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Angeles D.C.,Neuroscience Laboratory | Gan B.-H.,Neuroscience Laboratory | Zhao Y.,Singapore General Hospital | Lim K.-L.,National Neuroscience Institute | And 5 more authors.
Human Mutation | Year: 2011

Mutations in the leucine rich repeat kinase 2 (LRRK2) gene are responsible for autosomal dominant and sporadic Parkinson disease (PD), possibly exerting their effects via a toxic gain of function. A common p.G2019S mutation (rs34637584:A>G) is responsible for up to 30-40% of PD cases in some ethnic populations. Here, we show that LRRK2 interacts with human peroxiredoxin 3 (PRDX3), a mitochondrial member of the antioxidant family of thioredoxin (Trx) peroxidases. Importantly, mutations in the LRRK2 kinase domain significantly increased phosphorylation of PRDX3 compared to wild-type. The increase in PRDX3 phosphorylation was associated with decreased peroxidase activity and increased death in LRRK2-expressing but not in LRRK2-depleted or vector-transfected neuronal cells. LRRK2 mutants stimulated mitochondrial factors involved in apoptosis and induced production of reactive oxygen species (ROS) and oxidative modification of macromolecules. Furthermore, immunoblot and immunohistochemical analysis of postmortem human PD patients carrying the p.G2019S mutation showed a marked increase in phosphorylated PRDX3 (p-PRDX3) relative to normal brain. We showed that LRRK2 mutations increase the inhibition of an endogenous peroxidase by phosphorylation promoting dysregulation of mitochondrial function and oxidative damage. Our findings provide a mechanistic link between the enhanced kinase activity of PD-linked LRRK2 and neuronal cell death. © 2011 Wiley Periodicals, Inc.


PubMed | University of Pennsylvania and Neuroscience Laboratory
Type: Journal Article | Journal: Annals of neurology | Year: 2015

X-linked Charcot-Marie-Tooth disease (CMT1X) is a common inherited neuropathy caused by mutations in the GJB1 gene encoding the gap junction protein connexin32 (Cx32). Clinical studies and disease models indicate that neuropathy mainly results from Schwann cell autonomous, loss-of-function mechanisms; therefore, CMT1X may be treatable by gene replacement.A lentiviral vector LV.Mpz-GJB1 carrying the GJB1 gene under the Schwann cell-specific myelin protein zero (Mpz) promoter was generated and delivered into the mouse sciatic nerve by a single injection immediately distal to the sciatic notch. Enhanced green fluorescent protein (EGFP) reporter gene expression was quantified and Cx32 expression was examined on a Cx32 knockout (KO) background. A gene therapy trial was performed in a Cx32 KO model of CMT1X.EGFP was expressed throughout the length of the sciatic nerve in up to 50% of Schwann cells starting 2 weeks after injection and remaining stable for up to 16 weeks. Following LV.Mpz-GJB1 injection into Cx32 KO nerves, we detected Cx32 expression and correct localization in non-compact myelin areas where gap junctions are normally formed. Gene therapy trial by intraneural injection in groups of 2-month-old Cx32 KO mice, before demyelination onset, significantly reduced the ratio of abnormally myelinated fibers (p=0.00148) and secondary inflammation (p=0.0178) at 6 months of age compared to mock-treated animals.Gene delivery using a lentiviral vector leads to efficient gene expression specifically in Schwann cells. Restoration of Cx32 expression ameliorates nerve pathology in a disease model and provides a promising approach for future treatments of CMT1X and other inherited neuropathies.


Goncalves O.F.,University of Minho | Goncalves O.F.,Northeastern University | Pinheiro A.P.,University of Minho | Pinheiro A.P.,Harvard University | And 2 more authors.
Harvard Review of Psychiatry | Year: 2016

Auditory verbal hallucinations (AVH) are a core symptom of schizophrenia. Like "real" voices, AVH carry a rich amount of linguistic and paralinguistic cues that convey not only speech, but also affect and identity, information. Disturbed processing of voice identity, affective, and speech information has been reported in patients with schizophrenia. More recent evidence has suggested a link between voice-processing abnormalities and specific clinical symptoms of schizophrenia, especially AVH. It is still not well understood, however, to what extent these dimensions are impaired and how abnormalities in these processes might contribute to AVH. In this review, we consider behavioral, neuroimaging, and electrophysiological data to investigate the speech, identity, and affective dimensions of voice processing in schizophrenia, and we discuss how abnormalities in these processes might help to elucidate the mechanisms underlying specific phenomenological features of AVH. Schizophrenia patients exhibit behavioral and neural disturbances in the three dimensions of voice processing. Evidence suggesting a role of dysfunctional voice processing in AVH seems to be stronger for the identity and speech dimensions than for the affective domain. © 2016 President and Fellows of Harvard College.


