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"Lambert, Jonathan"
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Jonny Lambert's animal ABC
\"An illustrated lift-the-flap baby book that reveals an entire animal alphabet. E is for elephant, L is for lion, Q is for ... you'll have to lift the flap and see! Children and adults will delight in this magical menagerie of animals from all around the world, whilst developing a child's vocabulary and language skills.\"--Provided by publisher.
Book
Impaired mitochondrial calcium efflux contributes to disease progression in models of Alzheimer’s disease
Impairments in neuronal intracellular calcium (
i
Ca
2+
) handling may contribute to Alzheimer’s disease (AD) development. Metabolic dysfunction and progressive neuronal loss are associated with AD progression, and mitochondrial calcium (
m
Ca
2+
) signaling is a key regulator of both of these processes. Here, we report remodeling of the
m
Ca
2+
exchange machinery in the prefrontal cortex of individuals with AD. In the 3xTg-AD mouse model impaired
m
Ca
2+
efflux capacity precedes neuropathology. Neuronal deletion of the mitochondrial Na
+
/Ca
2+
exchanger (NCLX,
Slc8b1
gene) accelerated memory decline and increased amyloidosis and tau pathology. Further, genetic rescue of neuronal NCLX in 3xTg-AD mice is sufficient to impede AD-associated pathology and memory loss. We show that
m
Ca
2+
overload contributes to AD progression by promoting superoxide generation, metabolic dysfunction and neuronal cell death. These results provide a link between the calcium dysregulation and metabolic dysfunction hypotheses of AD and suggest
m
Ca
2+
exchange as potential therapeutic target in AD.
Dysregulation of intracellular calcium is reported in Alzheimer’s disease. Here the authors show that loss of the mitochondrial Na
+
/Ca
2
+
exchanger, NCLX – primary route of mitochondrial calcium efflux, precedes neuronal pathology in experimental models and contributes to Alzheimer’s disease progression.
Journal Article
Special you
\"Little Why just wants to be special. If only he had spiny-spiky horns like Wildebeest ... or long-lofty leggy legs like Giraffe! Join Little Why on a beautiful journey of discovery and love.\"--Back cover.
Book
The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability
Mitochondrial calcium (
m
Ca
2+
) has a central role in both metabolic regulation and cell death signalling, however its role in homeostatic function and disease is controversial
1
.
Slc8b1
encodes the mitochondrial Na
+
/Ca
2+
exchanger (NCLX), which is proposed to be the primary mechanism for
m
Ca
2+
extrusion in excitable cells
2
,
3
. Here we show that tamoxifen-induced deletion of
Slc8b1
in adult mouse hearts causes sudden death, with less than 13% of affected mice surviving after 14 days. Lethality correlated with severe myocardial dysfunction and fulminant heart failure. Mechanistically, cardiac pathology was attributed to
m
Ca
2+
overload driving increased generation of superoxide and necrotic cell death, which was rescued by genetic inhibition of mitochondrial permeability transition pore activation. Corroborating these findings, overexpression of NCLX in the mouse heart by conditional transgenesis had the beneficial effect of augmenting
m
Ca
2+
clearance, preventing permeability transition and protecting against ischaemia-induced cardiomyocyte necrosis and heart failure. These results demonstrate the essential nature of
m
Ca
2+
efflux in cellular function and suggest that augmenting
m
Ca
2+
efflux may be a viable therapeutic strategy in disease.
Conditional deletion of the mitochondrial Na
+
/Ca
2+
exchanger NCLX in adult mouse hearts causes sudden death due to mitochondrial calcium overload, whereas its overexpression limits cell death elicited by ischaemia reperfusion injury and heart failure.
Homeostasis 'chalked up' to mitochondrial calcium exchange
The relevance of mitochondrial calcium exchange
in vivo
has been controversial. Here, John Elrod and colleagues explore the physiological significance of this process in the mouse heart. Conditional deletion of the mitochondrial sodium–calcium exchanger NCLX in adult mouse hearts caused sudden death owing to mitochondrial calcium overload and necrotic cell death. Conversely, overexpression of NCLX in mouse hearts limited cell death caused by ischaemia reperfusion injury, the tissue damage caused when blood rushes back to a site that has suffered a lack of oxygen. The authors conclude that cardiomyocyte mitochondrial calcium exchange is a prominent mitochondrial regulatory mechanism in cardiac disease.
Journal Article
Little Why
\"Little Why just cannot seem to stay in line with the other elephants. There's just too much to see; Giraffe's long-lofty leggy legs, Wildebeest's spiny-spiky horns, and even Crocodile's snippy-snappy teeth! Look out, Little Why!\"-- Amazon.com.
