Morphometric analyses of the visual pathways in macular degeneration

Introduction. Macular degeneration (MD) causes central visual field loss. When field defects occur in both eyes and overlap, parts of the visual pathways are no longer stimulated. Previous reports have shown that this affects the grey matter of the primary visual cortex, but possible effects on the preceding visual pathway structures have not been fully established. Method. In this multicentre study, we used high-resolution anatomical magnetic resonance imaging and voxel-based morphometry to investigate the visual pathway structures up to the primary visual cortex of patients with age-related macular degeneration (AMD) and juvenile macular degeneration (JMD). Results. Compared to age-matched healthy controls, in patients with JMD we found volumetric reductions in the optic nerves, the chiasm, the lateral geniculate bodies, the optic radiations and the visual cortex. In patients with AMD we found volumetric reductions in the lateral geniculate bodies, the optic radiations and the visual cortex. An unexpected finding was that AMD, but not JMD, was associated with a reduction in frontal white matter volume. Conclusion. MD is associated with degeneration of structures along the visual pathways. A reduction in frontal white matter volume only present in the AMD patients may constitute a neural correlate of previously reported association between AMD and mild cognitive impairment. Keywords: macular degeneration - visual pathway - visual field - voxel-based morphometryComment: appears in Cortex (2013

Human immunodeficiency virus infection of the human thymus and disruption of the thymic microenvironment in the SCID-hu mouse.

Infection with the human immunodeficiency virus (HIV) results in immunosuppression and depletion of circulating CD4+ T cells. Since the thymus is the primary organ in which T cells mature it is of interest to examine the effects of HIV infection in this tissue. HIV infection has been demonstrated in the thymuses of infected individuals and thymocytes have been previously demonstrated to be susceptible to HIV infection both in vivo, using the SCID-hu mouse, and in vitro. The present study sought to determine which subsets of thymocytes were infected in the SCID-hu mouse model and to evaluate HIV-related alterations in the thymic microenvironment. Using two different primary HIV isolates, infection was found in CD4+/CD8+ double positive thymocytes as well as in both the CD4+ and CD8+ single positive subsets of thymocytes. The kinetics of infection and resulting viral burden differed among the three thymocyte subsets and depended on which HIV isolate was used for infection. Thymic epithelial (TE) cells were also shown to endocytose virus and to often contain copious amounts of viral RNA in the cytoplasm by in situ hybridization, although productive infection of these cells could not be definitively shown. Furthermore, degenerating TE cells were observed even without detection of HIV in the degenerating cells. Two striking morphologic patterns of infection were seen, involving either predominantly thymocyte infection and depletion, or TE cell involvement with detectable cytoplasmic viral RNA and/or TE cell toxicity. Thus, a variety of cells in the human thymus is susceptible to HIV infection, and infection with HIV results in a marked disruption of the thymic microenvironment leading to depletion of thymocytes and degeneration of TE cells

Comparative Respiratory Tract Pathology of Emerging Viral Infections

Increases in the number of infectious disease outbreaks affecting humans have been reported nearly every decade since the 1940’s. Many of these outbreaks have been caused by emerging zoonotic viruses. It has recently been estimated that there are at least 320,000 viruses in mammals that have yet to be discovered, some of which may affect humans. As humans continue to encroach upon previously isolated areas and have greater contact with wildlife, it is likely that zoonotic viruses will continue to emerge. Since many of these emerging viruses cause significant disease or death in humans it is vital that we study their pathology and pathogenesis in order to detect patterns in their mechanisms of disease, which could then be used to develop broad spectrum antivirals or vaccines. As such, we focused our studies on two recently emerged viruses, Nipah virus and the Middle East respiratory syndrome coronavirus (MERS-CoV), which have caused significant respiratory disease and death in humans

Examination of Novel Cardiac Mechanisms Influencing Mitochondrial Proteomes during Diabetes Mellitus

