Thalamocortical connectivity in major depressive disorder

Background: Major Depressive Disorder (MDD) is highly prevalent and potentially devastating, with widespread aberrations in brain activity. Thalamocortical networks are a potential candidate marker for psychopathology in MDD, but have not yet been thoroughly investigated. Here we examined functional connectivity between major cortical areas and thalamus. Method: Resting-state fMRI from 54 MDD patients and 40 healthy controls were collected. The cortex was segmented into six regions of interest (ROIs) consisting of frontal, temporal, parietal, and occipital lobes and pre-central and post-central gyri. BOLD signal time courses were extracted from each ROI and correlated with voxels in thalamus, while removing signals from every other ROI. Results: Our main findings showed that MDD patients had predominantly increased connectivity between medial thalamus and temporal areas, and between medial thalamus and somatosensory areas. Furthermore, a positive correlation was found between thalamo-temporal connectivity and severity of symptoms. Limitations: Most of the patients in this study were not medication naïve and therefore we cannot rule out possible long-term effects of antidepressant use on the findings. Conclusion: The abnormal connectivity between thalamus and temporal, and thalamus and somatosensory regions may represent impaired cortico-thalamo-cortical modulation underlying emotional, and sensory disturbances in MDD. In the context of similar abnormalities in thalamocortical systems across major psychiatric disorders, thalamocortical dysconnectivity could be a reliable transdiagnostic marker

Subcompartments of the macrophage recycling endosome direct the differential secretion of IL-6 and TNFα

Activated macrophages secrete an array of proinflammatory cytokines, including tumor necrosis factor-α (TNFα) and interleukin 6 (IL-6), that are temporally secreted for sequential roles in inflammation. We have previously characterized aspects of the intracellular trafficking of membrane-bound TNFα and its delivery to the cell surface at the site of phagocytic cups for secretion (Murray, R.Z., J.G. Kay, D.G. Sangermani, and J.L. Stow. 2005. Science. 310:1492–1495). The trafficking pathway and surface delivery of IL-6, a soluble cytokine, were studied here using approaches such as live cell imaging of fluorescently tagged IL-6 and immunoelectron microscopy. Newly synthesized IL-6 accumulates in the Golgi complex and exits in tubulovesicular carriers either as the sole labeled cargo or together with TNFα, utilizing specific soluble NSF attachment protein receptor (SNARE) proteins to fuse with the recycling endosome. Within recycling endosomes, we demonstrate the compartmentalization of cargo proteins, wherein IL-6 is dynamically segregated from TNFα and from surface recycling transferrin. Thereafter, these cytokines are independently secreted, with TNFα delivered to phagocytic cups but not IL-6. Therefore, the recycling endosome has a central role in orchestrating the differential secretion of cytokines during inflammation

137,138,139^{137,138,139}La(nn, γ\gamma) cross sections constrained with statistical decay properties of 138,139,140^{138,139,140}La nuclei

The nuclear level densities and $\gamma$-ray strength functions of $^{138,139,140}$La were measured using the $^{139}$La($^{3}$He, $\alpha$), $^{139}$La($^{3}$He, $^{3}$He$^\prime$) and $^{139}$La(d, p) reactions. The particle-$\gamma$ coincidences were recorded with the silicon particle telescope (SiRi) and NaI(Tl) (CACTUS) arrays. In the context of these experimental results, the low-energy enhancement in the A$\sim$140 region is discussed. The $^{137,138,139}$La($n, \gamma)$ cross sections were calculated at $s$- and $p$-process temperatures using the experimentally measured nuclear level densities and $\gamma$-ray strength functions. Good agreement is found between $^{139}$La($n, \gamma)$ calculated cross sections and previous measurements

The targeted delivery of multicomponent cargos to cancer cells by nanoporous particle-supported lipid bilayers.