Makkawi M.,RMIT University | Makkawi M.,University of Melbourne | Moheimani F.,RMIT University | Alserihi R.,RMIT University | And 4 more authors.
Thrombosis and Haemostasis | Year: 2015

P2Y12 receptor is required for sustained activation of integrin αIIbβ3, irreversible platelet aggregation and thrombus stabilisation. Tetraspanin superfamily member CD151 associates with integrin αIIbβ3 and plays critical roles in regulation of thrombus growth and stability in vivo. The possible functional relationship between P2Y12 and CD151 in a molecular cluster in platelets may affect thrombus formation. Hence our aim was to investigate the physical and functional requirements for this association in platelets. Our investigations reveal a specific and constitutive association between CD151 and P2Y12 receptor in human platelets shown by immunoprecipitation/western blot studies and by flow cytometry. Specifically, the prominent association involves CD151 with P2Y12 oligomers, and to a lesser extent P2Y12 monomers. This association is not altered by platelet aggregation induced by different agonists. There is also a distinct complex of tetraspanin CD151 with ADP purinergic receptor P2Y12 but not P2Y1. P2Y12 oligomer interaction with CD151 is selective as compared to other tetraspanins. To investigate the functional relationship between these receptors in platelets we used wild-type or CD151 knockout (KO) mice treated with either PBS or 50 mg/kg clopidogrel. CD151 KO mice treated with clopidogrel exhibited synergy in delayed kinetics of clot retraction, in PAR-4 and collagen-mediated platelet aggregation, platelet spreading on fibrinogen and without restricting cAMP inhibition. Clopidogrel treated CD151 KO arterioles showed smaller and less stable thrombi with increased tendency to embolise ex vivo and in vivo. These studies demonstrate a complementary role between CD151 and P2Y12 receptor in platelets in regulating thrombus growth and stability. © Schattauer 2015.


News Article | February 15, 2017
Site: www.eurekalert.org

BOSTON--Nutrition researcher Neal D. Barnard, M.D., and other speakers at the American Association for the Advancement of Science's Annual Meeting call for a new approach to research on Alzheimer's disease and related dementias. Since decades of animal experiments have failed to produce meaningful treatments or cures, the focus must shift to human-relevant research. "Population studies and other human-focused research suggests that one's risk of developing Alzheimer's disease and other dementias can be reduced with changes to diet and other modifiable lifestyle factors," says Ann Lam, Ph.D., senior medical research specialist at the Physicians Committee for Responsible Medicine and co-director of the Green Neuroscience Laboratory, Neurolinx Research Institute. "Research with human patients and populations holds the greatest promise." What: "Shifting Perspectives on Dementia, Science, and Health Policy," a symposium chaired by Dr. Lam at the 2017 AAAS Annual Meeting #AAASmtg When: 10 to 11:30 a.m. on Friday, Feb. 17, 2017 Rhoda Au, Ph.D., Professor, Department of Neurology, Boston University School of Medicine; Director of Neuropsychology, Framingham Heart Study Neal Barnard, M.D., President, Physicians Committee for Responsible Medicine; Adjunct Associate Professor of Medicine, George Washington University School of Medicine and Health Sciences In her talk, "Roads to Dementia Prevention: Leveraging the Past and Enabling the Future," Dr. Au will present on the historical significance of the Framingham Heart Study as well as her recent findings which show the untapped potential to better understand preclinical Alzheimer's using real-time data and other aspects captured with current technology. In addition, she will discuss the limitations of current diagnostic methods and how IoT can advance studies of modifiable risk factors for dementia and spawn solutions for precision health of dementia. Dr. Barnard's talk "Alzheimer's Disease: Prevention Through Dietary Interventions," will provide an overview of the failures in translation from animal models in Alzheimer's research and the rapidly refining human-based approaches and clinical studies on prevention of dementia. He will present examples of global communities that are highly engaged in prevention research and are models of harmonizing traditional knowledge and perspectives on lifestyle factors. He will also describe how to better integrate nutrition and lifestyle factors into research design. In her talk "The Need for National Engagement in Alzheimer's Disease Prevention Strategies," Dr. Langbaum will present an overview of the evolution and strategies of the state-wide Arizona Alzheimer's Registry to the nationwide Alzheimer's Prevention Registry and discuss the enormous potential of engaging citizens in science at the national level. She will also show how new infrastructure for prevention research can unlock potential for individuals to change perceptions on their role in research and educate participants in their impact in scientific discoveries and health policy. For an interview with Dr. Barnard, please contact Jeanne McVey at 202-527-7316 or jeannem@pcrm.org. Founded in 1985, the Physicians Committee for Responsible Medicine is a nonprofit health organization that promotes preventive medicine, conducts clinical research, and encourages higher standards for ethics and effectiveness in research.