Cardiac complications, including diabetic cardiomyopathy, are the leading cause of morbidity and mortality within diabetes mellitus. Mitochondrial dysfunction has been suggested as an underlying factor in the initiation and progression of the pathology. Cardiac mitochondria are characterized as two spatially distinct subpopulations within the myocyte including mitochondria located beneath the sarcolemma, termed subsarcolemmal mitochondria (SSM), and those located between myofibrils, termed interfibrillar mitochondria (IFM). Mitochondrial subpopulations have been shown to respond differently to physiological and pathological stimuli with the IFM being the most impacted in a type 1 diabetic setting. Proteomic evaluations within various models of diabetes have highlighted dynamic alterations of the mitochondrial proteome as a consequence of the pathology. To date, no studies have identified how the proteomes of mitochondrial subpopulations are differentially impacted during a type 1 diabetic insult. Further, the mechanisms involved in diabetes-driven mitochondrial proteomic alterations remain limited. Therefore, the goal of the present studies was to determine whether subpopulation-specific proteomes were altered with type 1 diabetes mellitus. Further, we sought to identify mechanisms involved in mitochondrial proteomic dysregulation prevalent within diabetic cardiomyopathy. Type 1 diabetes mellitus was induced in 8 week old mice with multiple low dose (50mg/kg) injections of streptozotocin (STZ) administered for 5 days. Five weeks post hyperglycemic onset, hearts were excised and mitochondrial subpopulations were isolated. Proteomic analyses revealed that the proteome of diabetic IFM was significantly dysregulated compared to control with no changes within diabetic SSM compared to control. Further, nuclear-encoded mitochondrial protein import was significantly decreased in the diabetic IFM, which correlated with decreased abundance of essential protein import constituent mitochondrial heat shock protein 70 (MtHsp70). Because greater than 99% of proteins are of nuclear encoded origin and must be imported into the mitochondria, decrements to the import process may prove to be a novel mechanism of dysfunction within the diabetic IFM. The inner mitochondrial membrane (IMM), the location of essential mitochondrial complexes including import translocases of the inner membrane (TIM), has been shown to be particularly prone to diabetes induced oxidative damage. Reduction in oxidative damage within various pathologies has been shown to have beneficial effects upon mitochondrial functionality. Therefore, we overexpressed antioxidant mitochondrial phospholipid hydroperoxide glutathione peroxidase (mPHGPx) to assess its impact upon the mitochondrial import process and proteomic makeup during a diabetic insult. Remarkably, nuclear-encoded mitochondrial protein import was corrected within the diabetic mPHGPx IFM, which correlated with restitution of a large proportion of mitochondrial proteins negatively impacted by diabetes mellitus including those involved in oxidative phosphorylation, the tricarboxylic acid cycle, fatty acid oxidation, and mitochondrial protein import. MPHGPx is capable of scavenging mitochondrial lipid hydroperoxides specifically in mitochondrial membranes and hydrogen peroxide to a lesser extent. Overexpression of the antioxidant preserved or enhanced the protein content of essential mitochondrial import constituents translocase of the outer membrane 20 (Tom20), Tim23, Tim50, and MtHsp70 in mPHGPX diabetic IFM. Therefore, we believe proteomic correction within mPHGPx diabetic IFM may be a consequence of preservation of mitochondrial protein import machinery. These findings support the rationale for the use of mPHGPx as a mitochondrial-targeted therapeutic capable of protection in the diabetic heart. Additional mechanisms of mitochondrial proteomic dysregulation within diabetes mellitus may exist including alterations to the transcriptional/translational regulators, microRNAs (miRNAs). Therefore, we performed a broad scale miRNA analysis on control and STZ-treated mouse hearts 5 weeks post diabetic onset to determine the effect of diabetes mellitus on miRNA modulation. Twenty nine miRNAs were shown to be dysregulated within the diabetic heart including miRNA-141 (miR-141), which was enhanced by 5 fold. miRNA targeting analyses (targetscan.org) revealed miR-141 likely to regulated Slc25a3, the mitochondrial inorganic phosphate carrier. Slc25a3 is essential for ATP production as it acts as conduit for inorganic phosphate to pass from the cytoplasm into the matrix, providing phosphate to fuel the ATP synthase. IFM Slc25a3 protein content was decreased in the diabetic IFM, which correlated with decreased ATP synthesis rates. Similarly, overexpression of miR-141 decreased Slc25a3 protein content and ATP synthase activity within HEK293 cells. These findings show, for the first time, miRNA modulation within diabetes mellitus has a direct impact upon mitochondrial proteomic makeup as well as mitochondrial functionality. Further, miR-141 ablation may provide a protective benefit to mitochondria and subsequent cardiac function during a type 1 diabetic insult. Taken together, the studies highlighted above prove that mitochondrial proteomic dysregulation prevalent within diabetes mellitus is a complicated process involving spatially distinct mitochondrial subpopulations and multiple mechanisms of action. Targeted therapeutics aimed at the correction of one or more of these mechanisms may provide cardiac benefit from diabetic induced dysfunction via preservation of the mitochondrial proteome

A comparison of residual nitrite and nitrate, lipid oxidation, cut-surface color, and sensory and visual characteristics for nitrite-added and no-nitrite- or -nitrate-added Canadian-style bacon

