreover, TPI1 interacts with sequestosome-1 (SQSTM1)/P62, and P62 decreases the protein expression of TPI1 by promoting its ubiquitination in MDA-MB-231 cells.Conclusions: TPI1 promotes BRCA progression by stabilizing CDCA5, which then activates the PI3K/AKT/mTOR pathway. P62 promotes ubiquitin-dependent proteasome degradation of TPI1. Collectively, TPI1 promotes tumor development and progression, which may serve as a therapeutic target for BRCA. [ABSTRACT FROM AUTHOR]

Purpose: Cancer stem cells (CSCs) reported in various tumors play a crucial role in tumorigenesis and metastasis of retinoblastoma (Rb). Following the efforts to reduce, replace, and refine the use of mammalian models, we aimed to establish a short-term xenograft for Rb to evaluate the CSC properties of CD133- Rb Y79 cells, using the well-established chick embryo chorioallantoic membrane (CE-CAM) assay.Methods: Y79 cells were cultured, labeled with two different dyes (CM-Dil Y79 and enhanced green fluorescent protein (eGFP)) and sorted for CD133- and CD133 + subsets. Two million cells from each of the labeled groups were transplanted onto the abraded CAM on embryonic day 7 (E7). On E14, the tumor nodule formation on CAM and spontaneous metastasis to the embryos were evaluated by confocal microscopy, in vivo imaging, and histology.Results: Y79 cells formed pink-white raised perivascular nodules with feeder vessels on the CAM with both the types of labeled CD133- cells. CD133- cells, when compared to CD133 + cells, demonstrated significantly larger tumor volume (40.45 ± 7.744 mm3 vs 3.478 ± 0.69 mm3, P = 0.0014) and higher fluorescence intensity (CM-Dil: AUF = 6.37 × 107 ± 7.7 × 106 vs 1.08 × 107 ± 1.6 × 106; P < 0.0001; eGFP: AUF = 13.94 × 104 ± 2.54 × 104 vs AUF = 1.39 × 104 ± 0.4 × 104; P = 0.0003). The metastatic potential of CD133- cells was also observed to be higher as noted by in vivo imaging and histopathology.Conclusion: This study highlights that CE-CAM is a feasible alternative nonmammalian model for evaluating tumorigenicity and metastatic potential of Y79 CSCs. Increased tumorigenicity and metastatic potential of CD133- subset of tumor cells substantiate their CSC properties. [ABSTRACT FROM AUTHOR]

Endothelial nitric oxide synthase (eNOS) monomerization and uncoupling play crucial roles in mediating vascular dysfunction in diabetes, although the underlying mechanisms are still incompletely understood. Increasing evidence indicates that autophagic dysregulation is involved in the pathogenesis of diabetic endothelial dysfunction; however, whether autophagy regulates eNOS activity through controlling eNOS monomerization or dimerization remains elusive. In this study, autophagic flux was impaired in the endothelium of diabetic db/db mice and in human endothelial cells exposed to advanced glycation end products or oxidized low-density lipoprotein. Inhibition of autophagic flux by chloroquine or bafilomycin A1 were sufficient to induce eNOS monomerization and lower nitric oxide bioavailability by increasing mitochondrial reactive oxygen species (mtROS). Restoration of autophagic flux by overexpressing transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis, decreased endothelial cell oxidative stress, increased eNOS dimerization, and improved endothelium-dependent relaxations (EDRs) in db/db mouse aortas. Inhibition of mammalian target of rapamycin kinase (mTOR) increased TFEB nuclear localization, reduced mtROS accumulation, facilitated eNOS dimerization, and enhanced EDR in db/db mice. Moreover, calorie restriction also increased TFEB expression, improved autophagic flux, and restored EDR in the aortas of db/db mice. Taken together, the findings of this study reveal that mtROS-induced eNOS monomerization is closely associated with the impaired TFEB-autophagic flux axis leading to endothelial dysfunction in diabetic mice. [ABSTRACT FROM AUTHOR]