News Article | November 10, 2016
Site: www.eurekalert.org

The Physicians Committee and the Green Neuroscience Lab to host event at San Diego's Manchester Grand Hyatt Hotel On Monday, November 14, at 6:30 p.m., the Physicians Committee for Responsible Medicine and the founders of the Green Neuroscience Laboratory will recognize individuals and organizations that help forward the principles and culture of Green and Open Neuroscience. Green and open neuroscience aims to help improve our understanding of the brain, as well as health, through research and perspectives that strengthen ethics, the environment, education, arts, and protection of neurodiversity. Award recipients will present short talks about their work and vision for an ethical science future that forwards health and saves lives. Hosts: The Physicians Committee for Responsible Medicine and the founders of the Green Neuroscience Laboratory Jacopo Annese, Ph.D., Founder and President, the Institute for Brain and Society HOW: Please RSVP at: https:/ . The event is free and is open to anyone (registration for the Society for Neuroscience conference is not necessary). Children are welcome and encouraged to attend. Founded in 1985, the Physicians Committee is a nonprofit organization that encourages higher standards for ethics and effectiveness in education and research.


Chung H.-K.,China Medical University at Taichung | Tsai C.-H.,Neuroscience Laboratory | Tsai C.-H.,China Medical University at Taichung | Lin Y.-C.,Neuroscience Laboratory | And 7 more authors.
Audiology and Neurotology | Year: 2012

Objectives: Repetitive transcranial magnetic stimulation (rTMS), a noninvasive method for altering cortical excitability, is becoming a therapeutic strategy in auditory research institutions worldwide. Application of inhibiting rTMS on these overactive cortical regions can result in effective tinnitus suppression. The aim of this study is to investigate the efficacy of theta-burst rTMS in patients with chronic tinnitus. Study Design: Parallel randomized control study. Setting: Tertiary referral center. Patients: We enrolled 2 female and 20 male patients in this study. The evaluative tools included tinnitus frequency-and loudness-matching, tinnitus questionnaires (TQ), and the Tinnitus Handicap Inventory (THI). Methods: The orthogonal projection of the auditory cortex on the scalp was focalized. A figure-eight coil was placed on the surface of the skull over the targeted region with the intensity setting at 80% of the resting motor threshold. We delivered 900 pulses of theta-burst rTMS daily for 10 business days. Main Outcome Measures: Nine of twelve patients (75%) in the active-stimulation group reported tinnitus suppression following treatment with rTMS. The treatment led to reductions of 8.58 and 8.33 in the mean TQ global and THI scores, respectively. Tinnitus loudness also decreased significantly after delivering rTMS. Results: Descriptive analysis of the TQs revealed that patients experienced significant improvements in emotional distress levels and somatic symptoms. Conclusions: Our preliminary results demonstrate that theta-burst rTMS treatments offer a method of modulating tinnitus. Patients could benefit from emotional improvements, even more than auditory perceptive relief. Further studies are needed to establish a standard protocol and to clarify nervous propagation along the auditory and psychological projection following treatment with rTMS. © 2011 S. Karger AG, Basel.


Schiza N.,Neuroscience Laboratory | Sargiannidou I.,Neuroscience Laboratory | Kagiava A.,Neuroscience Laboratory | Karaiskos C.,Neuroscience Laboratory | And 2 more authors.
Human Molecular Genetics | Year: 2014

