Primate sanctuaries across Africa play a pivotal role in the rescue and rehabilitation of confiscated and rescued wild primates, many of whom have had extensive contact with humans prior to their arrival and throughou...Primate sanctuaries across Africa play a pivotal role in the rescue and rehabilitation of confiscated and rescued wild primates, many of whom have had extensive contact with humans prior to their arrival and throughout the rehabilitation process, heightening the risk of disease transmission. While tuberculosis is not naturally occurring in free-living chimpanzees, it has been extensively observed in captive primates that have been in close proximity to humans or other captive primates infected with Mycobacterium tuberculosis. This case report delves into an outbreak of extra-pulmonary tuberculosis among juvenile chimpanzees within a sanctuary, detailing the associated diagnostic challenges and treatment approaches. The five cases had close contact with a caregiver infected with tuberculosis, subsequently transmitting the infection to other in-contact chimpanzees. Prolonged treatment, employing the human protocol of quadri-therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol), followed by bi-therapy (rifampicin and isoniazid), resulted in complete resolution for all five cases. These cases underscore the critical importance of maintaining high levels of biosecurity, implementing effective quarantine measures, and adhering to strict hygiene practices when working with non-human primates.展开更多
Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases (RIPK) associated with the tumor necrosis fact...Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases (RIPK) associated with the tumor necrosis factor-alpha (TNF-a)/death receptor. Recent evidence shows RIPK inhibitors are neuroprotective and al- leviate ischemic brain injury in a number of animal models, however, most have not yet undergone clinical trials and safety in humans remains in question. Dabrafenib, originally identified as a B-raf inhibitor that is currently used to treat melanoma, was later revealed to be a potent RIPK3 inhibitor at micromolar con- centrations. Here, we investigated whether Dabrafenib would show a similar neuroprotective effect in mice subjected to ischemic brain injury by photothrombosis. Dabrafenib administered intraperitoneally at 10 mg/ kg one hour after photothrombosis-induced focal ischemic injury significantly reduced infarct lesion size in C57BL6 mice the following day, accompanied by a markedly attenuated upregulation of TNF-u. However, subsequent lower doses (5 mg/kg/day) failed to sustain this neuroprotective effect after 4 days. Dabrafenib bl ocked lipopolysaccharides-induced activation of TNF-ct in bone marrow-derived macrophages, suggesting that Dabrafenib may attenuate TNF-ct-induced necroptotic pathway after ischemic brain injury. Since Dab- rafenib is already in clinical use for the treatment of melanoma, it might be repurposed for stroke therapy.展开更多
Alzheimer’s disease is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Recent preclinical and epidemiological studies proposed statins as a possible therapeutic drug...Alzheimer’s disease is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Recent preclinical and epidemiological studies proposed statins as a possible therapeutic drug for Alzheimer’s disease, but the exact mechanisms of action are still unknown. Biliverdin reductase-A is a pleiotropic enzyme involved in cellular stress responses. It not only transforms biliverdin-IX alpha into the antioxidant bilirubin-IX alpha but its serine/threonine/ tyrosine kinase activity is able to modulate cell signaling networks. We previously reported the beneficial effects of atorvastatin treatment on biliverdin reductase-A and heme oxygenase-1 in the brains of a well characterized pre-clinical model of Alzheimer’s disease, aged beagles, together with observed improvement in cognition. Here we extend our knowledge of the effects of atorvastatin on inducible nitric oxide synthase in parietal cortex, cerebellum and liver of the same animals. We demonstrated that atorvastatin treatment (80 mg/day for 14.5 months) to aged beagles selectively increased inducible nitric oxide synthase in the parietal cortex but not in the cerebellum. In contrast, inducible nitric oxide synthase protein levels were significantly decreased in the liver. Significant positive correlations were found between biliverdin reductase-A and inducible nitric oxide synthase as well as heme oxygenase-1 protein levels in the parietal cortex. The opposite was observed in the liver. Inducible nitric oxide synthase up-regulation in the parietal cortex was positively associated with improved biliverdin reductase-A functions, whereas the oxidative-induced impairment of biliverdin reductase-A in the liver negatively affected inducible nitric oxide synthase expression, thus suggesting a role for biliverdin reductase-A in atorvastatin-dependent inducible nitric oxide synthase changes. Interestingly, increased inducible nitric oxide synthase levels in the parietal cortex were not associated with higher oxidative/nitrosative stress levels. We hypothesize that biliverdin reductase-A-dependent inducible nitric oxide synthase regulation strongly contributes to the cognitive improvement observed following atorvastatin treatment.展开更多
