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LAL overexpression also resulted in abnormal phagosome accumulation and lysosomal lipid accumulation depending upon the dietary treatment. Overall, we found that hepatic overexpression of LAL drove immune cell infiltration and inflammation and did not attenuate the development of NAFLD, suggesting that targeting LAL expression may not be a viable route to treat NAFLD in humans.Understanding the spatial gene expression and regulation in the heart is key to uncovering its developmental and physiological processes, during homeostasis and disease. Numerous techniques exist to gain gene expression and regulation information in organs such as the heart, but few utilize intuitive true-to-life three-dimensional representations to analyze and visualise results. Here we combined transcriptomics with 3D-modelling to interrogate spatial gene expression in the mammalian heart. N-Nitroso-N-methylurea For this, we microdissected and sequenced transcriptome-wide 18 anatomical sections of the adult mouse heart. Our study has unveiled known and novel genes that display complex spatial expression in the heart sub-compartments. We have also created 3D-cardiomics, an interface for spatial transcriptome analysis and visualization that allows the easy exploration of these data in a 3D model of the heart. link2 3D-cardiomics is accessible from http//3d-cardiomics.erc.monash.edu/.3,4 Methylenedioxymethamphetamine generally referred to as MDMA or 'ecstasy' is a ring-substituted phenethylamine stimulant which produces powerful empathogenic effects. Use of MDMA remains popular despite prohibition, and potential long-term negative consequences of repeated use. MDMA produces its acute subjective effects primarily by stimulating the release of serotonin via action at the serotonin transporter (SERT). There is evidence that MDMA administration may lead to long lasting neurotoxic effects on serotonin neurons in primates, and reductions in markers of central serotonin axons, and axon terminals in animals. In humans, demonstration of serotonergic neurotoxicity is much more difficult to identify, and much of the research is complicated by confounding issues of polysubstance use, genetic and environmental factors and reliance on self-reports of previous drug use. We do not review the mechanisms for neurotoxicity in detail as they are covered elsewhere in this special issue. There is a large body of literature, however, which has investigated potential cognitive and neurocognitive consequences of repeated MDMA use. Here we review the literature on cognition, and neuroimaging studies that have investigated structural and functional brain changes associated with ecstasy use.Spinal cord injury (SCI) leads to irreversible functional deficits due to the disruption of axons and the death of neurons and glial cells. The inflammatory response that occurs in the injured spinal cord results in tissue degeneration; thus, targeting inflammation after acute SCI is expected to ameliorate histopathological evidence indicative of damage and, consequently, reduce functional disabilities. Interleukin 1 beta (IL-1β) and interleukin 18 (IL-18) are pro-inflammatory cytokines members of the IL-1 family that initiate and propagate inflammation. Here, we report that protein levels of IL-1β and IL-18 were increased in spinal cord parenchyma after SCI, but with different expression profiles. Whereas levels of IL-1β were rapidly increased reaching peak levels at 12 h after the injury, levels of IL-18 did not increase until 7 days after the injury. Since activation of the NLRP3 inflammasome is required for the processing and release of IL-1β and IL-18, we intraperitoneally administered OLT1177, a selective inhibitor of the NLRP3 inflammasome, to reduce the contribution of these cytokines to SCI. At a dose of 200 mg/kg, OLT1177 protected against neurological deficits and histological evidence of damage. OLT1177 also reduced the levels of IL-1β in the spinal cord after contusion injury and diminished the accumulation of neutrophils and macrophages at later time points. These data suggest that targeting the NLRP3 inflammasome with OLT1177 could be a novel therapeutic strategy to arrest neuroinflammation and reduce functional impairments after acute SCI in humans.Traumatic Brain Injury (TBI) is a one of the leading causes of death and disability worldwide. The consequences of TBI can be divided into two stages 1) the immediate neuronal destruction during the initial trauma, resulting in the primary brain injury and pathophysiologic sequelae, and 2) the secondary brain injury, encompassing mitochondrial dysfunction, inflammation, cellular excitotoxicity, oxidative stress, and cortical edema, resulting in increased intracranial pressure (ICP) with exacerbated brain damage. Although the pathophysiology in TBI has been thoroughly investigated, the effectivity of therapeutic approaches for TBI is still lacking. Vagus nerve stimulation (VNS) has been used for treating medical refractory epilepsy and chronic drug-resistant depression. Several previous studies also demonstrated that VNS has beneficial effects for TBI in animal models and patients. The neuroprotective effects of VNS on TBI are possibly explained through several mechanisms, including a noradrenergic mechanism, anti-inflammatory effects, regulation of neurotransmitters, and attenuation of blood brain barrier breakdown, and brain edema. The aims of this review are to summarize and discuss the current evidence pertinent to the effect of VNS on both primary and secondary brain injury following TBI from both in vivo and clinical studies.Respiratory failure is the main cause of death in amyotrophic lateral sclerosis (ALS). Since no effective treatments to preserve independent breathing are available, there is a critical need for new therapies to preserve or restore breathing ability. Since