Encapsulation of drugs within nanocarriers that selectively target malignant cells promises to mitigate side effects of conventional chemotherapy and to enable delivery of the unique drug combinations needed for personalized medicine. To realize this potential, however, targeted nanocarriers must simultaneously overcome multiple challenges, including specificity, stability and a high capacity for disparate cargos. Here we report porous nanoparticle-supported lipid bilayers (protocells) that synergistically combine properties of liposomes and nanoporous particles. Protocells modified with a targeting peptide that binds to human hepatocellular carcinoma exhibit a 10,000-fold greater affinity for human hepatocellular carcinoma than for hepatocytes, endothelial cells or immune cells. Furthermore, protocells can be loaded with combinations of therapeutic (drugs, small interfering RNA and toxins) and diagnostic (quantum dots) agents and modified to promote endosomal escape and nuclear accumulation of selected cargos. The enormous capacity of the high-surface-area nanoporous core combined with the enhanced targeting efficacy enabled by the fluid supported lipid bilayer enable a single protocell loaded with a drug cocktail to kill a drug-resistant human hepatocellular carcinoma cell, representing a 10(6)-fold improvement over comparable liposomes

Interleukin-1β Maturation Triggers Its Relocation to the Plasma Membrane for Gasdermin-D-Dependent and -Independent Secretion

IL-1β requires processing by caspase-1 to generate the active, pro-inflammatory cytokine. Acute IL-1β secretion from inflammasome-activated macrophages requires caspase-1-dependent GSDMD cleavage, which also induces pyroptosis. Mechanisms of IL-1β secretion by pyroptotic and non-pyroptotic cells, and the precise functions of caspase-1 and GSDMD therein, are unresolved. Here, we show that, while efficient early secretion of endogenous IL-1β from primary non-pyroptotic myeloid cells in vitro requires GSDMD, later IL-1β release in vitro and in vivo proceeds independently of GSDMD. IL-1β maturation is sufficient for slow, caspase-1/GSDMD-independent secretion of ectopic IL-1β from resting, non-pyroptotic macrophages, but the speed of IL-1β release is boosted by inflammasome activation, via caspase-1 and GSDMD. IL-1β cleavage induces IL-1β enrichment at PIP2-enriched plasma membrane ruffles, and this is a prerequisite for IL-1β secretion and is mediated by a polybasic motif within the cytokine. We thus reveal a mechanism in which maturation-induced IL-1β trafficking facilitates its unconventional secretion

Bridging Alone: Religious Conservatism, Marital Homogamy, and Voluntary Association Membership

This study characterizes social insularity of religiously conservative American married couples by examining patterns of voluntary associationmembership. Constructing a dataset of 3938 marital dyads from the second wave of the National Survey of Families and Households, the author investigates whether conservative religious homogamy encourages membership in religious voluntary groups and discourages membership in secular voluntary groups. Results indicate that couples’ shared affiliation with conservative denominations, paired with beliefs in biblical authority and inerrancy, increases the likelihood of religious group membership for husbands and wives and reduces the likelihood of secular group membership for wives, but not for husbands. The social insularity of conservative religious groups appears to be reinforced by homogamy—particularly by wives who share faith with husbands

The genome of Aeromonas salmonicida subsp. salmonicida A449: insights into the evolution of a fish pathogen