Study Question: Does direct kisspeptin signaling in the oocyte have a role in the control of follicular dynamics and ovulation?Summary Answer: Kisspeptin signaling in the oocyte plays a relevant physiological role in the direct control of ovulation; oocyte-specific ablation of kisspeptin receptor, Gpr54, induces a state of premature ovulatory failure in mice that recapitulates some features of premature ovarian insufficiency (POI).What Is Known Already: Kisspeptins, encoded by the Kiss1 gene, are essential for the control of ovulation and fertility, acting primarily on hypothalamic GnRH neurons to stimulate gonadotropin secretion. However, kisspeptins and their receptor, Gpr54, are also expressed in the ovary of different mammalian species, including humans, where their physiological roles remain contentious and poorly characterized.Study Design, Size, Duration: A novel mouse line with conditional ablation of Gpr54 in oocytes, named OoGpr54-/-, was generated and studied in terms of follicular and ovulatory dynamics at different age-points of postnatal maturation. A total of 59 OoGpr54-/- mice and 47 corresponding controls were analyzed. In addition, direct RNA sequencing was applied to ovarian samples from 8 OoGpr54-/- and 7 control mice at 6 months of age, and gonadotropin priming for ovulatory induction was conducted in mice (N = 7) from both genotypes.Participants/materials, Setting, Methods: Oocyte-selective ablation of Gpr54 in the oocyte was achieved in vivo by crossing a Gdf9-driven Cre-expressing transgenic mouse line with a Gpr54 LoxP mouse line. The resulting OoGpr54-/- mouse line was subjected to phenotypic, histological, hormonal and molecular analyses at different age-points of postnatal maturation (Day 45, and 2, 4, 6 and 10-11 months of age), in order to characterize the timing of puberty, ovarian follicular dynamics and ovulation, with particular attention to identification of features reminiscent of POI. The molecular signature of ovaries from OoGpr54-/- mice was defined by direct RNA sequencing. Ovulatory responses to gonadotropin priming were also assessed in OoGpr54-/- mice.Main Results and the Role Of Chance: Oocyte-specific ablation of Gpr54 caused premature ovulatory failure, with some POI-like features. OoGpr54-/- mice had preserved puberty onset, without signs of hypogonadism. However, already at 2 months of age, 40% of OoGpr54-/- females showed histological features reminiscent of ovarian failure and anovulation. Penetrance of the phenotype progressed with age, with >80% and 100% of OoGpr54-/- females displaying complete ovulatory failure by 6- and 10 months, respectively. This occurred despite unaltered hypothalamic Gpr54 expression and gonadotropin levels. Yet, OoGpr54-/- mice had decreased sex steroid levels. While the RNA signature of OoGpr54-/- ovaries was dominated by the anovulatory state, oocyte-specific ablation of Gpr54 significantly up- or downregulated of a set of 21 genes, including those encoding pituitary adenylate cyclase-activating polypeptide, Wnt-10B, matrix-metalloprotease-12, vitamin A-related factors and calcium-activated chloride channel-2, which might contribute to the POI-like state. Notably, the anovulatory state of young OoGpr54-/- mice could be rescued by gonadotropin priming.Large Scale Data: N/A. .Limitations, Reasons For Caution: Conditional ablation of Gpr54 in oocytes unambiguously caused premature ovulatory failure in mice; yet, the ultimate molecular mechanisms for such state of POI can be only inferred on the basis of RNAseq data and need further elucidation, since some of the molecular changes observed in OoGpr54-/- ovaries were secondary to the anovulatory state. Direct translation of mouse findings to human disease should be made with caution since, despite the conserved expression of Kiss1/kisspeptin and Gpr54 in rodents and humans, our mouse model does not recapitulate all features of common forms of POI.Wider Implications Of the Findings: Deregulation of kisspeptin signaling in the oocyte might be an underlying, and previously unnoticed, cause for some forms of POI in women.Study Funding/competing Interest(s): This work was primarily supported by a grant to M.P. and M.T.-S. from the FiDiPro (Finnish Distinguished Professor) Program of the Academy of Finland. Additional financial support came from grant BFU2017-83934-P (M.T.-S.; Ministerio de Economía y Competitividad, Spain; co-funded with EU funds/FEDER Program), research funds from the IVIRMA International Award in Reproductive Medicine (M.T.-S.), and EFSD Albert Renold Fellowship Programme (S.T.R.). The authors have no conflicts of interest to declare in relation to the contents of this work.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Objective: The corticotropin-releasing factor neuropeptides (corticotropin-releasing hormone [CRH] and urocortin [UCN]-1,2,3) and spexin contribute to the regulation of energy balance and inhibit food intake in mammals. However, the status of these neuropeptides in children with overweight has yet to be elucidated. This study investigated the effect of increased body weight on the circulating levels of these neuropeptides.Methods: A total of 120 children with a mean age of 12 years were enrolled in the study. Blood samples were collected to assess the circulating levels of neuropeptides and were correlated with various anthropometric, clinical, and metabolic markers.Results: Plasma levels of UCNs were altered in children with overweight but less so in those with obesity. Furthermore, the expression pattern of UCN1 was opposite to that of UCN2 and UCN3, which suggests a compensatory effect. However, no significant effect of overweight and obesity was observed on CRH and spexin levels. Finally, UCN3 independently associated with circulating zinc-alpha-2-glycoprotein and UCN2 levels, whereas UCN1 was strongly predicted by TNFα levels.Conclusions: Significant changes in neuropeptide levels were primarily observed in children with overweight and were attenuated with increased obesity. This suggests the presence of a compensatory mechanism for neuropeptides to curb the progression of obesity. [ABSTRACT FROM AUTHOR]

Objective: G protein-coupled receptor 43 (GPR43), a receptor for short-chain fatty acids, plays a role in suppressing tumor growth; however, the detailed underlying mechanism needs to be comprehensively elucidated. In this study, we investigated the role of GPR43 in inhibiting tumor growth using ApcMin/+, a murine model of intestinal tumors.Materials and Methods: Using GPR43-/- ApcMin/+ and GPR43+/- ApcMin/+ mice, the number of tumors was analyzed at the end of the experimental period. Immunohistochemistry, quantitative polymerase chain reaction, and Western blotting were performed to analyze cellular proliferation and proliferation-associated signal pathways.Results: Our results revealed that GPR43 deficiency resulted in increased tumor numbers in ApcMin/+ mice. Ki67 was highly expressed in GPR43-/- mice (p > 0.05). Increased expression levels of proinflammatory cytokines, including interleukin-6 and tumor necrosis factor-α, and amino acid transporters were not observed in GPR43-deficient mice compared to GPR43-sufficient mice. Furthermore, GPR43-deficient tumor tissues showed enhanced mammalian target of rapamycin-mediated phosphorylated ribosomal protein S6 kinase beta-1 (p > 0.05) and phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (p > 0.05), but not Akt (protein kinase B) phosphorylation (p = 0.7088).Conclusion: Collectively, GPR43 affords protection against tumor growth at least partly through inhibition of the mammalian target of rapamycin complex 1 pathway. [ABSTRACT FROM AUTHOR]

Background: Neurotrophins of the nerve growth factor family are soluble polypeptides that are best known for their role in nerve growth, survival and differentiation in the central nervous system. A growing body of literature shows that neurotrophins and their receptors are also expressed throughout the reproductive tract.Objective and Rationale: Neurotrophins are key regulatory proteins in reproductive physiology during development and throughout adult life. Of the neurotrophins, the literature describing the expression and function of brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, neurotrophin receptor kinase-2 (NTRK2), has been expanding rapidly. We therefore conducted a systematic inductive qualitative review of the literature to better define the role of the BDNF in the reproductive tract. We postulate that BDNF and NTRK2 are central regulatory proteins throughout the reproductive system.Search Methods: An electronic search of Medline (PubMed) and Web of Science for articles relating to BDNF and the reproductive system was carried out between January 2018 and February 2019.Outcomes: In the ovary, BDNF expression and levels have been linked with follicle organisation during ovarian development, follicle recruitment and growth and oocyte maturation. In the endometrium, BDNF is involved in cell proliferation and neurogenesis. In contrast, literature describing the role of BDNF in other reproductive tissues is sparse and BDNF-NTRK2 signalling in the male reproductive tract has been largely overlooked. Whilst estradiol appears to be the primary regulator of BDNF expression, we also identified reports describing binding sites for glucocorticoid and myocyte enhancer factor-2, a calcium-response element through activation of an N-methyl-D-aspartate (NMDA) receptor, and aryl hydrocarbon receptor nuclear transporter protein-4 (ARNT) response elements in promoter regions of the BDNF gene. Expression is also regulated by multiple microRNAs and post-translational processing of precursor proteins and intracellular shuttling. BDNF-NTRK2 signalling is modulated through tissue specific receptor expression of either the full-length or truncated NTRK2 receptor; however, the functional importance remains to be elucidated. Dysregulation of BDNF expression and circulating concentrations have been implicated in several reproductive disorders including premature ovarian failure, endometriosis, pre-eclampsia, intra-uterine growth restriction (IUGR) and several reproductive cancers.Wider Implications: We conclude that BDNF and its receptors are key regulatory proteins central to gonadal development, ovarian regulation and uterine physiology, as well as embryo and placenta development. Furthermore, dysregulation of BDNF-NTRK2 in reproductive diseases suggests their potential role as candidate clinical markers of disease and potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Combined training was beneficial for body composition HIV-infected people. • Combined training did not modify lipid profile and cytokines levels. • Reduction of body fat was not accompanied by metabolic changes. • Patients with lipodystrophy showed reduction of android fat when compared to non-lipodystrophic. Abstract Purpose The aim of this study was to conduct a randomized clinical trial to assess the effects of 16 weeks of combined training on body composition, lipid profile, adiponectin, C-reactive protein (CRP), and leptin levels in people living with HIV/AIDS (PLWHA). Methods Fifty-eight HIV-infected individuals were randomized into a training group (T) or a control group (C). Combined training consisted of aerobic and resistance exercises performed at the same training session, applied at a frequency of three times a week for a total of 16 weeks. Waist circumference, body mass, body fat percentage (%fat), fat mass, lipid profile, adiponectin, CRP, and leptin levels were measured pre- and post-training in both groups. Results Sixteen weeks of combined training decreased (P < 0.05) body fat in different body segments in PLWHA. Lipodystrophic PLWHA experienced greater reduction in body fat in the android region than non-lipodystrophic PLWHA after combined training. Lipid profile and circulating levels of adiponectin, leptin, and CRP remained unchanged. Conclusions Sixteen weeks of combined training was effective to reduce body fat in different body segments, without altering plasma lipid and cytokine levels. [ABSTRACT FROM AUTHOR]