Book
HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation
A cure for HIV-1 remains unattainable as only one case has been reported, a decade ago
1
,
2
. The individual—who is known as the ‘Berlin patient’—underwent two allogeneic haematopoietic stem-cell transplantation (HSCT) procedures using a donor with a homozygous mutation in the HIV coreceptor CCR5 (CCR5Δ32/Δ32) to treat his acute myeloid leukaemia. Total body irradiation was given with each HSCT. Notably, it is unclear which treatment or patient parameters contributed to this case of long-term HIV remission. Here we show that HIV-1 remission may be possible with a less aggressive and toxic approach. An adult infected with HIV-1 underwent allogeneic HSCT for Hodgkin’s lymphoma using cells from a CCR5Δ32/Δ32 donor. He experienced mild gut graft-versus-host disease. Antiretroviral therapy was interrupted 16 months after transplantation. HIV-1 remission has been maintained over a further 18 months. Plasma HIV-1 RNA has been undetectable at less than one copy per millilitre along with undetectable HIV-1 DNA in peripheral CD4 T lymphocytes. Quantitative viral outgrowth assays from peripheral CD4 T lymphocytes show no reactivatable virus using a total of 24 million resting CD4 T cells. CCR5-tropic, but not CXCR4-tropic, viruses were identified in HIV-1 DNA from CD4 T cells of the patient before the transplant. CD4 T cells isolated from peripheral blood after transplantation did not express CCR5 and were susceptible only to CXCR4-tropic virus ex vivo. HIV-1 Gag-specific CD4 and CD8 T cell responses were lost after transplantation, whereas cytomegalovirus-specific responses were detectable. Similarly, HIV-1-specific antibodies and avidities fell to levels comparable to those in the Berlin patient following transplantation. Although at 18 months after the interruption of treatment it is premature to conclude that this patient has been cured, these data suggest that a single allogeneic HSCT with homozygous CCR5Δ32 donor cells may be sufficient to achieve HIV-1 remission with reduced intensity conditioning and no irradiation, and the findings provide further support for the development of HIV-1 remission strategies based on preventing CCR5 expression.
An adult infected with HIV-1 who underwent allogeneic haematopoietic stem-cell transplantation for Hodgkin’s lymphoma using cells from a CCR5Δ32/Δ32 donor achieved full remission of HIV-1 for 18 months after transplantation and 16 months after cessation of antiretroviral therapy.
Journal Article
Near-synchronous Northern Hemisphere and Patagonian Ice Sheet variation over the last glacial cycle
Northern Hemisphere insolation intensity is roughly in phase with Southern Hemisphere climate proxies, leading to a common conclusion that northern insolation forces southern climate during the Late Quaternary. However, mid-latitude Southern Hemisphere records place the advance of Patagonian and New Zealand glaciers before the Last Glacial Maximum (29,000–18,000 years ago) by several millennia. To resolve the cause(s) of nearly synchronous global climate change requires continuous archives of mid-latitude glacial activity for the last glacial cycle. Here we assess the position of the Patagonian Ice Sheet’s marine-terminating margin over the last ~89,000 years using a sedimentary-beryllium-isotope record from the Chilean margin to track the proximity of local glaciers. We find that glaciations and deglaciations are synchronous with or precede Northern Hemisphere ice sheets by thousands of years. Glacial expansion was driven by equatorward migration and strengthening of the southern westerly winds, linked to global cooling and a steeper meridional temperature gradient. Glacial terminations occurred when global warming coincided with increasing obliquity and dramatic Northern Hemisphere cooling. Our results suggest that, on orbital timescales, a complex interaction between mean global climate, obliquity and interhemispheric teleconnections could have led to near-synchronous global ice sheet evolution through displacements of the southern westerlies.
Patagonian ice sheet changes largely mirrored those of the Northern Hemisphere over the last glacial cycle owing to displacements of the southern westerly winds, according to beryllium isotope constraints.
Journal Article
Where in the wild
\"Animals are found in every environment around the world from the rain forest to the savanna to the desert. Some creatures, like butterflies and foxes, can survive in many different habitats. Lyrical text and stunning illustrations bring to life the inhabitants of these unique environments\"--Jacket.
Book
Inhibition of Mitochondrial Complex I Impairs Release of α-Galactosidase by Jurkat Cells
Fabry disease (FD) is caused by mutations in the GLA gene that encodes lysosomal α-galactosidase-A (α-gal-A). A number of pathogenic mechanisms have been proposed and these include loss of mitochondrial respiratory chain activity. For FD, gene therapy is beginning to be applied as a treatment. In view of the loss of mitochondrial function reported in FD, we have considered here the impact of loss of mitochondrial respiratory chain activity on the ability of a GLA lentiviral vector to increase cellular α-gal-A activity and participate in cross correction. Jurkat cells were used in this study and were exposed to increasing viral copies. Intracellular and extracellular enzyme activities were then determined; this in the presence or absence of the mitochondrial complex I inhibitor, rotenone. The ability of cells to take up released enzyme was also evaluated. Increasing transgene copies was associated with increasing intracellular α-gal-A activity but this was associated with an increase in Km. Release of enzyme and cellular uptake was also demonstrated. However, in the presence of rotenone, enzyme release was inhibited by 37%. Excessive enzyme generation may result in a protein with inferior kinetic properties and a background of compromised mitochondrial function may impair the cross correction process.
Journal Article