The National NeuroAIDS Tissue Consortium (NNTC) performed a brain gene expression array to elucidate pathophysiologies of Human Immunodeficiency Virus type 1 (HIV-1)-associated neurocognitive ...disorders.
Twenty-four human subjects in four groups were examined A) Uninfected controls; B) HIV-1 infected subjects with no substantial neurocognitive impairment (NCI); C) Infected with substantial NCI without HIV encephalitis (HIVE); D) Infected with substantial NCI and HIVE. RNA from neocortex, white matter, and neostriatum was processed with the Affymetrix® array platform.
With HIVE the HIV-1 RNA load in brain tissue was three log(10) units higher than other groups and over 1,900 gene probes were regulated. Interferon response genes (IFRGs), antigen presentation, complement components and CD163 antigen were strongly upregulated. In frontal neocortex downregulated neuronal pathways strongly dominated in HIVE, including GABA receptors, glutamate signaling, synaptic potentiation, axon guidance, clathrin-mediated endocytosis and 14-3-3 protein. Expression was completely different in neuropsychologically impaired subjects without HIVE. They had low brain HIV-1 loads, weak brain immune responses, lacked neuronally expressed changes in neocortex and exhibited upregulation of endothelial cell type transcripts. HIV-1-infected subjects with normal neuropsychological test results had upregulation of neuronal transcripts involved in synaptic transmission of neostriatal circuits.
Two patterns of brain gene expression suggest that more than one pathophysiological process occurs in HIV-1-associated neurocognitive impairment. Expression in HIVE suggests that lowering brain HIV-1 replication might improve NCI, whereas NCI without HIVE may not respond in kind; array results suggest that modulation of transvascular signaling is a potentially promising approach. Striking brain regional differences highlighted the likely importance of circuit level disturbances in HIV/AIDS. In subjects without impairment regulation of genes that drive neostriatal synaptic plasticity reflects adaptation. The array provides an infusion of public resources including brain samples, clinicopathological data and correlative gene expression data for further exploration (http://www.nntc.org/gene-array-project).
Psi4: an open-source ab initio electronic structure program Turney, Justin M.; Simmonett, Andrew C.; Parrish, Robert M. ...
Wiley interdisciplinary reviews. Computational molecular science,
July/August 2012, Letnik:
2, Številka:
4
Journal Article
The ever-increasing usage of ceramic materials in restorative dentistry necessitates a simple and effective method to evaluate flexural strength σF and fracture toughness KC. We propose a novel ...method to determine these quantities using a bilayer specimen composed of a brittle plate adhesively bonded onto a transparent polycarbonate substrate. When this bilayer structure is placed under spherical indentation, tunneling radial cracks initiate and propagate in the lower surface of the brittle layer. The failure analysis is based on previous theoretical relationships, which correlate σF with the indentation force P and layer thickness d, and KC with P and mean length of radial cracks. This work examines the accuracy and limitations of this approach using a wide range of contemporary dental ceramic materials. The effect of layer thickness, indenter radius, load level, and length and number of radial cracks are carefully examined. The accuracy of the predicted σF and KC is similar to those obtained with other concurrent test methods, such as biaxial flexure and 3-point bending (σF), and bending specimens with crack-initiation flaws (KC). The benefits of the present approach include treatment for small and thin plates, elimination of the need to introduce a precrack, and avoidance of dealing with local material nonlinearity effects for the KC measurements. Finally, the bilayer configuration resembles occlusal loading of a ceramic restoration (brittle layer) bonded to a posterior tooth (compliant substrate).
Recent pill-related deaths of young people at music festivals in Australia have led to a concerted push for on-site pill testing as a means for preventing such events. However, whether pill testing ...(also termed 'safety checking') is an effective harm reduction strategy remains uncertain. This narrative review concludes that pill testing currently lacks evidence of efficacy sufficient to justify publicly funded national roll-out of on-site pill-testing programmes. Australian governments, addiction specialists and public health experts should collaborate in conducting properly designed field studies aimed at confirming clear benefits from such programmes in reducing pill-related harm.
