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d to assess the direction and causality of the relationships between QoL and brain integrity.Better self-perceived physical health, encompassing daily living activities and pain and discomfort, was the only QoL domain related to brain structural integrity including higher global gray matter volume and global white matter microstructural integrity in cognitively unimpaired older adults. The relationships involved brain structures belonging to the salience network, the pain pathway and the empathy network. While previous studies showed a link between objective measures of physical health, our findings specifically highlight the relevance of monitoring and promoting self-perceived physical health in the older population. Longitudinal studies are needed to assess the direction and causality of the relationships between QoL and brain integrity.Neural networks involved in placebo analgesia and nocebo hyperalgesia processes have been widely investigated with neuroimaging methods. However, few studies have directly compared these two processes and it remains unclear whether common or distinct neural circuits are involved. To address this issue, we implemented a coordinate-based meta-analysis and compared neural representations of placebo analgesia (30 studies; 205 foci; 677 subjects) and nocebo hyperalgesia (22 studies; 301 foci; 401 subjects). Contrast analyses confirmed placebo-specific concordance in the right ventral striatum, and nocebo-specific concordance in the dorsal anterior cingulate cortex (dACC), left posterior insula and left parietal operculum during combined pain anticipation and administration stages. Importantly, no overlapping regions were found for these two processes in conjunction analyses, even when the threshold was low. Meta-analytic connectivity modeling (MACM) and resting-state functional connectivity (RSFC) analyses on key regions further confirmed the distinct brain networks underlying placebo analgesia and nocebo hyperalgesia. Together, these findings indicate that the placebo analgesia and nocebo hyperalgesia processes involve distinct neural circuits, which supports the view that the two phenomena may operate via different neuropsychological processes.The General Linear Model (GLM) used in task-fMRI relates activated brain areas to extrinsic task conditions. The translation of resulting neural activation into a hemodynamic response is commonly approximated with a linear convolution model using a hemodynamic response function (HRF). There are two major limitations in GLM analysis. Firstly, the GLM assumes that neural activation is either on or off and matches the exact stimulus duration in the corresponding task timings. Secondly, brain networks observed in resting-state fMRI experiments present also during task experiments, but the GLM approach models these task-unrelated brain activity as noise. A novel kernel matrix factorization approach, called hemodynamic matrix factorization (HMF), is therefore proposed that addresses both limitations by assuming that task-related and task-unrelated brain activity can be modeled with the same convolution model as in GLM analysis. By contrast to the GLM, the proposed HMF is a blind source separation (BSS) technique, w HMF also produced seemingly task-unrelated modes whose spatial maps matched known resting-state networks. The validity of a fMRI task experiment relies on the assumption that the exposure to a stimulus for a given time causes an imminent increase in neural activation of equal duration. The proposed HMF is an attempt to falsify this assumption and allows to identify subject task participation that does not comply with the experiment instructions.Resting-state functional connectivity is suggested to be cross-sectionally associated with both vascular burden and Alzheimer's disease (AD) pathology. However, evidence is lacking regarding longitudinal changes in functional connectivity. This study includes 247 cognitively unimpaired individuals with a family history of sporadic AD (185 women/ 62 men; mean [SD] age of 63 [5.3] years). Plasma total-, HDL-, and LDL-cholesterol and systolic and diastolic blood pressure were measured at baseline. Global (whole-brain) brain functional connectivity and connectivity from canonical functional networks were computed from resting-state functional MRI obtained at baseline and ~3.5 years of annual follow-ups, using a predefined functional parcellation. A subsample underwent Aβ- and tau-PET (n=91). Linear mixed-effects models demonstrated that global functional connectivity increased over time across the entire sample. In contrast, higher total-cholesterol and LDL-cholesterol levels were associated with greater reduction of functional connectivity in the default-mode network over time. In addition, higher diastolic blood pressure was associated with global functional connectivity reduction. The associations were similar when the analyses were repeated using two other functional brain parcellations. Aβ and tau deposition in the brain were not associated with changes in functional connectivity over time in the subsample. These findings provide evidence that vascular burden is associated with a decrease in functional connectivity over time in older adults with elevated risk for AD. Future studies are needed to determine if the impact of vascular risk factors on functional brain changes precede the impact of AD pathology on functional brain changes.Changes in resting-state functional connectivity (rs-FC) under general anesthesia have been widely studied with the goal of identifying neural signatures of consciousness. This work has commonly revealed an apparent fragmentation