The effects of the intra-ruminal dosing of a glucogenic mixture including 70% glycerol, 20% propylene glycol and 10% water was studied on thirty late lactation dairy ewes of Sarda breed. The animals were divided in two homogeneous groups receiving by gavage either 200 mL of water (CTR group; body weight 40.9 ± 1.5 kg) or 200 mL of the above mixture (GLY group; body weight 39.4 ± 1.3 kg) twice daily from d 16 to d 19 of the oestrus cycle, synchronised by “ram effect”. The ewes were then mated and their reproductive responses to the synchronised mating evaluated by scanning on d 50 and at lambing. During the treatment, the ewes were housed in an open hut, machine milked twice daily and fed concentrate and hay to meet their nutrient requirements. During the treatment, concentrate intake was markedly reduced in GLY when compared with CTR (P < 0.001), without any effect on ewe body weight or body condition. The administration of the glucogenic mixture increased plasma osmolarity and blood volume as estimated by serum total protein concentration. Moreover, it increased plasma content of glycerol, glucose (P < 0.001) and insulin (P < 0.01) while decreasing plasma level of NEFA (P < 0.001) and urea (P < 0.05). Milk yield (P < 0.01) and milk lactose content (P < 0.001) were decreased by the glucogenic treatment, whereas milk protein and casein contents were increased (P < 0.001). As for reproductive performance, the glucogenic treatment numerically increased ewe’s conception rate, but the difference was not statistically significant. Prolificacy did not change between groups. In conclusion, the administration of a glucogenic mixture to late lactation dairy ewes caused significant changes both in plasma and in milk composition during the treatment. However, reproductive performances were unaffected by the treatment. [ABSTRACT FROM AUTHOR]

Abstract: Pesticides must be effective to be commercially viable but they must also be reasonably safe for those who manufacture them, apply them, or consume the food they are used to produce. Animal testing is key to ensuring safety, but it comes late in the agrochemical development process, is expensive, and requires relatively large amounts of material. Surrogate assays used as in vitro models require less material and shift identification of potential mammalian toxicity back to earlier stages in development. Modern in silico methods are cost‐effective complements to such in vitro models that make it possible to predict mammalian metabolism, toxicity and exposure for a pesticide, crop residue or other metabolite before it has been synthesized. Their broader use could substantially reduce the amount of time and effort wasted in pesticide development. This contribution reviews the kind of in silico models that are currently available for vetting ideas about what to synthesize and how to focus development efforts; the limitations of those models; and the practical considerations that have slowed development in the area. Detailed discussions are provided of how bacterial mutagenicity, human cytochrome P450 (CYP) metabolism, and bioavailability in humans and rats can be predicted. © 2018 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Background: Both anesthetic-induced and ischemic preconditioning are protective against hepatic ischemia-reperfusion injury. However, the effects of these preventive methods on the metabolic function remain to be elucidated. We investigated the anesthetic conditioning and ischemic preconditioning on the metabolic function of the rabbit model of hepatic ischemia-reperfusion.Methods: After approval by the institutional animal care and use committee, 36 Japanese White rabbits underwent partial hepatic ischemia for 90 min either under sevoflurane or propofol anesthesia. All the rabbits underwent 90 min of hepatic ischemia, and half of the rabbits in each group underwent additional 10-min ischemia and 10-min reperfusion before index ischemia. Hepatic microvascular blood flow was intermittently measured during reperfusion period, and galactose clearance, serum aminotransferase activities, and lactate concentrations were determined 180 min after reperfusion.Results: Neither anesthetic conditioning with sevoflurane nor ischemic preconditioning altered hepatic microvascular blood flow during reperfusion and serum transaminase activities after reperfusion. However, galactose clearance of reperfused liver was significantly higher under sevoflurane anesthesia than propofol (0.016 ± 0.005/min vs. 0.011 ± 0.004/min). Statistically significant interaction between anesthetic choice and application of ischemic preconditioning suggests that the ischemic preconditioning is selectively protective under propofol anesthesia. Increase of blood lactate concentration was significantly suppressed under sevoflurane anesthesia compared to propofol (1.5 ± 0.8 vs. 3.9 ± 1.4 mmol/l) without any statistically significant interaction with the application of ischemic preconditioning.Conclusion: Sevoflurane attenuated the decrease of galactose clearance and increase of the blood lactate after reperfusion compared to propofol. Application of ischemic preconditioning was significantly protective under propofol anesthesia. [ABSTRACT FROM AUTHOR]

Recent studies highlight that the gut mycobiota play essential roles in mammalian metabolic and immune systems, but to date we lack information on the forces that naturally shape the gut mycobiota of wild primates. To investigate the contributions of host and environmental factors in the taxonomic variation of the gut mycobiota, we examined the effects of age, sex, and season on the fecal mycobiota in wild‐living Tibetan macaques (Macaca thibetana). Using next generation sequencing and a longitudinal set of fecal samples collected over 1 year, we identified a set of core fungal taxa present in the Tibetan macaque's fecal samples. The predominant genera Aspergillus and Penicillium, which promote the digestion of cellulose and hemicellulose in herbivorous mammals, were detected in this study. Similar to humans, we found age and sex effects on the macaques’ fecal mycobiota. We also found that both fecal fungal composition and diversity (alpha and beta diversity) varied significantly by season. In particular, the Penicillium enriched mycobiota in summer samples may aid in the digestion of cellulose and hemicellulose present in mature leaves. The high alpha diversity detected in Tibetan macaques’ winter fecal samples may facilitate a diet rich in fiber ingested during this season. We propose that the gut mycobiota play an important role in the macaques’ ability to adapt to seasonal fluctuations in food availability and nutrient content. [ABSTRACT FROM AUTHOR]