Oligodendrocytes are coupled by gap junctions (GJs) formed mainly by connexin47 (Cx47) and Cx32. Recessive GJC2/Cx47 mutations cause Pelizaeus-Merzbacher-like disease, a hypomyelinating leukodystrophy, while GJB1/Cx32 mutations cause neuropathy and chronic or acute-transient encephalopathy syndromes. Cx32/Cx47 double knockout (Cx32/Cx47dKO) mice develop severe CNS demyelination beginning at 1 month of age leading to death within weeks, offering a relevant model to study disease mechanisms. In order to clarify whether the loss of oligodendrocyte connexins has cell autonomous effects, we generated transgenic mice expressing the wild-type human Cx32 under the control of the mouse proteolipid protein promoter, obtaining exogenous hCx32 expression in oligodendrocytes. By crossing these mice with Cx32KO mice, we obtained expression of hCx32 on Cx32KO background. Immunohistochemical and immunoblot analysis confirmed strong CNS expression of hCx32 specifically in oligodendrocytes and correct localization forming GJs at cell bodies and along the myelin sheath. TG+Cx32/ Cx47dKO mice generated by further crossing with Cx47KO mice showed that transgenic expression of hCx32 rescued the severe early phenotype of CNS demyelination in Cx32/Cx47dKO mice, resulting in marked improvement of behavioral abnormalities at 1 month of age, and preventing the early mortality. Furthermore, TG+Cx32/Cx47dKO mice showed significant improvement of myelination compared with Cx32/Cx47dKO CNS at 1 month of age, while the inflammatory and astrogliotic changes were fully reversed. Our study confirms that loss of oligodendrocyte GJs has cell autonomous effects and that re-establishment of GJ connectivity by replacement of least one GJ protein provides correction of the leukodystrophy phenotype. © The Author 2014. Published by Oxford University Press.


News Article | November 17, 2016
Site: www.eurekalert.org

For decades, the influential "broken windows" theory has linked signs of petty crime to bigger problems in a neighborhood. Largely left out of such discussions, however, is the role simple perceptual features in physical environments play in encouraging rule-breaking. In a new study, researchers at the University of Chicago explored whether mostly subconscious visual cues embedded in dilapidated buildings, overgrown lots and littered streets can fuel deviant behavior. The study, to be published in the December issue of the Journal of Experimental Psychology, finds that exposure to simple perceptual features that make an environment look disorderly affect people in ways that can make rule-breaking more likely. "There is an ever-present physical environment that people are never separated from, and our research suggests it's having an influence in marked and important ways on human behavior and possibly the functioning of a neighborhood," said lead author Hiroki Kotabe, a postdoctoral scholar at UChicago's Environmental Neuroscience Laboratory, which studies how the physical environment affects the brain and behavior. "Our work in many ways is bringing attention to the importance of physical elements, particularly the visual features." Through a series of experiments, researchers including Kotabe; Marc G. Berman, a UChicago assistant professor of psychology and the lab's principal investigator; and doctoral student Omid Kardan identified elements of visual disorder embedded in the environment--from excessive curvy lines to a lack of symmetry. They then tested the impact of such elements on a form of rule-breaking: cheating. Traditionally, broken windows theory has revolved around how social cues such as graffiti, litter and vagrancy can snowball into more serious and widespread crime. It posits that when people see rule-breaking in the environment they reason that misconduct is acceptable, making them more likely to break rules themselves. The theory has been particularly influential on policing in the United States, ushering in a series of controversial policies around crime prevention. "The prevailing wisdom is that one must see social cues of rule-breaking in order for rule-breaking behavior to spread, but many of these social cues have visually disordered components. Imagine graffiti or a broken window both of which tend to have messy and often disorganized lines," Berman said. "Our research calls into question the necessity of having a social cue of disorder to promote rule-breaking, rather one might only need to perceive disorderly lines to cause disorderly behavior." In the study, researchers started by running experiments to identify basic visual cues that drive perceptions of disorder. They had people rate scenes on how orderly or disorderly they looked, showing images of neatly landscaped parks and a pristine lake as well as unkempt urban lots and an overgrown forest. Such scenes then were broken down further and similar questions were asked. For example, they extracted and scrambled basic spatial and color features of the scenes to test whether they could predict how disorderly the scenes looked based on these features, even though participants could not make out the scenes these features came from. Some of these scrambled stimuli to which the participants were exposed could be compared to a Jackson Pollock painting. They found that spatial features such as the density of non-straight lines and asymmetry were better able to predict a scene's disorder than color features such as hue and saturation. Next Kotabe and his colleagues created nonsense orderly and disorderly stimuli based on these visual disorder cues to test whether exposure to visual disorder cues alone could encourage rule-breaking. They turned to a commonly used test of cheating, in which researchers gave participants a challenging math test and told them they would grade their own work. The participants also were told they would receive bonus money for each additional question they reported as correct. After the test, but before grading their work, the participants were exposed to either the visually disordered stimuli or visually ordered stimuli. The researchers found for participants exposed to the visually disordered stimuli compared to those exposed to the visually ordered stimuli the likelihood of cheating increased by 35 percent and the average magnitude of cheating increased by 87 percent. So what is happening in the brain to produce such results? The researchers theorize a few possibilities. It could be that the visually disordered images are more taxing on the brain to process, thus resulting in reduced self-control. Another possibility is that prolonged exposure to visual disorder may activate mental metaphors such as a "straight-edge lifestyle" or a "crooked politician" deeply embedded in human thought, creating effects on behaviors such as rule-breaking. "These possible mechanisms paint a completely different picture from current explanations for (broken windows theory) phenomena. Thus, they point to a vast and unattended area of research, which we encourage researchers to venture into," the researchers wrote.


