Controlling Magnetic Anisotropy in a Zero-Dimensional S=1 Magnet Using Isotropic Cation Substitution

The [Zn_{1–x}_Ni-{x}(HF_{2})(pyz)_{2}]SbF_{6} (x = 0.2; pyz = pyrazine) solid solution exhibits a zero-field splitting (D) that is 22% larger [D = 16.2(2) K (11.3(2) cm^{–1})] than that observed in the x = 1 material [D = 13.3(1) K (9.2(1) cm^{–1)}]. The substantial change in D is accomplished by an anisotropic lattice expansion in the MN_{4} (M = Zn or Ni) plane, wherein the increased concentration of isotropic Zn(II) ions induces a nonlinear variation in M-F and M-N bond lengths. In this, we exploit the relative donor atom hardness, where M-F and M-N form strong ionic and weak coordinate covalent bonds, respectively, the latter being more sensitive to substitution of Ni by the slightly larger Zn(II) ion. In this way, we are able to tune the single-ion anisotropy of a magnetic lattice site by Zn-substitution on nearby sites. This effect has possible applications in the field of single-ion magnets and the design of other molecule-based magnetic systems

Expression of Stretch-Activated Two-Pore Potassium Channels in Human Myometrium in Pregnancy and Labor

Background: We tested the hypothesis that the stretch-activated, four-transmembrane domain, two pore potassium channels (K2P), TREK-1 and TRAAK are gestationally-regulated in human myometrium and contribute to uterine relaxation during pregnancy until labor. Methodology: We determined the gene and protein expression of K2P channels in non-pregnant, pregnant term and preterm laboring myometrium. We employed both molecular biological and functional studies of K2P channels in myometrial samples taken from women undergoing cesarean delivery of a fetus. Principal Findings: TREK-1, but not TREK-2, channels are expressed in human myometrium and significantly up-regulated during pregnancy. Down-regulation of TREK-1 message was seen by Q-PCR in laboring tissues consistent with a role for TREK-1 in maintaining uterine quiescence prior to labor. The TRAAK channel was unregulated in the same women. Blockade of stretch-activated channels with a channel non-specific tarantula toxin (GsMTx-4) or the more specific TREK-1 antagonist L-methionine ethyl ester altered contractile frequency in a dose-dependent manner in pregnant myometrium. Arachidonic acid treatment lowered contractile tension an effect blocked by fluphenazine. Functional studies are consistent with a role for TREK-1 in uterine quiescence. Conclusions: We provide evidence supporting a role for TREK-1 in contributing to uterine quiescence during gestation an

Effects of deletion of the Streptococcus pneumoniae lipoprotein diacylglyceryl transferase gene lgt on ABC transporter function and on growth in vivo

Lipoproteins are an important class of surface associated proteins that have diverse roles and frequently are involved in the virulence of bacterial pathogens. As prolipoproteins are attached to the cell membrane by a single enzyme, prolipoprotein diacylglyceryl transferase (Lgt), deletion of the corresponding gene potentially allows the characterisation of the overall importance of lipoproteins for specific bacterial functions. We have used a Δlgt mutant strain of Streptococcus pneumoniae to investigate the effects of loss of lipoprotein attachment on cation acquisition, growth in media containing specific carbon sources, and virulence in different infection models. Immunoblots of triton X-114 extracts, flow cytometry and immuno-fluorescence microscopy confirmed the Δlgt mutant had markedly reduced lipoprotein expression on the cell surface. The Δlgt mutant had reduced growth in cation depleted medium, increased sensitivity to oxidative stress, reduced zinc uptake, and reduced intracellular levels of several cations. Doubling time of the Δlgt mutant was also increased slightly when grown in medium with glucose, raffinose and maltotriose as sole carbon sources. These multiple defects in cation and sugar ABC transporter function for the Δlgt mutant were associated with only slightly delayed growth in complete medium. However the Δlgt mutant had significantly reduced growth in blood or bronchoalveolar lavage fluid and a marked impairment in virulence in mouse models of nasopharyngeal colonisation, sepsis and pneumonia. These data suggest that for S. pneumoniae loss of surface localisation of lipoproteins has widespread effects on ABC transporter functions that collectively prevent the Δlgt mutant from establishing invasive infection

Design and rationale of the Post-Intensive Care Syndrome - paediatrics (PICS-p) Longitudinal Cohort Study.

