Artificial Neural Network Inference (ANNI): A Study on Gene-Gene Interaction for Biomarkers in Childhood Sarcomas

Objective: To model the potential interaction between previously identified biomarkers in children sarcomas using artificial neural network inference (ANNI). Method: To concisely demonstrate the biological interactions between correlated genes in an interaction network map, only 2 types of sarcomas in the children small round blue cell tumors (SRBCTs) dataset are discussed in this paper. A backpropagation neural network was used to model the potential interaction between genes. The prediction weights and signal directions were used to model the strengths of the interaction signals and the direction of the interaction link between genes. The ANN model was validated using Monte Carlo cross-validation to minimize the risk of over-fitting and to optimize generalization ability of the model. Results: Strong connection links on certain genes (TNNT1 and FNDC5 in rhabdomyosarcoma (RMS); FCGRT and OLFM1 in Ewing’s sarcoma (EWS)) suggested their potency as central hubs in the interconnection of genes with different functionalities. The results showed that the RMS patients in this dataset are likely to be congenital and at low risk of cardiomyopathy development. The EWS patients are likely to be complicated by EWS-FLI fusion and deficiency in various signaling pathways, including Wnt, Fas/Rho and intracellular oxygen. Conclusions: The ANN network inference approach and the examination of identified genes in the published literature within the context of the disease highlights the substantial influence of certain genes in sarcomas

Extended Distal Pancreatectomy with En Bloc Resection of the Celiac Axis for Locally Advanced Pancreatic Cancer: A Case Report and Review of the Literature

Due to a lack of early symptoms, pancreatic cancers of the body and tail are discovered mostly at advanced stages. These locally advanced cancers often involve the celiac axis or the common hepatic artery and are therefore declared unresectable. The extended distal pancreatectomy with en bloc resection of the celiac artery may offer a chance of complete resection. We present the case of a 48-year-old female with pancreatic body cancer invading the celiac axis. The patient underwent laparoscopy to exclude hepatic and peritoneal metastasis. Subsequently, a selective embolization of the common hepatic artery was performed to enlarge arterial flow to the hepatobiliary system and the stomach via the pancreatoduodenal arcades from the superior mesenteric artery. Fifteen days after embolization, the extended distal pancreatectomy with splenectomy and en bloc resection of the celiac axis was carried out. The postoperative course was uneventful, and complete tumor resection was achieved. This case report and a review of the literature show the feasibility and safety of the extended distal pancreatectomy with en bloc resection of the celiac axis. A preoperative embolization of the celiac axis may avoid ischemia-related complications of the stomach or the liver

Maternal Weaning Modulates Emotional Behavior and Regulates the Gut-Brain Axis.

Evidence shows that nutritional and environmental stress stimuli during postnatal period influence brain development and interactions between gut and brain. In this study we show that in rats, prevention of weaning from maternal milk results in depressive-like behavior, which is accompanied by changes in the gut bacteria and host metabolism. Depressive-like behavior was studied using the forced-swim test on postnatal day (PND) 25 in rats either weaned on PND 21, or left with their mother until PND 25 (non-weaned). Non-weaned rats showed an increased immobility time consistent with a depressive phenotype. Fluorescence in situ hybridization showed non-weaned rats to harbor significantly lowered Clostridium histolyticum bacterial groups but exhibit marked stress-induced increases. Metabonomic analysis of urine from these animals revealed significant differences in the metabolic profiles, with biochemical phenotypes indicative of depression in the non-weaned animals. In addition, non-weaned rats showed resistance to stress-induced modulation of oxytocin receptors in amygdala nuclei, which is indicative of passive stress-coping mechanism. We conclude that delaying weaning results in alterations to the gut microbiota and global metabolic profiles which may contribute to a depressive phenotype and raise the issue that mood disorders at early developmental ages may reflect interplay between mammalian host and resident bacteria

The oxytocin analogue carbetocin prevents emotional impairment and stress-induced reinstatement of opioid-seeking in morphine-abstinent mice.