Gender differences are investigated from the viewpoint of cognitive neuroscience in the domain of spatial ability. Five task types of geometric problems are used for the collection of task-evoked fMRI data. Although t...Gender differences are investigated from the viewpoint of cognitive neuroscience in the domain of spatial ability. Five task types of geometric problems are used for the collection of task-evoked fMRI data. Although there was no gender-difference in task performance, we found gender differences in neural activity. Some of the important gender differences that we found are 1) that there are far more joint neuro-activations among the brain regions, co-activations or reverse-activations, in males than in females, 2) that the two types of joint activations were nearly half and half in females while it was mostly co-activations in males, 3) that males tend to have more co-activations in the left hemisphere than expected while females tend to have more between-hemisphere co-activations than expected, and 4) that the left-right pairs of BA's are more highly associated than average for males while they are far less associated than average for females.展开更多
Ischemic brain injury causes neuronal death and inflammation.Inflammation activates protein-tyrosine phosphatase 1B(PTP1B).Here,we tested the significance of PTP1B activation in glutamatergic projection neurons on fun...Ischemic brain injury causes neuronal death and inflammation.Inflammation activates protein-tyrosine phosphatase 1B(PTP1B).Here,we tested the significance of PTP1B activation in glutamatergic projection neurons on functional recovery in two models of stroke:by photothrombosis,focal ischemic lesions were induced in the sensorimotor cortex(SM stroke)or in the peri-prefrontal cortex(peri-PFC stroke).Elevated PTP1B expression was detected at 4 days and up to 6 weeks after stroke.While ablation of PTP1B in neurons of neuronal knockout(NKO)mice had no effect on the volume or resorption of ischemic lesions,markedly different effects on functional recovery were observed.SM stroke caused severe sensory and motor deficits(adhesive removal test)in wild type and NKO mice at 4 days,but NKO mice showed drastically improved sensory and motor functional recovery at 8 days.In addition,peri-PFC stroke caused anxiety-like behaviors(elevated plus maze and open field tests),and depression-like behaviors(forced swimming and tail suspension tests)in wild type mice 9 and 28 days after stroke,respectively,with minimal effect on sensory and motor function.Peri-PFC stroke-induced affective disorders were associated with fewer active(FosB+)neurons in the PFC and nucleus accumbens but more FosB+neurons in the basolateral amygdala,compared to sham-operated mice.In contrast,mice with neuronal ablation of PTP1B were protected from anxiety-like and depression-like behaviors and showed no change in FosB+neurons after peri-PFC stroke.Taken together,our study identifies neuronal PTP1B as a key component that hinders sensory and motor functional recovery and also contributes to the development of anxiety-like and depression-like behaviors after stroke.Thus,PTP1B may represent a novel therapeutic target to improve stroke recovery.All procedures for animal use were approved by the Animal Care and Use Committee of the University of Ottawa Animal Care and Veterinary Service(protocol 1806)on July 27,2018.展开更多
Glutamate is the main exc i tatory neurotransmitter in the brain and binds to two major classes of receptors,theα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid(AMPA)and the N-methyl-D-aspartate(NMDA)receptors.U...Glutamate is the main exc i tatory neurotransmitter in the brain and binds to two major classes of receptors,theα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid(AMPA)and the N-methyl-D-aspartate(NMDA)receptors.Unlike AMPA receptors that are immediately activated by glutamate release,NMDA receptors are blocked by magnesium and can only be activated by glutamate after membrane depolarization.Thus,NMDA receptors are only activated after repeated AMPA receptor activation by glutamate.NMDA receptors are,for the most part,calcium-permeable channels.Calcium influx through NMDA receptors modulates synaptic transmission in neurons based on prior history of excitation,and provides a means of scaling the strength of synapses required for Hebbian plasticity.展开更多