The objective of this research was to compare residual nitrite, residual nitrate, lipid oxidation, and sensory and visual characteristics of conventionally cured Canadian-style bacon containing sodium nitrite to no-nitrite- or -nitrate-added Canadian-style bacon (naturally cured) during 7 or 12 weeks of storage. Three treatments were used for the first and second experiments: control, natural cure (NC) using celery powder with a nitrate reducing culture, and natural cure with cherry powder (NCCP) with a nitrate reducing culture; all of the pork loins used for these treatments were mechanically injected with brines. Six treatments were evaluated in a third experiment: control, control with ascorbate (NA), natural cure with preformed nitrite in celery powder (NCEL), NC, NCCP, and natural cure with lemon powder (NCLP); all treatments in the third experiment were processed by grinding the pork loins, then mixing with the ingredients. All natural cure treatments included celery powder and starter culture as ingredients and finished products were found to contain both residual nitrite and nitrate after incubation of the products for nitrate conversion. The control had significantly more (P\u3c0.05) residual nitrite than NC and NCCP in the first experiment whereas in the second and third experiments the control and NC treatments had significantly more residual nitrite than NCCP. The control had significantly less residual nitrate (P\u3c0.05) than the naturally cured treatments in the first experiment, but significantly more (P\u3c0.05) in the second experiment. NCLP had significantly less residual nitrate (P\u3c0.05) than NCCP in the third experiment, but no other treatments were significantly different. Significant differences between TBARS values were observed only in the third experiment where NC and NCLP had significantly higher levels of TBARS (P\u3c0.05) than all other treatments. The control was significantly darker and more red (P\u3c0.05) than NC and NCCP in the first experiment, while in the second experiment it had similar lightness and redness to NCCP when evaluated by a Hunter Lab instrument. No significant differences (P\u3e0.05) between the treatments for lightness or redness were found in the third experiment. Results from sensory panelists indicated that the control had more cured meat color intensity and was more tender, but contained more off-flavor (P\u3c0.05) than NC and NCCP. According to the panel scores, NC and NCCP had significantly greater cured meat flavor intensity and overall were rated as having better flavor acceptability (P\u3c0.05) than the control, although these results were not consistent with chemical analyses. These results demonstrate that natural curing processes can be successfully utilized for both injected and ground and then formed Canadian-style bacon

The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Does Not Replicate in Syrian Hamsters

In 2012 a novel coronavirus, MERS-CoV, associated with severe respiratory disease emerged in the Arabian Peninsula. To date, 55 human cases have been reported, including 31 fatal cases. Several of the cases were likely a result of human-to-human transmission. The emergence of this novel coronavirus prompts the need for a small animal model to study the pathogenesis of this virus and to test the efficacy of potential intervention strategies. In this study we explored the use of Syrian hamsters as a small animal disease model, using intratracheal inoculation and inoculation via aerosol. Clinical signs of disease, virus replication, histological lesions, cytokine upregulation nor seroconversion were observed in any of the inoculated animals, indicating that MERS-CoV does not replicate in Syrian hamsters

Modeling Airline Frequency Competition for Airport Congestion Mitigation

Demand often exceeds capacity at congested airports. Airline frequency competition is partially responsible for the growing demand for airport resources. We propose a game-theoretic model for airline frequency competition under slot constraints. The model is solved to obtain a Nash equilibrium using a successive optimizations approach, wherein individual optimizations are performed using a dynamic programming-based technique. The model predictions are validated against actual frequency data, with the results indicating a close fit to reality. We use the model to evaluate different strategic slot allocation schemes from the perspectives of the airlines and the passengers. The most significant result of this research shows that a small reduction in the total number of allocated slots translates into a substantial reduction in flight and passenger delays and also a considerable improvement in airlines' profits

Modelling the perceptual similarity of facial expressions from image statistics and neural responses

The ability to perceive facial expressions of emotion is essential for effective social communication. We investigated how the perception of facial expression emerges from the image properties that convey this important social signal, and how neural responses in face-selective brain regions might track these properties. To do this, we measured the perceptual similarity between expressions of basic emotions, and investigated how this is reflected in image measures and in the neural response of different face-selective regions. We show that the perceptual similarity of different facial expressions (fear, anger, disgust, sadness, happiness) can be predicted by both surface and feature shape information in the image. Using block design fMRI, we found that the perceptual similarity of expressions could also be predicted from the patterns of neural response in the face-selective posterior superior temporal sulcus (STS), but not in the fusiform face area (FFA). These results show that the perception of facial expression is dependent on the shape and surface properties of the image and on the activity of specific face-selective regions

Contributions of feature shapes and surface cues to the recognition and neural representation of facial identity

A full understanding of face recognition will involve identifying the visual information that is used to discriminate different identities and how this is represented in the brain. The aim of this study was to explore the importance of shape and surface properties in the recognition and neural representation of familiar faces. We used image morphing techniques to generate hybrid faces that mixed shape properties (more specifically, second order spatial configural information as defined by feature positions in the 2D-image) from one identity and surface properties from a different identity. Behavioural responses showed that recognition and matching of these hybrid faces was primarily based on their surface properties. These behavioural findings contrasted with neural responses recorded using a block design fMRI adaptation paradigm to test the sensitivity of Haxby et al.'s (2000) core face-selective regions in the human brain to the shape or surface properties of the face. The fusiform face area (FFA) and occipital face area (OFA) showed a lower response (adaptation) to repeated images of the same face (same shape, same surface) compared to different faces (different shapes, different surfaces). From the behavioural data indicating the critical contribution of surface properties to the recognition of identity, we predicted that brain regions responsible for familiar face recognition should continue to adapt to faces that vary in shape but not surface properties, but show a release from adaptation to faces that vary in surface properties but not shape. However, we found that the FFA and OFA showed an equivalent release from adaptation to changes in both shape and surface properties. The dissociation between the neural and perceptual responses suggests that, although they may play a role in the process, these core face regions are not solely responsible for the recognition of facial identity