The main challenge in treating opioid addicts is to maintain abstinence due to the affective consequences associated with withdrawal which may trigger relapse. Emerging evidence suggests a role of the neurohypophysial peptide oxytocin (OT) in the modulation of mood disorders as well as drug addiction. However, its involvement in the emotional consequences of drug abstinence remains unclear. We investigated the effect of 7-day opioid abstinence on the oxytocinergic system and assessed the effect of the OT analogue carbetocin (CBT) on the emotional consequences of opioid abstinence, as well as relapse. Male C57BL/6J mice were treated with a chronic escalating-dose morphine regimen (20-100 mg/kg/day, i.p.). Seven days withdrawal from this administration paradigm induced a decrease of hypothalamic OT levels and a concomitant increase of oxytocin receptor (OTR) binding in the lateral septum and amygdala. Although no physical withdrawal symptoms or alterations in the plasma corticosterone levels were observed after 7 days of abstinence, mice exhibited increased anxiety-like and depressive-like behaviors and impaired sociability. CBT (6.4 mg/kg, i.p.) attenuated the observed negative emotional consequences of opioid withdrawal. Furthermore, in the conditioned place preference paradigm with 10 mg/kg morphine conditioning, CBT (6.4 mg/kg, i.p.) was able to prevent the stress-induced reinstatement to morphine-seeking following extinction. Overall, our results suggest that alterations of the oxytocinergic system contribute to the mechanisms underlying anxiety, depression, and social deficits observed during opioid abstinence. This study also highlights the oxytocinergic system as a target for developing pharmacotherapy for the treatment of emotional impairment associated with abstinence and thereby prevention of relapse

Childbirth and consequent atopic disease: emerging evidence on epigenetic effects based on the hygiene and EPIIC hypotheses

Background: In most high and middle income countries across the world, at least 1:4 women give birth by cesarean section. Rates of labour induction and augmentation are rising steeply; and in some countries up to 50 % of laboring women and newborns are given antibiotics. Governments and international agencies are increasingly concerned about the clinical, economic and psychosocial effects of these interventions. Discussion: There is emerging evidence that certain intrapartum and early neonatal interventions might affect the neonatal immune response in the longer term, and perhaps trans-generationally. Two theories lead the debate in this area. Those aligned with the hygiene (or ‘Old Friends’) hypothesis have examined the effect of gut microbiome colonization secondary to mode of birth and intrapartum/neonatal pharmacological interventions on immune response and epigenetic phenomena. Those working with the EPIIC (Epigenetic Impact of Childbirth) hypothesis are concerned with the effects of eustress and dys-stress on the epigenome, secondary to mode of birth and labour interventions. Summary: This paper examines the current and emerging findings relating to childbirth and atopic/autoimmune disease from the perspective of both theories, and proposes an alliance of research effort. This is likely to accelerate the discovery of important findings arising from both approaches, and to maximize the timely understanding of the longer-term consequences of childbirth practices

Involvement in surface antigen expression by a moonlighting FG-repeat nucleoporin in trypanosomes

Components of the nuclear periphery coordinate a multitude of activities, including macromolecular transport, cell-cycle progression, and chromatin organization. Nuclear pore complexes (NPCs) mediate nucleocytoplasmic transport, mRNA processing, and transcriptional regulation, and NPC components can define regions of high transcriptional activity in some organisms at the nuclear periphery and nucleoplasm. Lineage-specific features underpin several core nuclear functions and in trypanosomatids, which branched very early from other eukaryotes, unique protein components constitute the lamina, kinetochores, and parts of the NPCs. Here we describe a phenylalanine-glycine (FG)-repeat nucleoporin, TbNup53b, that has dual localizations within the nucleoplasm and NPC. In addition to association with nucleoporins, TbNup53b interacts with a known trans-splicing component, TSR1, and has a role in controlling expression of surface proteins including the nucleolar periphery-located, procyclin genes. Significantly, while several nucleoporins are implicated in intranuclear transcriptional regulation in metazoa, TbNup53b appears orthologous to components of the yeast/human Nup49/Nup58 complex, for which no transcriptional functions are known. These data suggest that FG-Nups are frequently co-opted to transcriptional functions during evolution and extend the presence of FG-repeat nucleoporin control of gene expression to trypanosomes, suggesting that this is a widespread and ancient eukaryotic feature, as well as underscoring once more flexibility within nucleoporin function

Yes, I Am Ready Now: Differential Effects of Paced versus Unpaced Mating on Anxiety and Central Oxytocin Release in Female Rats

Sexual activity and partner intimacy results in several positive consequences in the context of stress-coping, both in males and females, such as reduced state anxiety in male rats after successful mating. However, in female rats, mating is a rewarding experience only when the estrous female is able to control sexual interactions, i.e., under paced-mating conditions. Here, we demonstrate that sex-steroid priming required for female mating is anxiolytic; subsequent sexual activity under paced mating conditions did not disrupt this anxiolytic priming effect, whereas mating under unpaced conditions increased anxiety-related behavior. In primed females, the release of the neuropeptide oxytocin (OT) within the hypothalamic paraventricular nucleus was found to be elevated and to further increase during paced, but not unpaced mating. Central administration of an OT receptor antagonist partly prevented priming/mating-induced anxiolysis indicating the involvement of brain OT in the anxiolysis triggered by priming and/or sexual activity