The visual guidance of goal-directed movements requires transformations of incoming visual information that are different from those required for visual perception.For us to grasp an object successfully,our brain must...The visual guidance of goal-directed movements requires transformations of incoming visual information that are different from those required for visual perception.For us to grasp an object successfully,our brain must use justin-time computations of the object’s real-world size and shape,and its orientation and disposition with respect to our hand.These requirements have led to the emergence of dedicated visuomotor modules in the posterior parietal cortex of the human brain(the dorsal visual stream)that are functionally distinct from networks in the occipito-temporal cortex(the ventral visual stream)that mediate our conscious perception of the world.Although the identification and selection of goal objects and an appropriate course of action depends on the perceptual machinery of the ventral stream and associated cognitive modules,the execution of the subsequent goal-directed action is mediated by dedicated online control systems in the dorsal stream and associated motor areas.The dorsal stream allows an observer to reach out and grasp objects with exquisite ease,but by itself,deals only with objects that are visible at the moment the action is being programmed.The ventral stream,however,allows an observer to escape the present and bring to bear information from the past-including information about the function of objects,their intrinsic properties,and their location with reference to other objects in the world.Ultimately then,both streams contribute to the production of goal-directed actions.The principles underlying this division of labour between the dorsal and ventral streams are relevant to the design and implementation of autonomous robotic systems.展开更多
文摘Primate sanctuaries across Africa play a pivotal role in the rescue and rehabilitation of confiscated and rescued wild primates, many of whom have had extensive contact with humans prior to their arrival and throughout the rehabilitation process, heightening the risk of disease transmission. While tuberculosis is not naturally occurring in free-living chimpanzees, it has been extensively observed in captive primates that have been in close proximity to humans or other captive primates infected with Mycobacterium tuberculosis. This case report delves into an outbreak of extra-pulmonary tuberculosis among juvenile chimpanzees within a sanctuary, detailing the associated diagnostic challenges and treatment approaches. The five cases had close contact with a caregiver infected with tuberculosis, subsequently transmitting the infection to other in-contact chimpanzees. Prolonged treatment, employing the human protocol of quadri-therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol), followed by bi-therapy (rifampicin and isoniazid), resulted in complete resolution for all five cases. These cases underscore the critical importance of maintaining high levels of biosecurity, implementing effective quarantine measures, and adhering to strict hygiene practices when working with non-human primates.
基金supported by grants from the Heart and Stroke Foundation of Canada(HHC,AFRS)the Canadian Institutes of Health Research(to HHC and AFRS)supported by a Mid-Career Investigator Award from the Heart and Stroke Foundation of Ontario
文摘Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases (RIPK) associated with the tumor necrosis factor-alpha (TNF-a)/death receptor. Recent evidence shows RIPK inhibitors are neuroprotective and al- leviate ischemic brain injury in a number of animal models, however, most have not yet undergone clinical trials and safety in humans remains in question. Dabrafenib, originally identified as a B-raf inhibitor that is currently used to treat melanoma, was later revealed to be a potent RIPK3 inhibitor at micromolar con- centrations. Here, we investigated whether Dabrafenib would show a similar neuroprotective effect in mice subjected to ischemic brain injury by photothrombosis. Dabrafenib administered intraperitoneally at 10 mg/ kg one hour after photothrombosis-induced focal ischemic injury significantly reduced infarct lesion size in C57BL6 mice the following day, accompanied by a markedly attenuated upregulation of TNF-u. However, subsequent lower doses (5 mg/kg/day) failed to sustain this neuroprotective effect after 4 days. Dabrafenib bl ocked lipopolysaccharides-induced activation of TNF-ct in bone marrow-derived macrophages, suggesting that Dabrafenib may attenuate TNF-ct-induced necroptotic pathway after ischemic brain injury. Since Dab- rafenib is already in clinical use for the treatment of melanoma, it might be repurposed for stroke therapy.