Background Aeromonas salmonicida subsp. salmonicida is a Gram-negative bacterium that is the causative agent of furunculosis, a bacterial septicaemia of salmonid fish. While other species of Aeromonas are opportunistic pathogens or are found in commensal or symbiotic relationships with animal hosts, A. salmonicida subsp. salmonicida causes disease in healthy fish. The genome sequence of A. salmonicida was determined to provide a better understanding of the virulence factors used by this pathogen to infect fish. Results The nucleotide sequences of the A. salmonicida subsp. salmonicida A449 chromosome and two large plasmids are characterized. The chromosome is 4,702,402 bp and encodes 4388 genes, while the two large plasmids are 166,749 and 155,098 bp with 178 and 164 genes, respectively. Notable features are a large inversion in the chromosome and, in one of the large plasmids, the presence of a Tn21 composite transposon containing mercury resistance genes and an In2 integron encoding genes for resistance to streptomycin/spectinomycin, quaternary ammonia compounds, sulphonamides and chloramphenicol. A large number of genes encoding potential virulence factors were identified; however, many appear to be pseudogenes since they contain insertion sequences, frameshifts or in-frame stop codons. A total of 170 pseudogenes and 88 insertion sequences (of ten different types) are found in the A. salmonicida genome. Comparison with the A. hydrophila ATCC 7966T genome reveals multiple large inversions in the chromosome as well as an approximately 9% difference in gene content indicating instances of single gene or operon loss or gain. A limited number of the pseudogenes found in A. salmonicida A449 were investigated in other Aeromonas strains and species. While nearly all the pseudogenes tested are present in A. salmonicida subsp. salmonicida strains, only about 25% were found in other A. salmonicida subspecies and none were detected in other Aeromonas species. Conclusion Relative to the A. hydrophila ATCC 7966T genome, the A. salmonicida subsp. salmonicida genome has acquired multiple mobile genetic elements, undergone substantial rearrangement and developed a significant number of pseudogenes. These changes appear to be a consequence of adaptation to a specific host, salmonid fish, and provide insights into the mechanisms used by the bacterium for infection and avoidance of host defence systems.Peer reviewed: YesNRC publication: Ye

Sheep Updates 2009

This session covers seven papers from different authors: 1. Scouring Management and Worm Control, Brown Besier, Department of Agriculture and Food, Western Australia 2.Breeding sheep for resistance to breech strike:- Selection results in WA, LJE Karlsson, JC Greeff & AC Schlink, Department of Agriculture and Food, Western Australia 3.Future Ewe - matching genetics to the production system, Mark Ferguson, Department of Agriculture and Food, Western Australia 4. Within-flock selection of ewes: opportunities for gains in reproduction, Greg Leeand Sue Hatcher, NSW Department of Primary Industries & Australian CRCforSheep Industry Innovation (Orange) 5. Managing Merinos on Murrayfield, Bruce Michael, Murryfield, Bruny Island, Tasmania 6. Managing [breech] flystrike in [unmulesed] sheep, Rob Woodgate, Darren Michael, Mandy Curnow and Julia Smith, Department of Agriculture and Food, Western Australia 7. Value of Pregnancy Scanning and Differential Feeding of Dry, Single amd Twin Ewes, John Young, Farming Systems Analysis Service, Kojonup, WA, Andrew Thompson, Chris Oldham Department of Agriculture and Food, Western Australi

Peroxide Antimalarial Drugs Target Redox Homeostasis in Plasmodium Falciparum Infected Red Blood Cells

Plasmodium falciparum causes the most lethal form of malaria. Peroxide antimalarials based on artemisinin underpin the frontline treatments for malaria, but artemisinin resistance is rapidly spreading. Synthetic peroxide antimalarials, known as ozonides, are in clinical development and offer a potential alternative. Here, we used chemoproteomics to investigate the protein alkylation targets of artemisinin and ozonide probes, including an analogue of the ozonide clinical candidate, artefenomel. We greatly expanded the list of proteins alkylated by peroxide antimalarials and identified significant enrichment of redox-related proteins for both artemisinins and ozonides. Disrupted redox homeostasis was confirmed by dynamic live imaging of the glutathione redox potential using a genetically encoded redox-sensitive fluorescence-based biosensor. Targeted liquid chromatography-mass spectrometry (LC-MS)-based thiol metabolomics also confirmed changes in cellular thiol levels. This work shows that peroxide antimalarials disproportionately alkylate proteins involved in redox homeostasis and that disrupted redox processes are involved in the mechanism of action of these important antimalarials