Decreased SGK1 Expression and Function Contributes to Behavioral Deficits Induced by Traumatic Stress

Exposure to extreme stress can trigger the development of major depressive disorder (MDD) as well as post-traumatic stress disorder (PTSD). The molecular mechanisms underlying the structural and functional alterations within corticolimbic brain regions, including the prefrontal cortex (PFC) and amygdala of individuals subjected to traumatic stress, remain unknown. In this study, we show that serum and glucocorticoid regulated kinase 1 (SGK1) expression is down-regulated in the postmortem PFC of PTSD subjects. Furthermore, we demonstrate that inhibition of SGK1 in the rat medial PFC results in helplessness- and anhedonic-like behaviors in rodent models. These behavioral changes are accompanied by abnormal dendritic spine morphology and synaptic dysfunction. Together, the results are consistent with the possibility that altered SGK1 signaling contributes to the behavioral and morphological phenotypes associated with traumatic stress pathophysiology

Altered maternal profiles in corticotropin-releasing factor receptor 1 deficient mice

BACKGROUND: During lactation, the CNS is less responsive to the anxiogenic neuropeptide, corticotropin-releasing factor (CRF). Further, central injections of CRF inhibit maternal aggression and some maternal behaviors, suggesting decreased CRF neurotransmission during lactation supports maternal behaviors. In this study, we examined the maternal profile of mice missing the CRF receptor 1 (CRFR1). Offspring of knockout (CRFR1-/-) mice were heterozygote to offset possible deleterious effects of low maternal glucocorticoids on pup survival and all mice contained a mixed 50:50 inbred/outbred background to improve overall maternal profiles and fecundity. RESULTS: Relative to littermate wild-type (WT) controls, CRFR1-/- mice exhibited significant deficits in total time nursing, including high arched-back, on each test day. Consistent with decreased nursing, pups of CRFR1-deficient dams weighed significantly less than WT offspring. Licking and grooming of pups was significantly higher in WT mice on postpartum Day 2 and when both test days were averaged, but not on Day 3. Time off nest was higher for CRFR1-/- mice on Day 2, but not on Day 3 or when test days were averaged. Licking and grooming of pups did not differ on Day 2 when this measure was examined as a proportion of time on nest. CRFR1-/- mice showed significantly higher nest building on Day 3 and when tests were averaged. Mean pup number was almost identical between groups and no pup mortality occurred. Maternal aggression was consistently lower in CRFR1-/- mice and in some measures these differences approached, but did not reach significance. Because of high variance, general aggression results are viewed as preliminary. In terms of sites of attacks on intruders, CRFR1-/- mice exhibited significantly fewer attacks to the belly of the intruder on Day 5 and when tests were averaged. Performance on the elevated plus maze was similar between genotypes. Egr-1 expression differences in medial preoptic nucleus and c-Fos expression differences in bed nucleus of stria terminalis between genotype suggest possible sites where loss of gene alters behavioral output. CONCLUSION: Taken together, the results suggest that the presence of an intact CRFR1 receptor supports some aspects of nurturing behavior

Forest biodiversity, ecosystem functioning and the provision of ecosystem services

Forests are critical habitats for biodiversity and they are also essential for the provision of a wide range of ecosystem services that are important to human well-being. There is increasing evidence that biodiversity contributes to forest ecosystem functioning and the provision of ecosystem services. Here we provide a review of forest ecosystem services including biomass production, habitat provisioning services, pollination, seed dispersal, resistance to wind storms, fire regulation and mitigation, pest regulation of native and invading insects, carbon sequestration, and cultural ecosystem services, in relation to forest type, structure and diversity. We also consider relationships between forest biodiversity and multifunctionality, and trade-offs among ecosystem services. We compare the concepts of ecosystem processes, functions and services to clarify their definitions. Our review of published studies indicates a lack of empirical studies that establish quantitative and causal relationships between forest biodiversity and many important ecosystem services. The literature is highly skewed; studies on provisioning of nutrition and energy, and on cultural services, delivered by mixed-species forests are under-represented. Planted forests offer ample opportunity for optimising their composition and diversity because replanting after harvesting is a recurring process. Planting mixed-species forests should be given more consideration as they are likely to provide a wider range of ecosystem services within the forest and for adjacent land uses. This review also serves as the introduction to this special issue of Biodiversity and Conservation on various aspects of forest biodiversity and ecosystem services