I simulate the natural selection of metabolism and mass to explain the curvature in the metabolic allometry for placental and marsupial mammals. The simulation model starts with a single ancestor in each clade at the Cretaceous–Palaeogene boundary 65 million years ago. The release of inter‐specific competition by the extinction of dinosaurs make it possible for each clade to diversify into a multitude of species across a wide range of empty niches. The selection of mass in these species depends on the net assimilated energy that depends on 1) the handling of the resources in the different niches, and on 2) mass‐specific metabolism that defines the pace of the handling process. The model is fitted to explain the maximum observed body masses over time and the current inter‐specific allometry for metabolism. The selection of mass‐specific metabolism is found to bend the metabolic allometry over time, even when all species have the same selection on the per‐generation time‐scale of natural selection. This is because the smaller species evolve over a larger number of generations than the larger species. The strongest curvature is in the placental clade, where the estimated rate of exponential increase in mass‐specific metabolism is 9.3 × 10−9 (95% CI: 7.3 × 10−9 – 1.1 × 10−8) on the per‐generation time‐scale. This is an order of magnitude larger than the estimate for marsupials, in agreement with an average metabolism that is 30% larger in placentals relative to marsupials of similar size. [ABSTRACT FROM AUTHOR]

Abstract: Understanding the mechanisms driving geographic range sizes of species is a central issue in ecology, but remarkably few rules link physiology with the distributions of species. Maximal metabolic rate (MMR) during exercise is an important measure of physiological performance. It sets an upper limit to sustained activity and locomotor capacity, so MMR may influence ability to migrate, disperse and maintain population connectivity. Using both conventional ordinary least squares (OLS) analyses and phylogenetically generalized least squares (PGLS), we tested whether MMR helps explain geographic range size in 51 species of placental mammals. Log body mass alone (OLS r2 = .074, p = .053; PGLS r2 = .016, p = .373) and log MMR alone (OLS r2 = .140, p = .007; PGLS r2 = .061, p = .081) were weak predictors of log range size. However, multiple regression of log body mass and log MMR accounted for over half of the variation in log range size (OLS R2 = .527, p < .001). The relationship was also strong after correcting for the phylogenetic non‐independence (PGLS R2 = .417, p < .001). In analyses restricted to rodents (34 species), neither log body mass alone (OLS r2 = .004, p = .720; PGLS r2 = .003, p = .77) nor log MMR alone was useful in predicting log geographic range size (OLS r2 = .008, p = .626; PGLS r2 = .046, p = .225), but multiple regressions of log body mass and log MMR accounted for roughly a third to a half of the variation in log range size (OLS R2 = .443, p < .001, PGLS R2 = .381, p < .001). Mass‐independent MMR is a strong predictor of mass‐independent geographic range size in placental mammals. The ability of body mass and MMR to explain nearly 50% of the variation in the geographic ranges of mammals is surprising and powerful, particularly when neither variable alone is strongly predictive. A better understanding of MMR during exercise may be important to understanding the limits of geographic ranges of mammals, and perhaps other animal groups. A plain language summary is available for this article. [ABSTRACT FROM AUTHOR]

Kisspeptin was initially identified as a metastasis suppressor. Shortly after the initial discovery, a key physiologic role for kisspeptin emerged in the regulation of fertility, with kisspeptin acting as a neurotransmitter via the kisspeptin receptor, its cognate receptor, to regulate hypothalamic GnRH neurons, thereby affecting pituitary--gonadal function. Recent work has demonstrated a more expansive role for kisspeptin signaling in a variety of organ systems. Kisspeptin has been revealed as a significant player in regulating glucose homeostasis, feeding behavior, body composition as well as cardiac function. The direct impact of kisspeptin on peripheral metabolic tissues has only recently been recognized. Here, we review the emerging endocrine role of kisspeptin in regulating metabolic function. Controversies and current limitations in the field as well as areas of future studies toward kisspeptin's diverse array of functions will be highlighted. [ABSTRACT FROM AUTHOR]

The immune state of wild animals is largely unknown. Knowing this and what affects it is important in understanding how infection and disease affects wild animals. The immune state of wild animals is also important in understanding the biology of their pathogens, which is directly relevant to explaining pathogen spillover among species, including to humans. The paucity of knowledge about wild animals' immune state is in stark contrast to our exquisitely detailed understanding of the immunobiology of laboratory animals. Making an immune response is costly, and many factors (such as age, sex, infection status, and body condition) have individually been shown to constrain or promote immune responses. But, whether or not these factors affect immune responses and immune state in wild animals, their relative importance, and how they interact (or do not) are unknown. Here, we have investigated the immune ecology of wild house mice—the same species as the laboratory mouse—as an example of a wild mammal, characterising their adaptive humoral, adaptive cellular, and innate immune state. Firstly, we show how immune variation is structured among mouse populations, finding that there can be extensive immune discordance among neighbouring populations. Secondly, we identify the principal factors that underlie the immunological differences among mice, showing that body condition promotes and age constrains individuals’ immune state, while factors such as microparasite infection and season are comparatively unimportant. By applying a multifactorial analysis to an immune system-wide analysis, our results bring a new and unified understanding of the immunobiology of a wild mammal. [ABSTRACT FROM AUTHOR]

Agmatine (1-amino-4-guanidinobutane), a precursor for polyamine biosynthesis, has been identified as an important neuromodulator with anticonvulsant, antineurotoxic and antidepressant actions in the brain. In this context it has emerged as an important mediator of addiction/satiety pathways associated with alcohol misuse. Consequently, the regulation of the activity of key enzymes in agmatine metabolism is an attractive strategy to combat alcoholism and related addiction disorders. Agmatine results from the decarboxylation of L-arginine in a reaction catalyzed by arginine decarboxylase (ADC), and can be converted to either guanidine butyraldehyde by diamine oxidase (DAO) or putrescine and urea by the enzyme agmatinase (AGM) or the more recently identified AGM-like protein (ALP). In rat brain, agmatine, AGM and ALP are predominantly localised in areas associated with roles in appetitive and craving (drug-reinstatement) behaviors. Thus, inhibitors of AGM or ALP are promising agents for the treatment of addictions. In this review, the properties of DAO, AGM and ALP are discussed with a view to their role in the agmatine metabolism in mammals. [ABSTRACT FROM AUTHOR]