News Article | November 18, 2016
Site: www.sciencedaily.com

For decades, the influential "broken windows" theory has linked signs of petty crime to bigger problems in a neighborhood. Largely left out of such discussions, however, is the role simple perceptual features in physical environments play in encouraging rule-breaking. In a new study, researchers at the University of Chicago explored whether mostly subconscious visual cues embedded in dilapidated buildings, overgrown lots and littered streets can fuel deviant behavior. The study, to be published in the December issue of the Journal of Experimental Psychology, finds that exposure to simple perceptual features that make an environment look disorderly affect people in ways that can make rule-breaking more likely. "There is an ever-present physical environment that people are never separated from, and our research suggests it's having an influence in marked and important ways on human behavior and possibly the functioning of a neighborhood," said lead author Hiroki Kotabe, a postdoctoral scholar at UChicago's Environmental Neuroscience Laboratory, which studies how the physical environment affects the brain and behavior. "Our work in many ways is bringing attention to the importance of physical elements, particularly the visual features." Through a series of experiments, researchers including Kotabe; Marc G. Berman, a UChicago assistant professor of psychology and the lab's principal investigator; and doctoral student Omid Kardan identified elements of visual disorder embedded in the environment -- from excessive curvy lines to a lack of symmetry. They then tested the impact of such elements on a form of rule-breaking: cheating. Traditionally, broken windows theory has revolved around how social cues such as graffiti, litter and vagrancy can snowball into more serious and widespread crime. It posits that when people see rule-breaking in the environment they reason that misconduct is acceptable, making them more likely to break rules themselves. The theory has been particularly influential on policing in the United States, ushering in a series of controversial policies around crime prevention. "The prevailing wisdom is that one must see social cues of rule-breaking in order for rule-breaking behavior to spread, but many of these social cues have visually disordered components. Imagine graffiti or a broken window both of which tend to have messy and often disorganized lines," Berman said. "Our research calls into question the necessity of having a social cue of disorder to promote rule-breaking, rather one might only need to perceive disorderly lines to cause disorderly behavior." In the study, researchers started by running experiments to identify basic visual cues that drive perceptions of disorder. They had people rate scenes on how orderly or disorderly they looked, showing images of neatly landscaped parks and a pristine lake as well as unkempt urban lots and an overgrown forest. Such scenes then were broken down further and similar questions were asked. For example, they extracted and scrambled basic spatial and color features of the scenes to test whether they could predict how disorderly the scenes looked based on these features, even though participants could not make out the scenes these features came from. Some of these scrambled stimuli to which the participants were exposed could be compared to a Jackson Pollock painting. They found that spatial features such as the density of non-straight lines and asymmetry were better able to predict a scene's disorder than color features such as hue and saturation. Next Kotabe and his colleagues created nonsense orderly and disorderly stimuli based on these visual disorder cues to test whether exposure to visual disorder cues alone could encourage rule-breaking. They turned to a commonly used test of cheating, in which researchers gave participants a challenging math test and told them they would grade their own work. The participants also were told they would receive bonus money for each additional question they reported as correct. After the test, but before grading their work, the participants were exposed to either the visually disordered stimuli or visually ordered stimuli. The researchers found for participants exposed to the visually disordered stimuli compared to those exposed to the visually ordered stimuli the likelihood of cheating increased by 35 percent and the average magnitude of cheating increased by 87 percent. So what is happening in the brain to produce such results? The researchers theorize a few possibilities. It could be that the visually disordered images are more taxing on the brain to process, thus resulting in reduced self-control. Another possibility is that prolonged exposure to visual disorder may activate mental metaphors such as a "straight-edge lifestyle" or a "crooked politician" deeply embedded in human thought, creating effects on behaviors such as rule-breaking. "These possible mechanisms paint a completely different picture from current explanations for (broken windows theory) phenomena. Thus, they point to a vast and unattended area of research, which we encourage researchers to venture into," the researchers wrote.

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