基金Funding for the canine atorvastatin study was through the Alzheimer's Association IIRG-03-5673 to Elizabeth Head
文摘Alzheimer’s disease is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Recent preclinical and epidemiological studies proposed statins as a possible therapeutic drug for Alzheimer’s disease, but the exact mechanisms of action are still unknown. Biliverdin reductase-A is a pleiotropic enzyme involved in cellular stress responses. It not only transforms biliverdin-IX alpha into the antioxidant bilirubin-IX alpha but its serine/threonine/ tyrosine kinase activity is able to modulate cell signaling networks. We previously reported the beneficial effects of atorvastatin treatment on biliverdin reductase-A and heme oxygenase-1 in the brains of a well characterized pre-clinical model of Alzheimer’s disease, aged beagles, together with observed improvement in cognition. Here we extend our knowledge of the effects of atorvastatin on inducible nitric oxide synthase in parietal cortex, cerebellum and liver of the same animals. We demonstrated that atorvastatin treatment (80 mg/day for 14.5 months) to aged beagles selectively increased inducible nitric oxide synthase in the parietal cortex but not in the cerebellum. In contrast, inducible nitric oxide synthase protein levels were significantly decreased in the liver. Significant positive correlations were found between biliverdin reductase-A and inducible nitric oxide synthase as well as heme oxygenase-1 protein levels in the parietal cortex. The opposite was observed in the liver. Inducible nitric oxide synthase up-regulation in the parietal cortex was positively associated with improved biliverdin reductase-A functions, whereas the oxidative-induced impairment of biliverdin reductase-A in the liver negatively affected inducible nitric oxide synthase expression, thus suggesting a role for biliverdin reductase-A in atorvastatin-dependent inducible nitric oxide synthase changes. Interestingly, increased inducible nitric oxide synthase levels in the parietal cortex were not associated with higher oxidative/nitrosative stress levels. We hypothesize that biliverdin reductase-A-dependent inducible nitric oxide synthase regulation strongly contributes to the cognitive improvement observed following atorvastatin treatment.
文摘Gender differences are investigated from the viewpoint of cognitive neuroscience in the domain of spatial ability. Five task types of geometric problems are used for the collection of task-evoked fMRI data. Although there was no gender-difference in task performance, we found gender differences in neural activity. Some of the important gender differences that we found are 1) that there are far more joint neuro-activations among the brain regions, co-activations or reverse-activations, in males than in females, 2) that the two types of joint activations were nearly half and half in females while it was mostly co-activations in males, 3) that males tend to have more co-activations in the left hemisphere than expected while females tend to have more between-hemisphere co-activations than expected, and 4) that the left-right pairs of BA's are more highly associated than average for males while they are far less associated than average for females.
