Multimodal data fusion reveals functional and neurochemical correlates of Parkinson's disease.

BACKGROUND: Neurotransmitter deficits and spatial associations among neurotransmitter distribution, brain activity, and clinical features in Parkinson's disease (PD) remain unclear. Better understanding of neurotransmitter impairments in PD may provide potential therapeutic targets. Therefore, we aimed to investigate the spatial relationship between PD-related patterns and neurotransmitter deficits. METHODS: We included 59 patients with PD and 41 age- and sex-matched healthy controls (HCs). The voxel-wise mean amplitude of the low-frequency fluctuation (mALFF) was calculated and compared between the two groups. The JuSpace toolbox was used to test whether spatial patterns of mALFF alterations in patients with PD were associated with specific neurotransmitter receptor/transporter densities. RESULTS: Compared to HCs, patients with PD showed reduced mALFF in the sensorimotor- and visual-related regions. In addition, mALFF alteration patterns were significantly associated with the spatial distribution of the serotonergic, dopaminergic, noradrenergic, glutamatergic, cannabinoid, and acetylcholinergic neurotransmitter systems (p < 0.05, false discovery rate-corrected). CONCLUSIONS: Our results revealed abnormal brain activity patterns and specific neurotransmitter deficits in patients with PD, which may provide new insights into the mechanisms and potential targets for pharmacotherapy.

Ir-Doped CuPd Single-Crystalline Mesoporous Nanotetrahedrons for Ethylene Glycol Oxidation Electrocatalysis: Enhanced Selective Cleavage of C-C Bond.

The development of highly efficient electrocatalysts for complete oxidation of ethylene glycol (EG) in direct EG fuel cells is of decisive importance to hold higher energy efficiency. Despite some achievements, their progress, especially electrocatalytic selectivity to complete oxidated C1 products, is remarkably slower than expected. In this work, we developed a facile aqueous synthesis of Ir-doped CuPd single-crystalline mesoporous nanotetrahedrons (Ir-CuPd SMTs) as high-performance electrocatalyst for promoting oxidation cleavage of C-C bond in alkaline EG oxidation reaction (EGOR) electrocatalysis. The synthesis relied on precise reduction/co-nucleation and epitaxial growth of Ir, Cu and Pd precursors with cetyltrimethylammonium chloride as the mesopore-forming surfactant and extra Br- as the facet-selective agent under ambient conditions. The products featured concave nanotetrahedron morphology enclosed by well-defined (111) facets, single-crystalline and mesoporous structure radiated from the center, and uniform elemental composition without any phase separation. Ir-CuPd SMTs disclosed remarkably enhanced electrocatalytic activity and excellent stability as well as superior selectivity of C1 products for alkaline EGOR electrocatalysis. Detailed mechanism studies demonstrated that performance improvement came from structural and compositional synergies, which kinetically accelerated transports of electrons/reactants within active sites of penetrated mesopores and facilitated oxidation cleavage of high-energy-barrier C-C bond of EG for desired C1 products. More interestingly, Ir-CuPd SMTs performed well in coupled electrocatalysis of anode EGOR and cathode nitrate reduction, highlighting its high potential as bifunctional electrocatalyst in various applications.

Loss of NEDD8 in cancer cells causes vulnerability to immune checkpoint blockade in triple-negative breast cancer.

Immune checkpoint blockade therapy aims to activate the immune system to eliminate cancer cells. However, clinical benefits are only recorded in a subset of patients. Here, we leverage genome-wide CRISPR/Cas9 screens in a Tumor-Immune co-Culture System focusing on triple-negative breast cancer (TNBC). We reveal that NEDD8 loss in cancer cells causes a vulnerability to nivolumab (anti-PD-1). Genetic deletion of NEDD8 only delays cell division initially but cell proliferation is unaffected after recovery. Since the NEDD8 gene is commonly essential, we validate this observation with additional CRISPR screens and uncover enhanced immunogenicity in NEDD8 deficient cells using proteomics. In female immunocompetent mice, PD-1 blockade lacks efficacy against established EO771 breast cancer tumors. In contrast, we observe tumor regression mediated by CD8+ T cells against Nedd8 deficient EO771 tumors after PD-1 blockade. In essence, we provide evidence that NEDD8 is conditionally essential in TNBC and presents as a synergistic drug target for PD-1/L1 blockade therapy.

Alteration of intracerebral metabolites and subjective sleepiness by acute caffeine administration in adults.

Background: Caffeine is the most widely consumed psychostimulant. Despite this, the effects of acute caffeine intake on brain metabolite levels remain largely unknown. We aimed to investigate the effect of acute caffeine intake on brain metabolite concentrations in different caffeine consumption habit groups and to explore the association between metabolite changes and sleepiness. Methods: Forty-five healthy adults were divided into groups based on their daily caffeine consumption: ≥1 cup/day, <1 cup/day, and no consumption. The exclusion criteria were the presence of neurological disorder, habitual consumption of mind-altering substances, and individuals who were unable to undergo magnetic resonance imaging. Mescher-Garwood point resolved spectroscopy and conventional spectroscopy data were acquired at 3 Tesla from voxels in the thalamus and posterior cingulate cortex (PCC). Subjective sleepiness was measured with the Karolinska Sleepiness Scale. Results: The results of two-way repeated measures analysis of variance indicated a significant interaction effect between time and group for glutamate, glycerylphosphocholine and phosphocholine (GPC + PCH), myo-inositol, glutamate + glutamine (Glx), and creatine and phosphocreatine (Cr + PCr) of the thalamus (all P<0.01), and glutamate (P<0.0001), GPC + PCH (P=0.016), and Glx (P<0.0001) of the PCC. The change between pre- and post-caffeine intake results with significant reductions in γ-aminobutyric acid-positive macromolecule (GABA+) (thalamus, P=0.011), Glx (thalamus, P=0.002), glutamate (PCC, P<0.0001), and significant increments in GPC + PCH (thalamus, P=0.012 and PCC, P<0.0001), myo-inositol (thalamus, P=0.009), and Glx (PCC, P<0.0001). The change among the groups, with the ≥1 cup/day was significantly higher than the <1 cup/day or no consumption for glutamate (PCC, P=0.028), GPC (thalamus, P=0.001; PCC, P=0.026), and Cr + PCr (PCC, P=0.035); ≥1 cup/day was significantly lower than <1 cup/day and no consumption for glutamate (thalamus, P<0.0001), Cr + PCr (thalamus, P=0.003), Glx (thalamus, P=0.014), and myo-inositol (PCC, P=0.009). Bivariate correlation analysis revealed that GABA+ in the thalamus voxel (r=-0.7676; P<0.0001) was negatively correlated with subjective sleepiness. Conclusions: Higher caffeine consumption had a significant impact on brain metabolites. Magnetic resonance spectroscopy was sensitive in measuring brain metabolite fluctuations after caffeine intake, particularly the levels of GABA+ in the thalamus, which was significantly correlated with sleepiness.