Summary: Objective measures of oxygen consumption and carbon dioxide production by mammals are used to predict their energy expenditure. Since energy expenditure is not directly observable, it can be viewed as a latent construct with multiple physical indirect measures such as respiratory quotient, volumetric oxygen consumption, and volumetric carbon dioxide production. Metabolic rate is defined as the rate at which metabolism occurs in the body. Metabolic rate is also not directly observable. However, heat is produced as a result of metabolic processes within the body. Therefore, metabolic rate can be approximated by heat production plus some errors. While energy expenditure and metabolic rates are correlated, they are not equivalent. Energy expenditure results from physical function, while metabolism can occur within the body without the occurrence of physical activities. In this manuscript, we present a novel approach for studying the relationship between metabolic rate and indicators of energy expenditure. We do so by extending our previous work on MIMIC ME models to allow responses that are sparsely observed functional data, defining the sparse functional multiple indicators, multiple cause measurement error (FMIMIC ME) models. The mean curves in our proposed methodology are modeled using basis splines. A novel approach for estimating the variance of the classical measurement error based on functional principal components is presented. The model parameters are estimated using the EM algorithm and a discussion of the model's identifiability is provided. We show that the defined model is not a trivial extension of longitudinal or functional data methods, due to the presence of the latent construct. Results from its application to data collected on Zucker diabetic fatty rats are provided. Simulation results investigating the properties of our approach are also presented. [ABSTRACT FROM AUTHOR]

After having revolutionized our understanding of the mechanisms of animal development, Drosophila melanogaster has more recently emerged as an equally valid genetic model in the field of animal metabolism. An increasing number of studies have revealed that many signaling pathways that control metabolism in mammals, including pathways controlled by nutrients (insulin, TOR), steroid hormone, glucagon, and hedgehog, are functionally conserved between mammals and Drosophila . In fact, genetic screens and analyses in Drosophila have identified new players and filled in gaps in the signaling networks that control metabolism. This review focuses on data that show how these networks control the formation and breakdown of triacylglycerol energy stores in the fat tissue of Drosophila . [ABSTRACT FROM AUTHOR]

Thyroid hormone (TH) is a key driver of metabolism in mammals. Plasma concentrations of TH are kept within a narrow range by negative feedback regulation in the hypothalamus-pituitary-thyroid (HPT) axis. Plasma TH concentrations are an important determinant of metabolic processes in liver and brown adipose tissue (BAT). In addition to endocrine effects of TH derived from the circulation, recent studies have demonstrated additional neural routes for intrahypothalamic thyroid hormone to regulate metabolism in liver and BAT via the sympathetic and parasympathetic branch of the autonomic nervous system (ANS). This review provides an overview of studies reporting metabolic effects of selective administration of T3 within hypothalamic nuclei including the paraventricular nucleus (PVN), the ventromedial nucleus (VMH), the arcuate nucleus (Arc), and the anterior hypothalamic area (AHA). This overview of the literature suggests that intrahypothalamic T3 can have profound effects on hepatic glucose production and insulin sensitivity, energy expenditure in BAT, cardiovascular function and feeding behavior. As the experiments have been performed in experimental animals exclusively, and the timing and route of T3 administration may be an important determinant of effect size, the clinical relevance of these metabolic effects in the chronic setting remains to be established. [ABSTRACT FROM AUTHOR]

The pygmy hippopotamus ( Choeropsis liberiensis ) is endangered in the wild and very little is known about its reproductive biology. In zoological facilities, this species experiences a number of reproductive issues that complicate breeding management, including a high rate of stillbirths and failure of many pairs to reproduce. We conducted a comprehensive study to evaluate reproductive cycles and pregnancy in this species using enzyme immunoassays (EIAs) for fecal hormone metabolite analysis. Fresh fecal samples were collected twice weekly for a one to three year period from 36 female pygmy hippos housed at 24 zoological institutions. Samples were analyzed in three separate laboratories. Three progestogen metabolite EIAs ( Pg-diol : 5β-pregnane-3α,20α-diol 3HS:BSA; PdG : pregnanediol-3-glucuronide R13904; mono-P4 : Quidel clone 425) and three estrogen metabolite EIAs ( E2a : estradiol-17β-OH 17-HS:BSA; E2b : estradiol 17β R0008; E2c : estradiol 17β R4972) accurately reflected reproductive events. Average estrous cycle length was 31.8 ± 7.4 days based on estrogen metabolite peaks and 30.9 ± 7.3 days based on nadir to nadir progestogen metabolite concentrations. Cyclical patterns in both estrogen and progestogen metabolites were detected throughout the year, indicating a lack of seasonality. Estrogen metabolite peaks were also observed during pregnancy and lactation, suggesting that follicular development occurs during both reproductive states. Pregnancy was most reliably demonstrated by elevation in progestogen metabolites (Pg-diol or PdG) in the second half of gestation. Average gestation length based on breeding to calving date was 203 ± 4 days for 15 pregnancies. This comprehensive overview of the reproductive biology of the female pygmy hippo provides valuable data for guiding long-term breeding management for this endangered species and serves as a baseline for future studies addressing the potential influence of social structure, diet, body condition, and other husbandry factors on estrous cycling and reproduction. [ABSTRACT FROM AUTHOR]

To maximize foraging duration at depth, diving mammals are expected to use the lowest cost optimal speed during descent and ascent transit and to minimize the cost of transport by achieving neutral buoyancy. Here, we outfitted 18 deep-diving long-finned pilot whales with multi-sensor data loggers and found indications that their diving strategy is associated with higher costs than those of other deep-diving toothed whales. Theoretical models predict that optimal speed is proportional to (basal metabolic rate/drag)1/3 and therefore to body mass0.05. The transit speed of tagged animals (2.7±0.3 m s-1) was substantially higher than the optimal speed predicted from body mass (1.4-1.7 m s-1). According to the theoretical models, this choice of high transit speed, given a similar drag coefficient (median, 0.0035) to that in other cetaceans, indicated greater basal metabolic costs during diving than for other cetaceans. This could explain the comparatively short duration (8.9±1.5 min) of their deep dives (maximum depth, 444±85 m). Hydrodynamic gliding models indicated negative buoyancy of tissue body density (1038.8± 1.6 kg m-3, ±95% credible interval, CI) and similar diving gas volume (34.6±0.6 ml kg-1, ±95% CI) to those in other deep-diving toothed whales. High diving metabolic rate and costly negative buoyancy imply a 'spend more, gain more' strategy of long-finned pilot whales, differing from that in other deep-diving toothed whales, which limits the costs of locomotion during foraging. We also found that net buoyancy affected the optimal speed: high transit speeds gradually decreased during ascent as the whales approached neutral buoyancy owing to gas expansion. [ABSTRACT FROM AUTHOR]