The chromatin associated transcription factor HMGA2 is a downstream target of let-7 miRNAs and binds to chromatin to regulate gene expression. Inhibition of let-7 miRNAs by RNA-binding proteins ...LIN28A and LIN28B is necessary during early embryogenesis to ensure stable expression of HMGA2. In addition to LIN28, HMGA2 is regulated by a BRCA1/ZNF350/CtIP repressor complex. In normal tissues, the BRCA1/ZNF350/CtIP complex binds to the HMGA2 promoter to prevent transcription. However, in many cancers the oncomiR miR-182 targets BRCA1, preventing BRCA1 translation and allowing for increased HMGA2. Little is known about the regulation of HMGA2 during early placental development; therefore, we hypothesized that both LIN28 and BRCA1 can regulate HMGA2 in placental cells. Using siRNA and CRISPR gene editing techniques, we found that knockdowns of both LIN28A and LIN28B increase HMGA2 levels in ACH-3P cells. These cells also demonstrated deficiencies in cell differentiation, seemingly differentiating solely towards the syncytiotrophoblast sublineage, secreting higher amounts of hCG, and displaying upregulated ERVW-1. Additionally, we found that a knockout of both LIN28A and LIN28B caused a significant increase of miR-182 and a decrease in BRCA1 allowing HMGA2 mRNA levels to increase and protein levels to remain the same. Using chromatin immunoprecipitation, we saw binding of the BRCA1 repressor complex to HMGA2. We also saw a decrease in binding to HMGA2's promoter in the LIN28A/B knockout cells. These findings suggest a novel role for BRCA1 during early human placental development. Summary Sentence HMGA2 expression is regulated by both the LIN28-let-7-HMGA2 axis and the BRCA1/CtIP/ZNF350 repressor complex.
The aim of this work was to further develop a synthetic model of ballistic head injury by the addition of skin and soft tissue layers to an anatomically correct polyurethane skull filled with ...gelatine 10% by mass. Six head models were impacted with 7.62 x 39 mm full metal jacket mild steel core (FMJ MSC) bullets with a mean velocity of 652 m/s. The impact events were filmed with high-speed cameras. The models were imaged pre- and post-impact using computed tomography. The models were assessed post impact by two experienced Home Office pathologists and the images assessed by an experienced military radiologist. The findings were scored against real injuries. The entry wounds, exit wounds and fracture patterns were scored positively, but the synthetic skin and soft tissue layer was felt to be too extendable. Further work is ongoing to address this.
Ixodes species ticks are competent vectors of tick-borne viruses including tick-borne encephalitis and Powassan encephalitis. Tick saliva has been shown to facilitate and enhance viral infection. ...This likely occurs by saliva-mediated modulation of host responses into patterns favorable for viral infection and dissemination. Because of the rapid kinetics of tick-borne viral transmission, this modulation must occur as early as tick attachment and initiation of feeding. In this study, cutaneous bite-site lesions were analyzed using Affymetrix mouse genome 430A 2.0 arrays and histopathology at 1, 3, 6, and 12 hours after uninfected Ixodes scapularis nymphal tick attachment. At 1 and 3 hrs after attachment, the gene expression profile is markedly different than at later time points. Upregulated gene ontology term clusters enriched at 1 and 3 hrs were related to post-translational modification. At 6 and 12 hrs, cytoskeletal rearrangements, DNA replication/cell division, inflammation, and chemotaxis were prominent clusters. At 6 and 12 hrs, extracellular matrix, signaling, and DNA binding clusters were downregulated. Histopathological analysis shows minimal inflammation at 1 and 3 hrs but an appreciable neutrophil infiltrate at 6 and 12 hrs. In addition, putative hyperemia, localized necrosis, and increased ECM deposition were identified. Putting the gene expression and histopathology analysis together suggests early tick feeding is characterized by modulation of host responses in resident cells that merges into a nascent, neutrophil-driven immune response by 12 hrs post-attachment.
White Blood Cell Counts and Malaria McKenzie, F. Ellis; Prudhomme, Wendy A.; Magill, Alan J. ...
The Journal of infectious diseases,
07/2005, Letnik:
192, Številka:
2
Journal Article
Recenzirano
Odprti dostop
White blood cells (WBCs) were counted in 4697 individuals who presented to outpatient malaria clinics in Maesod, Tak Province, Thailand, and Iquitos, Peru, between 28 May and 28 August 1998 and ...between 17 May and 9 July 1999. At each site and in each year, WBC counts in the Plasmodium falciparum–infected patients were lower than those in the Plasmodium vivax–infected patients, which, in turn, were lower than those in the uninfected patients. In Thailand, one-sixth of the P. falciparum–infected patients had WBC counts of <4000 cells/μL. Leukopenia may confound population studies that estimate parasite densities on the basis of an assumed WBC count of 8000 cells/μL. For instance, in the present study, use of this conventional approach would have overestimated average asexual parasite densities in the P. falciparum–infected patients in Thailand by nearly one-third
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