of whole-brain network structure during unconsciousness, which has been interpreted as reflecting a break-down in connectivity and a disruption of the brain's ability to integrate information. Here we show, by studying rs-FC under varying depths of isoflurane-induced anesthesia in nonhuman primates, that this apparent fragmentation, rather than reflecting an actual change in network structure, can be simply explained as the result of a global reduction in FC. Specifically, by comparing the actual FC data to surrogate data sets that we derived to test competing hypotheses of how FC changes as a function of dose, we found that increases in whole-brain modularity and the number of network communities - considered hallmarks of fragmentation - are artifacts of constructing FC networks by thresholding based on correlation magnitude. Taken together, our findings suggest that deepening levels of unconsciousness are instead associated with the increasingly muted expression of functional networks, an observation that constrains current interpretations as to how anesthesia-induced FC changes map onto existing neurobiological theories of consciousness.Gaucher disease (GD) is caused by homozygous mutations in the GBA1 gene, which encodes the lysosomal β-glucosidase (GBA) enzyme. GD affects several organs and tissues, including the brain in certain variants of the disease. Heterozygous GBA1 variants are a major genetic risk factor for developing Parkinson's disease. The RIPK3 kinase is relevant in GD and its deficiency improves the neurological and visceral symptoms in a murine GD model. RIPK3 mediates necroptotic-like cell death it is unknown whether the role of RIPK3 in GD is the direct induction of necroptosis or if it has a more indirect function by mediating necrosis-independent. Also, the mechanisms that activate RIPK3 in GD are currently unknown. In this study, we show that c-Abl tyrosine kinase participates upstream of RIPK3 in GD. We found that the active, phosphorylated form of c-Abl is increased in several GD models, including patient's fibroblasts and GBA null mice. Furthermore, its pharmacological inhibition with the FDA-approved drug Imatinib decreased RIPK3 signaling. We found that c-Abl interacts with RIPK3, that RIPK3 is phosphorylated at a tyrosine site, and that this phosphorylation is reduced when c-Abl is inhibited. Genetic ablation of c-Abl in neuronal GD and GD mice models significantly reduced RIPK3 activation and MLKL downstream signaling. https://www.selleckchem.com/products/derazantinib.html These results showed that c-Abl signaling is a new upstream pathway that activates RIPK3 and that its inhibition is an attractive therapeutic approach for the treatment of GD.Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is the most common inborn long-chain fatty acid oxidation (FAO) disorder. VLCAD deficiency is characterized by distinct phenotypes. The severe phenotypes are potentially life-threatening and affect the heart or liver, with a comparatively milder phenotype characterized by myopathic symptoms. There is an unmet clinical need for effective treatment options for the myopathic phenotype. The molecular mechanisms driving the gradual decrease in mitochondrial function and associated alterations of muscle fibers are unclear. The peroxisome proliferator-activated receptor (PPAR) pan-agonist bezafibrate is a potent modulator of FAO and multiple other mitochondrial functions and has been proposed as a potential medication for myopathic cases of long-chain FAO disorders. In vitro experiments have demonstrated the ability of bezafibrate to increase VLCAD expression and activity. However, the outcome of small-scale clinical trials has been controversial. We found VLCAD deficient patient fibroblasts to have an increased oxidative stress burden and deranged mitochondrial bioenergetic capacity, compared to controls. Applying heat stress under fasting conditions to bezafibrate pretreated patient cells, caused a marked further increase of mitochondrial superoxide levels. Patient cells failed to maintain levels of the essential thiol peptide antioxidant glutathione and experienced a decrease in cellular viability. Our findings indicate that chronic PPAR activation is a plausible initiator of long-term pathogenesis in VLCAD deficiency. Our findings further implicate disruption of redox homeostasis as a key pathogenic mechanism in VLCAD deficiency and support the notion that a deranged thiol metabolism might be an important pathogenic factor in VLCAD deficiency.GABA is the major inhibitory neurotransmitter that counterbalances excitation in the mature brain. The inhibitory action of GABA relies on the inflow of chloride ions (Cl-), which hyperpolarizes the neuron. In early development, GABA signaling induces outward Cl- currents and is depolarizing. The postnatal shift from depolarizing to hyperpolarizing GABA is a pivotal event in brain development and its timing affects brain function throughout life. Altered timing of the postnatal GABA shift is associated with several neurodevelopmental disorders. Here, we argue that the postnatal shift from depolarizing to hyperpolarizing GABA represents the final shift in a sequence of GABA shifts, regulating proliferation, migration, differentiation, and finally plasticity of developing neurons. Each developmental GABA shift ensures that the instructive role of GABA matches the circumstances of the developing network. Sensory input may be a crucial factor in determining proper timing of the postnatal GABA shift. A developmental perspective is necessary to interpret the full consequences of a mismatch between connectivity, activity and GABA signaling during brain development.