Toothed whales use echolocation to sense their environment and capture prey. However, their reliance on acoustic information makes them vulnerable to sound exposure. Odontocetes modify echolocation signals in response to ambient noise levels, yet the metabolic cost of producing and modifying echolocation signals are unknown. Studies on bats found that the metabolic cost of producing echolocation signals and modifying sonar parameters is high. Unlike terrestrial mammals, however, the conservation of oxygen is paramount for odontocetes that echolocate underwater on a breath-hold. Flow-through respirometry was used to determine the metabolic costs of producing and modifying echolocations signals in two trained bottlenose dolphins ( Tursiops truncatus ) that produced echolocation clicks with variable sound energy levels. Unlike bats, the metabolic cost of echolocation was negligible in dolphins. On average, the metabolic rate of submerged dolphins producing clicks was 1.1 times greater than the metabolic rate of submerged, silent dolphins. Similar to bats, the metabolic cost of producing echolocation signals increased significantly with acoustic energy in dolphins. Yet, for the sound energy levels produced, metabolic rates of dolphins producing clicks were within the range of metabolic rates measured when the dolphins were silent. These results can be used to better understand some of the energetic costs associated with dolphin foraging behavior as well as assess the relative energetic impacts of different delphinid behavioral responses to anthropogenic disturbance. [ABSTRACT FROM AUTHOR]

We tested the hypotheses that supplementation of a diet with elemental Mg increases ruminal dissolved H2 (dH2) in rumen fluid, which in turn alters rumen fermentation and microbial community in goats. In a randomised block design, twenty growing goats were allocated to two treatments fed the same basal diet with 1·45 % Mg(OH)2 or 0·6 % elemental Mg. After 28 d of adaptation, we collected total faeces to measure total tract digestibility, rumen contents to analyse fermentation end products and microbial groups, and measured methane (CH4) emission using respiration chambers. Ruminal Mg2+ concentration was similar in both treatments. Elemental Mg supplementation increased dH2 at 2·5 h post morning feeding (+180 %, P<0·001). Elemental Mg supplementation decreased total volatile fatty acid concentration (−8·6 %, P<0·001), the acetate:propionate ratio (−11·8 %, P<0·03) and fungal copy numbers (−63·6 %, P=0·006), and increased propionate molar percentage (+11·6 %, P<0·001), methanogen copy numbers (+47·9 %, P<0·001), dissolved CH4 (+35·6 %, P<0·001) and CH4 emissions (+11·7 %, P=0·03), compared with Mg(OH)2 supplementation. The bacterial community composition in both treatments was overall similar. Ruminal dH2 was negatively correlated with acetate molar percentage and fungal copy numbers (P<0·05), and positively correlated with propionate molar percentage and methanogen copy numbers (P<0·05). In summary, elemental Mg supplementation increased ruminal dH2 concentration, which inhibited rumen fermentation, enhanced methanogenesis and seemed to shift fermentation pathways from acetate to propionate, and altered microbiota by decreasing fungi and increasing methanogens. [ABSTRACT FROM AUTHOR]

This study aimed to establish a tree shrew model of bilateral electrolytic lesions in the medial geniculate body (MGB) to determine the advantages of using a tree shrew model and to assess the pattern of sound processing in tree shrews after bilateral electrolytic damage in different parts of the MGB. The auditory brainstem responses (ABRs) of a normal control group (n = 30) and an electrical damage group (n = 30) were tested at 0 h, 24 h, 48 h, 72 h, 7 days, 15 days, and 30 days after surgery. (1) The bilateral ablations group exhibited a significant increase in the ABR threshold of the electrolytic damage group between pre- and post-operation. (2) There were significant increases in the I-VI latencies at 0 h after MGBd and MGBm lesions and at 24 h after MGBv lesion. (3) The amplitudes of wave VI were significantly decreased at 24 h and 48 h after MGBd lesion, at 72 h and 7 days after MGBm lesion, and at 24 h, 48 h, 72 h, and 7 days after MGBv lesion. (1) The electrolytic damage group suffered hearing loss that did not recover and appeared to be difficult to fully repair after bilateral ablation. (2) The latencies and amplitudes of responses in the MGB following bilateral electrolytic lesion were restored to pre-operation levels after 15-30 days, suggesting that a portion of the central nuclei lesion was reversible. (3) The tree shrew auditory animal model has many advantages compared to other animal models, such as greater complexity of brain structure and auditory nuclei fiber connections, which make the results of this experiment more useful for clinical diagnoses compared with studies using rats and guinea pigs. [ABSTRACT FROM AUTHOR]

Although the pronghorn (Antilocapra americana) resembles an antelope, its nearest relatives are the giraffe and okapi. In this study we have examined the placentae of 6 pronghorns using lectin- and immunocytochemistry to identify giraffid and bovid features. Binucleate cells (BNC) of the placenta exhibited features intermediate between those of the giraffe and bovine; Dolichos biflorus agglutinin binding - strong in the bovine BNC and absent in the giraffe - was evident in only a subpopulation of BNC while binding to blood vessels, as in the giraffe. Binding of Phytolacca americana agglutinin resembled that of the giraffe and okapi whereas many other glycans were found in all four clades. PAG antigens were similar to bovine and okapi but not giraffe. In summary, although the pronghorn outwardly resembles an antelope, placental BNC show giraffid features. Although each clade has its own individual characteristics, there are far more similarities than differences between them, emphasizing the common ancestry of all four clades. [ABSTRACT FROM AUTHOR]

Biochar production, from pyrolysis of lignocellulosic feedstocks, agricultural residues, and animal and poultry manures are emerging globally as novel industrial and commercial products. It is important to develop and to validate a series of suitable protocols for the ecological monitoring of the qualities and properties of biochars. The highly sensitive Salmonella mutagenicity assays (the Ames test) are used widely by the toxicology community and, via the rat liver extract (S9), can reflect the potential for mammalian metabolic activation. We examined the Ames test for analyses of the mutagenic activities of dimethylsulphoxide (DMSO) extracts of biochars using two bacterial models ( S. typhimurium strains TA98 and TA100) in the presence and in the absence of the metabolic activation with the S9-mix. Tester strain TA98 was most sensitive in detecting mutagenic biochar products, and the contribution of S9 was established. Temperature and times of pyrolysis are important. Biochar pyrolysed at 400 °C for 10 min, from a lignocellulose precursor was mutagenic, but not when formed at 800 °C for 60 min, or at 600 °C for 30 min. Biochars from poultry litter, and manures of calves fed on grass had low mutagenicities. Biochar from pig manure had high mutagenicity; biochars from manures of cows fed on a grass plus cereals, those of calves fed on mother's milk, and biochars from solid industrial waste had intermediate mutagenicities. The methods outlined can indicate the need for further studies for screening and detection of the mutagenic residuals in a variety of biochar products. [ABSTRACT FROM AUTHOR]