INTRODUCTION: As paediatric intensive care unit (PICU) mortality declines, there is growing recognition of the morbidity experienced by children surviving critical illness and their families. A comprehensive understanding of the adverse physical, cognitive, emotional and social sequelae common to PICU survivors is limited, however, and the trajectory of recovery and risk factors for morbidity remain unknown. METHODS AND ANALYSIS: The Post-Intensive Care Syndrome - paediatrics Longitudinal Cohort Study will evaluate child and family outcomes over 2 years following PICU discharge and identify child and clinical factors associated with impaired outcomes. We will enrol 750 children from 30 US PICUs during their first PICU hospitalisation, including 500 case participants experiencing ≥3 days of intensive care that include critical care therapies (eg, mechanical ventilation, vasoactive infusions) and 250 age-matched, sex-matched and medical complexity-matched control participants experiencing a single night in the PICU with no intensive care therapies. Children, parents and siblings will complete surveys about health-related quality of life, physical function, cognitive status, emotional health and peer and family relationships at multiple time points from baseline recall through 2 years post-PICU discharge. We will compare outcomes and recovery trajectories of case participants to control participants, identify risk factors associated with poor outcomes and determine the emotional and social health consequences of paediatric critical illness on parents and siblings. ETHICS AND DISSEMINATION: This study has received ethical approval from the University of Pennsylvania Institutional Review Board (protocol #843844). Our overall objective is to characterise the ongoing impact of paediatric critical illness to guide development of interventions that optimise outcomes among children surviving critical illness and their families. Findings will be presented at key disciplinary meetings and in peer-reviewed publications at fixed data points. Published manuscripts will be added to our public study website to ensure findings are available to families, clinicians and researchers. TRIALS REGISTRATION NUMBER: NCT04967365

Mapping and identification of candidate loci responsible for Peromyscus hybrid overgrowth

Crosses between two recently diverged rodent species of the genus Peromyscus result in dramatic parent-of-origin effects on growth and development. P. maniculatus females crossed with P. polionotus males yield growth-retarded conceptuses, whereas the reciprocal cross results in overgrowth and lethality. These hybrid effects are particularly pronounced in the placenta. We previously detected linkage to two regions of the genome involved in the overgrowth effects. One locus, termed Peal, is a paternally expressed autosomal locus mapping to a domain whose house mouse equivalent contains several clusters of imprinted genes. The other locus, termed Mexl, maps to a gene-poor region of the X chromosome. Here we use an advanced intercross line to verify and narrow the regions of linkage and identify candidate genes for Mexl and Peal. While we have previously shown that Mexl affects both pre-and postnatal growth, we show here that Peal affects only prenatal growth. Utilizing criteria such as mutant phenotypes and allelic expression, we identify the loci encoding the homeobox protein Esx1 and the zinc-finger protein Pw1/Peg3 as candidates. Both loci exhibit expression changes in the hybrids

Evidence for biological roots in the transgenerational transmission of intimate partner violence

Intimate partner violence is a ubiquitous and devastating phenomenon for which effective interventions and a clear etiological understanding are still lacking. A major risk factor for violence perpetration is childhood exposure to violence, prompting the proposal that social learning is a major contributor to the transgenerational transmission of violence. Using an animal model devoid of human cultural factors, we showed that male rats became highly aggressive against their female partners as adults after exposure to non-social stressful experiences in their youth. Their offspring also showed increased aggression toward females in the absence of postnatal father–offspring interaction or any other exposure to violence. Both the females that cohabited with the stressed males and those that cohabited with their male offspring showed behavioral (including anxiety- and depression-like behaviors), physiological (decreased body weight and basal corticosterone levels) and neurobiological symptoms (increased activity in dorsal raphe serotonergic neurons in response to an unfamiliar male) resembling the alterations described in abused and depressed women. With the caution required when translating animal work to humans, our findings extend current psychosocial explanations of the transgenerational transmission of intimate partner violence by strongly suggesting an important role for biological factors