基金This work was supported by grants from the Heart and Stroke Foundation of Canada(Nos.G-13-0002596&G-18-0022157,to HHCNo.G-16-00014085,to AFRS)+2 种基金the Natural Science and Engineering Research Council of Canada(No.RGPIN/06212-2014,to HHC,No.RGPIN/2016-04985,to AFRS)the Canadian Institutes of Health Research(No.201610PJT,to HHC)HHC is also supported by a Mid-Career Investigator Award(No.7506)from the Heart and Stroke Foundation of Ontario.How to cite this article:Cruz SA。
文摘Ischemic brain injury causes neuronal death and inflammation.Inflammation activates protein-tyrosine phosphatase 1B(PTP1B).Here,we tested the significance of PTP1B activation in glutamatergic projection neurons on functional recovery in two models of stroke:by photothrombosis,focal ischemic lesions were induced in the sensorimotor cortex(SM stroke)or in the peri-prefrontal cortex(peri-PFC stroke).Elevated PTP1B expression was detected at 4 days and up to 6 weeks after stroke.While ablation of PTP1B in neurons of neuronal knockout(NKO)mice had no effect on the volume or resorption of ischemic lesions,markedly different effects on functional recovery were observed.SM stroke caused severe sensory and motor deficits(adhesive removal test)in wild type and NKO mice at 4 days,but NKO mice showed drastically improved sensory and motor functional recovery at 8 days.In addition,peri-PFC stroke caused anxiety-like behaviors(elevated plus maze and open field tests),and depression-like behaviors(forced swimming and tail suspension tests)in wild type mice 9 and 28 days after stroke,respectively,with minimal effect on sensory and motor function.Peri-PFC stroke-induced affective disorders were associated with fewer active(FosB+)neurons in the PFC and nucleus accumbens but more FosB+neurons in the basolateral amygdala,compared to sham-operated mice.In contrast,mice with neuronal ablation of PTP1B were protected from anxiety-like and depression-like behaviors and showed no change in FosB+neurons after peri-PFC stroke.Taken together,our study identifies neuronal PTP1B as a key component that hinders sensory and motor functional recovery and also contributes to the development of anxiety-like and depression-like behaviors after stroke.Thus,PTP1B may represent a novel therapeutic target to improve stroke recovery.All procedures for animal use were approved by the Animal Care and Use Committee of the University of Ottawa Animal Care and Veterinary Service(protocol 1806)on July 27,2018.
基金supported by grants from the Heart and Stroke Foundation of Canada(G-13-0002596&G-18-0022157,to HHCG-16-00014085,to AFRS)+4 种基金Ontario Mental Health Foundation(to HHC),the Canadian Institutes of Health Research(201610PJT#376403,to HHC201610PJT#376503,to AFRS)the Natural Science and Engineering Research Council of Canada(RGPIN/06212-2014,to HHCRGPIN/2016-04985,to AFRS)supported by a Mid-Career Investigator Award(grant#7506)from the Heart and Stroke Foundation of Ontario.
文摘Glutamate is the main exc i tatory neurotransmitter in the brain and binds to two major classes of receptors,theα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid(AMPA)and the N-methyl-D-aspartate(NMDA)receptors.Unlike AMPA receptors that are immediately activated by glutamate release,NMDA receptors are blocked by magnesium and can only be activated by glutamate after membrane depolarization.Thus,NMDA receptors are only activated after repeated AMPA receptor activation by glutamate.NMDA receptors are,for the most part,calcium-permeable channels.Calcium influx through NMDA receptors modulates synaptic transmission in neurons based on prior history of excitation,and provides a means of scaling the strength of synapses required for Hebbian plasticity.
文摘The visual guidance of goal-directed movements requires transformations of incoming visual information that are different from those required for visual perception.For us to grasp an object successfully,our brain must use justin-time computations of the object’s real-world size and shape,and its orientation and disposition with respect to our hand.These requirements have led to the emergence of dedicated visuomotor modules in the posterior parietal cortex of the human brain(the dorsal visual stream)that are functionally distinct from networks in the occipito-temporal cortex(the ventral visual stream)that mediate our conscious perception of the world.Although the identification and selection of goal objects and an appropriate course of action depends on the perceptual machinery of the ventral stream and associated cognitive modules,the execution of the subsequent goal-directed action is mediated by dedicated online control systems in the dorsal stream and associated motor areas.The dorsal stream allows an observer to reach out and grasp objects with exquisite ease,but by itself,deals only with objects that are visible at the moment the action is being programmed.The ventral stream,however,allows an observer to escape the present and bring to bear information from the past-including information about the function of objects,their intrinsic properties,and their location with reference to other objects in the world.Ultimately then,both streams contribute to the production of goal-directed actions.The principles underlying this division of labour between the dorsal and ventral streams are relevant to the design and implementation of autonomous robotic systems.