acute intermittent hypoxia (AIH) elicits spinal respiratory motor plasticity in rodent ALS models, and may restore breathing ability in people with ALS, we performed a proof-of-principle study to investigate this possibility in ALS patients. Quiet breathing, sniff nasal inspiratory pressure (SNIP) and maximal inspiratory pressure (MIP) were tested in 13 persons with ALS and 10 age-matched controls, before and 60 min post-AIH (15, 1 min episodes of 10% O2, 2 min normoxic intervals) or sham AIH (continuous normoxia). The root mean square (RMS) of the right and left diaphragm, 2nd parasternal, scalene and sternocleidomastoid muscles were monitored. A vector analysis was used to calculate summated vector magnitude (Mag) and similarity index (SI) of collective EMG activity during quiet breathing, SNIP and MIP maneuvers. AIH facilitated tidal volume and minute ventilation (treatment main effects p less then 0.05), and Mag (ie. collective respiratory muscle activity; p less then 0.001) during quiet breathing in ALS and control subjects, but there was no effect on SI during quiet breathing. SNIP SI decreased in both groups post-AIH (p less then 0.005), whereas Mag was unchanged (p = 0.09). No differences were observed in SNIP or MIP post AIH in either group. Discomfort was not reported during AIH by any subject, nor were adverse events observed. Thus, AIH may be a safe way to increase collective inspiratory muscle activity during quiet breathing in ALS patients, although a single AIH presentation was not sufficient to significantly increase peak inspiratory pressure generation. These preliminary results provide evidence that AIH may improve breathing function in people with ALS, and that future studies of prolonged, repetitive AIH protocols are warranted.Children with low physical activity and interactions with environment experience atypical sensorimotor development and maturation leading to anatomical and functional disorganization of the sensorimotor circuitry and also to enduring altered motor function. Previous data have shown that postnatal movement restriction in rats results in locomotor disturbances, functional disorganization and hyperexcitability of the hind limb representations in the somatosensory and motor cortices, without apparent brain damage. Due to the reciprocal interplay between the nervous system and muscle, it is difficult to determine whether muscle alteration is the cause or the result of the altered sensorimotor behavior (Canu et al., 2019). In the present paper, our objectives were to evaluate the impact of early movement restriction leading to sensorimotor restriction (SMR) during development on the postural soleus muscle and on sensorimotor performance in rats, and to determine whether changes were reversed when typical activity ws locomotor activity increased over time. Our results support the idea that proprioceptive feedback is at least as important as the amount of motor activity to promote a typical development of motor function. A better knowledge of the interplay between hypoactivity, muscle properties and central motor commands may offer therapeutic perspectives for children suffering from neurodevelopmental disorders.Motor deficits after stroke reflect both, focal lesion and network alterations in brain regions distant from infarction. This remote network dysfunction may be caused by aberrant signals from cortical motor regions travelling via mesencephalic locomotor region (MLR) to other locomotor circuits. A method for modulating disturbed network activity is deep brain stimulation. Recently, we have shown that high frequency stimulation (HFS) of the MLR in rats has restored gait impairment after photothrombotic stroke (PTS). However, it remains elusive which cerebral regions are involved by MLR-stimulation and contribute to the improvement of locomotion. Seventeen male Wistar rats underwent photothrombotic stroke of the right sensorimotor cortex and implantation of a microelectrode into the right MLR. 2-[18F]Fluoro-2-deoxyglucose ([18F]FDG)-positron emission tomography (PET) was conducted before stroke and thereafter, on day 2 and 3 after stroke, without and with MLR-HFS, respectively. [18F]FDG-PET imaging analyses yielded a reduced glucose metabolism in the right cortico-striatal thalamic loop after PTS compared to the state before intervention. When MLR-HFS was applied after PTS, animals exhibited a significantly higher uptake of [18F]FDG in the right but not in the left cortico-striatal thalamic loop. Furthermore, MLR-HFS resulted in an elevated glucose metabolism of right-sided association cortices related to the ipsilateral sensorimotor cortex. These data support the concept of diaschisis i.e., of dysfunctional brain areas distant to a focal lesion and suggests that MLR-HFS can reverse remote network effects following PTS in rats which otherwise may result in chronic motor symptoms.Ischemia reperfusion-induced acute kidney injury (IR-induced AKI) is a life-threatening disease with many complications. Mitofusin 2 (Mfn2) ubiquitination is related to AKI. But the underlying molecular mechanisms remain unknown. This study aimed to probe the mechanism of Mfn2 ubiquitination in IR-induced AKI development. In IR-induced AKI mouse models, orbital blood and urine were collected for assessing kidney function. The kidney injury, ultrastructure of mitochondria, and histopathology in mice were evaluated after injection of G5, an ubiquitination inhibitor. link3 Oxygen glucose deprivation/reoxygenation (OGD/R) models were established in HK-2 cells, and the mitochondria were extracted. Cell viability, apoptosis, oxidative stress, inflammatory reaction, mitochondrial membrane potential, and ATP production were measured. Mfn2 ubiquitination in mouse and cell models was evaluated. si-SIRT3 and pcDNA3.1-SIRT3 were transfected into cell models. Consequently, kidney function in mice was impaired by IR-induced AKI.