Background: Air pollution is involved in many pathologies. These pollutants act through several mechanisms that can affect numerous physiological functions, including reproduction: as endocrine disruptors or reactive oxygen species inducers, and through the formation of DNA adducts and/or epigenetic modifications. We conducted a systematic review of the published literature on the impact of air pollution on reproductive function. Eligible studies were selected from an electronic literature search from the PUBMED database from January 2000 to February 2016 and associated references in published studies. Search terms included (1) ovary or follicle or oocyte or testis or testicular or sperm or spermatozoa or fertility or infertility and (2) air quality or O3 or NO2 or PM2.5 or diesel or SO2 or traffic or PM10 or air pollution or air pollutants. The literature search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We have included the human and animal studies corresponding to the search terms and published in English. We have excluded articles whose results did not concern fertility or gamete function and those focused on cancer or allergy. We have also excluded genetic, auto-immune or iatrogenic causes of reduced reproduction function from our analysis. Finally, we have excluded animal data that does not concern mammals and studies based on results from in vitro culture. Data have been grouped according to the studied pollutants in order to synthetize their impact on fertility and the molecular pathways involved.Conclusion: Both animal and human epidemiological studies support the idea that air pollutants cause defects during gametogenesis leading to a drop in reproductive capacities in exposed populations. Air quality has an impact on overall health as well as on the reproductive function, so increased awareness of environmental protection issues is needed among the general public and the authorities. [ABSTRACT FROM AUTHOR]

Hibernation is a period of water deficit for some small mammals, and humidity strongly influences hibernation patterns. Dry conditions reduce length of torpor bouts, stimulate arousals, and decrease overwinter survival. To mitigate these effects, many small mammals hibernate in near saturated (100% RH) conditions. However, big brown bats ( Eptesicus fuscus) hibernate in a wider variety of conditions and tolerate lower humidity than most other bats. To assess arid tolerance in this species, we compared torpid metabolic rates (TMR) and rates of total evaporative water loss (TEWL) between two populations of E. fuscus with differing winter ecologies: one that hibernates in humid karst caves and one that hibernates in relatively dry rock crevices. We used flow-through respirometry to measure TMR and TEWL of bats in humid and dry conditions. Torpid metabolic rates did not differ between populations or with humidity treatments. Rates of TEWL were similar between populations in humid conditions, but higher for cave-hibernating bats than crevice-hibernating bats in dry conditions. Our results suggest that E. fuscus hibernating in arid environments have mechanisms to decrease evaporative water loss that are not evident at more humid sites. Drought tolerance may facilitate the sedentary nature of the species, allowing them to tolerate more variable microclimates during hibernation and thus increasing the availability of overwintering habitat. The ability to survive arid conditions may also lessen the susceptibility of E. fuscus to diseases that affect water balance. [ABSTRACT FROM AUTHOR]

Introduction: The fecal microbiota are relevant to the health and disease of many species. The importance of the fecal metabolome has more recently been appreciated, but our knowledge of the microbiota and metabolome at other sites along the gastrointestinal tract remains deficient. Objective: To analyze the gastrointestinal microbiota and metabolome of healthy domestic dogs at four anatomical sites. Methods: Samples of the duodenal, ileal, colonic, and rectal contents were collected from six adult dogs after humane euthanasia for an unrelated study. The microbiota were characterized using Illumina sequencing of 16S rRNA genes. The metabolome was characterized by mass spectrometry-based methods. Results: Prevalent phyla throughout the samples were Proteobacteria, Firmicutes, Fusobacteria, and Bacteroidetes, consistent with previous findings in dogs and other species. A total of 530 unique metabolites were detected; 199 of these were identified as previously named compounds, but 141 of them had at least one significantly different site-pair comparison. Noteworthy examples include relative concentrations of amino acids, which decreased from the small to large intestine; pyruvate, which peaked in the ileum; and several phenol-containing carboxylic acid compounds that increased in the large intestine. Conclusion: The microbiota and metabolome vary significantly at different sites along the canine gastrointestinal tract. [ABSTRACT FROM AUTHOR]

In response to variation in food availability and ambient temperature (Ta), many animals show seasonal adaptations in their physiology. Laboratory studies showed that thyroid hormones are involved in the regulation of metabolism, and their regulatory function is especially important when the energy balance of an individual is compromised. However, little is known about the relationship between thyroid hormones and metabolism in free-living animals and animals inhabiting seasonal environments. Here, we studied seasonal changes in triiodothyronine (T3) levels, resting metabolic rate (RMR) and two physiological markers of energy balance (blood glucose and ketone bodies) in 61 free-living African striped mice (Rhabdomys pumilio) that live in an semi-arid environment with food shortage during the dry season. We predicted a positive relationship between T3 levels and RMR. Further, we predicted higher T3 levels, blood glucose levels and RMR, but lower ketone body concentrations, during the moist season when food availability is high compared with summer when food availability is low. RMR and T3 levels were negatively related in the moist season but not in the dry season. Both RMR and T3 levels were higher in the moist than in the dry season, and T3 levels increased with increasing food availability. In the dry season, blood glucose levels were lower but ketone body concentrations were higher, indicating a change in substrate use. Seasonal adjustments in RMR and T3 levels permit a reduction of energy expenditure when food is scarce, and reflect an adaptive response to reduced food availability in the dry season. [ABSTRACT FROM AUTHOR]

Background: A previous 2-year rat feeding trial assessing potential toxicity of NK603 Roundup-tolerant genetically modified maize revealed blood and urine biochemical changes indicative of liver and kidney pathology. In an effort to obtain deeper insight into these findings, molecular profiling of the liver and kidneys from the same animals was undertaken. Results: Transcriptomics showed no segregation of NK603 maize and control feed groups with false discovery rates ranging from 43 to 83% at a cut-off p value of 1%. Changes in gene expression were not reflective of liver and kidney toxic effects. Metabolomics identified 692 and 673 metabolites in kidney and liver, respectively. None of the statistically significant disturbances detected (12-56 for different test groups) survived a false discovery rate analysis. Differences in these metabolites between individual animals within a group were greater than the effect of test diets, which prevents a definitive conclusion on either pathology or safety. Conclusions: Even if the biological relevance of the statistical differences presented in this study is unclear, our results are made available for scrutiny by the scientific community and for comparison in future studies investigating potential toxicological properties of the NK603 corn. [ABSTRACT FROM AUTHOR]