Genes Involved in the Metabolism of Poly-Unsaturated Fatty-Acids (PUFA) and Risk for Crohn's Disease in Children & Young Adults

Epidemiological evidence for the role of polyunsaturated fatty-acids (PUFA) in Crohn's disease (CD) is unclear, although the key metabolite leucotriene B4 (LTB(4)) is closely linked to the inflammatory process. We hypothesized that inherited variation in key PUFA metabolic enzymes may modify susceptibility for CD.A case-control design was implemented at three pediatric gastroenterology clinics in Canada. Children ≤20 yrs diagnosed with CD and controls were recruited. 19 single nucleotide polymorphisms (SNPs) across the ALOX5 (4) CYP4F3 (5) and CYP4F2 (10) genes, were genotyped. Associations between SNPs/haplotypes and CD were examined. A total of 431 cases and 507 controls were studied. The mean (±SD) age of the cases was 12.4 (±3.3) years. Most cases were male (56.4%), had ileo-colonic disease (L3±L4, 52.7%) and inflammatory behavior (B1±p, 87%) at diagnosis. One genotyped CYP4F3 SNP (rs2683037) not in Hardy-Weinberg Equilibrium was excluded. No associations with the remaining 4 CYP4F3 SNPs with CD were evident. However haplotype analysis revealed associations with a two-marker haplotype (TG) (rs3794987 & rs1290617) (p = 0.02; permuted p = 0.08). CYP4F2 SNPs, rs3093158 (OR (recessive) = 0.56, 95% CI = 0.35-0.89; p = 0.01), rs2074902 (OR (trend) = 1.26, 95% CI = 1.00-1.60; p = 0.05), and rs2108622 (OR (recessive) = 1.6, 95% CI = 1.00-2.57; p = 0.05) were significantly associated whereas rs1272 (OR (recessive) = 0.58, 95% CI = 0.30-1.13; p = 0.10) showed suggestions for associations with CD. A haplotype comprising these 4 SNPs was significantly associated (p = 0.007, permuted p = 0.02) with CD. Associations with SNP rs3780901 in the ALOX5 gene were borderline non-significant (OR (dominant) = 1.29, 95% CI = 0.99-1.67; p = 0.056). A haplotype comprising the 4 ALOX5 SNPs (TCAA, p = 0.036) was associated with CD, but did not withstand corrections for multiple comparisons (permuted p = 0.14).Inherited variation in enzymes involved in the synthesis/metabolism of LTB(4) may be associated with CD. These findings implicate PUFA metabolism as a important pathway in the CD pathogenesis

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

Mammalian Target of Rapamycin Is a Therapeutic Target for Murine Ovarian Endometrioid Adenocarcinomas with Dysregulated Wnt/β-Catenin and PTEN

Despite the fact that epithelial ovarian cancers are the leading cause of death from gynecological cancer, very little is known about the pathophysiology of the disease. Mutations in the WNT and PI3K pathways are frequently observed in the human ovarian endometrioid adenocarcinomas (OEAs). However, the role of WNT/β-catenin and PTEN/AKT signaling in the etiology and/or progression of this disease is currently unclear. In this report we show that mice with a gain-of-function mutation in β-catenin that leads to dysregulated nuclear accumulation of β-catenin expression in the ovarian surface epithelium (OSE) cells develop indolent, undifferentiated tumors with both mesenchymal and epithelial characteristics. Combining dysregulated β-catenin with homozygous deletion of PTEN in the OSE resulted in development of significantly more aggressive tumors, which was correlated with inhibition of p53 expression and cellular senescence. Induced expression of both mTOR kinase, a master regulator of proliferation, and phosphorylation of its downstream target, S6Kinase was also observed in both the indolent and aggressive mouse tumors, as well as in human OEA with nuclear β-catenin accumulation. Ectopic allotransplants of the mouse ovarian tumor cells with a gain-of-function mutation in β-catenin and PTEN deletion developed into tumors with OEA histology, the growth of which were significantly inhibited by oral rapamycin treatment. These studies demonstrate that rapamycin might be an effective therapeutic for human ovarian endometrioid patients with dysregulated Wnt/β-catenin and Pten/PI3K signaling