In order to understand the effects of changing prey availability on dive behavior and energetic costs, behavior and metabolism must be measured simultaneously. Video dive analysis and open-flow respirometry were used to assess changes in dive behavior and energetics of two captive trained California sea lions ( Zalophus californianus ) in response to high and low prey densities and increased cost of swimming. Differences in dive duration, foraging duration, dive efficiency and foraging efficiency were examined between high and low prey encounter rates, and between standard and cost-increased dives. Changes in foraging metabolic rate (FVO 2 ) and foraging carbon dioxide elimination (FVCO 2 ) were also assessed across all four conditions. Both animals had longer dive durations, greater dive efficiency and lower FVO 2 and FVCO 2 levels at high prey encounter rates. Foraging metabolic rate and FVCO 2 showed a slight increasing trend in cost-increased bouts for both animals, and surface interval durations were shorter. The results suggest that at high prey encounter rates animals minimize their metabolic rate to extend dive duration. These results also suggest that although FVCO 2 decreases under high prey encounter rates, increasing the cost of transport keeps VCO 2 levels elevated and increases the animal's oxygen debt . The authors hypothesize that as the level of work increases, the ability of the body to sequester CO 2 into bicarbonate diminishes due to an inability of the proton buffering process within the blood and muscles to keep pace with increasing CO 2 production. Therefore, CO 2 may be a more sensitive physiological marker than O 2 when examining the metabolic cost of foraging. [ABSTRACT FROM AUTHOR]

Mammals evolved an endogenous timing system to coordinate their physiology and behaviour to the 24h period of the solar day. While it is well accepted that circadian rhythms are generated by intracellular transcriptional feedback loops, it is still debated which network motifs are necessary and sufficient for generating self-sustained oscillations. Here, we systematically explore a data-based circadian oscillator model with multiple negative and positive feedback loops and identify a series of three subsequent inhibitions known as “repressilator” as a core element of the mammalian circadian oscillator. The central role of the repressilator motif is consistent with time-resolved ChIP-seq experiments of circadian clock transcription factors and loss of rhythmicity in core clock gene knockouts. [ABSTRACT FROM AUTHOR]

This review attempts to provide insights into factors associated with fatigue in human and nonhuman animals by using the two fundamental approaches of comparative physiology: determining common principles that govern structure and function in animals that are relatively invariant between animals and evaluating animals that have been highly adapted by natural selection to demonstrate extreme performance. In this review, I approach the topic of fatigue by considering factors that are associated with its reciprocal or inverse or duration of sustained performance before fatigue sets in to end the performance. The two general factors that I consider that affect endurance time more than any other are body temperature and body mass. The former affects endurance time because of thermodynamic effects on chemical reaction rates and metabolism; the latter acts through the mechanism of allometry or scaling. The examples of extreme animal performance that I discuss are two examples of bird migration, the diving performance of marine mammals, and the unique relationship that governs energy cost of locomotion in hopping kangaroos. [ABSTRACT FROM AUTHOR]

The actual health risk from exposure to combined mycotoxins is unknown, and few studies have focused on changes to cellular biological systems (e.g., metabolomics) caused by combined mycotoxic effects. To evaluate the combined mycotoxic effects of deoxynivalenol (DON) and zearalenone (ZEN) on the level of cellular biological systems, gas chromatographic, time-of-flight mass spectroscopy (GC-TOF/MS) of the complete murine macrophage ANA-1 cell metabolome was implemented in this study. Using optimized chromatography and mass spectrometry parameters, the metabolites detected by GC-TOF/MS were identified and processed using multivariate statistical analysis, including principal component analysis (PCA) and orthogonal projection on latent-structures discriminant analysis (OPLS-DA). The metabolite sets were screened for further pathway analysis under rules of t-test (P) value < 0.05, VIP value > 1, and similarity value > 500. The mainly interfered metabolism pathways were categorized into two dominant types: amino acid metabolism and glycometabolism. Four metabolites, palmitic acid, 1-monopalmitin, ribose-5-phosphate and 2-deoxy-D-galactose, occur only under combined “DON + ZEN” treatment, indicating abnormal metabolism in ANA-1 cells. The metabolic state of ANA-1 cells under induction by combined “DON + ZEN” illustrates that DON may inhibit the estrogenic effects of ZEN. Thus, the combined effect of “DON + ZEN” may exacerbate toxicity in the pentose phosphate pathway, while palmitic acid metabolism is likely a new pathway effected by the combination, “DON + ZEN.” [ABSTRACT FROM AUTHOR]

Periods of physical inactivity increase bone resorption and cause bone loss and increased fracture risk. However, hibernating bears, marmots, and woodchucks maintain bone structure and strength, despite being physically inactive for prolonged periods annually. We tested the hypothesis that bone turnover rates would decrease and bone structural and mechanical properties would be preserved in hibernating marmots (Marmota flaviventris). Femurs and tibias were collected from marmots during hibernation and in the summer following hibernation. Bone remodeling was significantly altered in cortical and trabecular bone during hibernation with suppressed formation and no change in resorption, unlike the increased bone resorption that occurs during disuse in humans and other animals. Trabecular bone architecture and cortical bone geometrical and mechanical properties were not different between hibernating and active marmots, but bonemarrow adiposity was significantly greater in hibernators. Of the 506 proteins identified in marmot bone, 40 were significantly different in abundance between active and hibernating marmots. Monoaglycerol lipase, which plays an important role in fatty acid metabolism and the endocannabinoid system, was 98-fold higher in hibernating marmots compared with summer marmots and may play a role in regulating the changes in bone and fat metabolism that occur during hibernation. [ABSTRACT FROM AUTHOR]

Research into Alzheimer's disease pathology and treatment has often focused on presenilin proteins. These proteins provide the key catalytic activity of the γ-secretase complex in the cleavage of amyloid-β precursor protein and resultant amyloid tangle deposition. Over the last 25 years, screening novel drugs to control this aberrant proteolytic activity has yet to identify effective treatments for the disease. In the search for other mechanisms of presenilin pathology, several studies have demonstrated that mammalian presenilin proteins also act in a non-proteolytic role as a scaffold to co-localize key signaling proteins. This role is likely to represent an ancestral presenilin function, as it has been described in genetically distant species including non-mammalian animals, plants, and a simple eukaryotic amoeba Dictyostelium that diverged from the human lineage over a billion years ago. Here, we review the non-catalytic scaffold role of presenilin, from mammalian models to other biomedical models, and include recent insights using Dictyostelium, to suggest that this role may provide an early evolutionary function of presenilin proteins. [ABSTRACT FROM AUTHOR]