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Mitochondria influence cellular function through both cell-autonomous and non-cell autonomous mechanisms, such as production of paracrine and endocrine factors. Here, we demonstrate that mitochondrial regulation of the secretome is more extensive than previously appreciated, as both genetic and pharmacological disruption of the electron transport chain caused upregulation of the Alzheimer’s disease risk factor apolipoprotein E (APOE) and other secretome components. This upregulation of secretory proteins was of a similar extent as modifications to the mitochondrial annotated proteome. Indirect disruption of the electron transport chain by gene editing of SLC25A mitochondrial membrane transporters as well as direct genetic and pharmacological disruption of either complexes I, III, or the copper-containing complex IV of the electron transport chain, elicited upregulation of APOE transcript, protein, and secretion, up to 49-fold. These APOE phenotypes were robustly expressed in diverse cell types and iPSC-derived human astrocytes as part of an inflammatory gene expression program. Moreover, age- and genotype-dependent decline in brain levels of respiratory complex I preceded an increase in APOE in the 5xFAD mouse model. We propose that mitochondria act as novel upstream regulators of APOE-dependent cellular processes in health and disease.

Proteomic studies utilizing postmortem human brain tissue samples have yielded robust assessments of the aging and neurodegenerative disease(s) proteomes. While these analyses provide lists of molecular alterations in human conditions, like Alzheimer’s disease (AD), identifying individual proteins that affect biological processes remains a challenge. To complicate matters, protein targets may be highly understudied and have limited information on their function. To address these hurdles, we sought to establish a blueprint to aid selection and functional validation of targets from proteomic datasets. A cross-platform pipeline was engineered to focus on synaptic processes in the entorhinal cortex of human patients, including controls, preclinical AD, and AD cases. Label-free quantification mass spectrometry data (n=2,260 proteins) was generated on synaptosome fractionated tissue from Brodmann area 28 (n=58 samples). In parallel, dendritic spine density and morphology was measured in the same individuals. Weighted gene co-expression network analysis was used to construct a network of protein co-expression modules that were correlated with dendritic spine metrics. Module-trait correlations were used to guide unbiased selection of Twinfilin-2 (TWF2), which was the top hub protein of a module that positively correlated with thin spine length. Using CRISPR-dCas9 activation strategies, we demonstrated that boosting endogenous TWF2 protein levels in primary hippocampal neurons increased thin spine length, thus providing experimental validation for the human network analysis. Collectively, this study describes alterations in dendritic spine density and morphology as well as synaptic proteins and phosphorylated tau from the entorhinal cortex of preclinical and advanced stage AD patients.Significance Statement:Proteomic studies can yield vast lists of molecules that are altered under various experimental or disease conditions. Here, we provide a blueprint to facilitate mechanistic validation of protein targets from human brain proteomic datasets. We conducted a proteomic analysis of human entorhinal cortex samples spanning cognitively normal and Alzheimer's disease cases with a comparison of dendritic spine morphology in the same samples. Network integration of proteomics with dendritic spine measurements allowed for unbiased discovery of Twinfilin-2 as a regulator of dendritic spine length. A proof-of-concept experiment in cultured neurons demonstrated that altering Twinfilin-2 protein level induced corresponding changes in dendritic spine length, thus providing experimental validation for the computational framework.

MECP2 loss-of-function mutations cause Rett syndrome, a disorder that results from a disrupted brain transcriptome. How these transcriptional defects are decoded into a disease proteome remains unknown. We studied the proteome in Rett syndrome cerebrospinal fluid (CSF) across vertebrates. We identified a consensus proteome and ontological categories shared across Rett syndrome cerebrospinal fluid (CSF) from three species, including humans. Rett CSF proteomes enriched proteins annotated to HDL lipoproteins, complement, mitochondria, citrate/pyruvate metabolism, as well as synapse compartments. We used these prioritized and shared ontologies to select analytes for orthogonal quantification. These studies independently validated our proteome and ontologies. Ontologically selected CSF hits had genotypic discriminatory capacity as determined by Receiver Operating Characteristic (ROC) analysis and distinguished Rett from a related neurodevelopmental disorder, CDKL5 deficiency disorder. We propose that Mecp2 mutant CSF proteomes and ontologies inform novel putative mechanisms and biomarkers of disease. We suggest that Rett syndrome is a metabolic disorder impacting synapse function.

Gulf War Illness (GWI), a chronic multisymptom illness with a complex and uncertain etiology and pathophysiology, is highly prevalent among veterans deployed to the 1990–1991 GW. We examined how GWI phenotypes varied by demographic and military characteristics among GW-era veterans. Data were from the VA’s Cooperative Studies Program 2006/Million Veteran Program (MVP) 029 cohort, Genomics of GWI. From June 2018 to March 2019, 109,976 MVP enrollees (out of a total of over 676,000) were contacted to participate in the 1990–1991 GW-era Survey. Of 109,976 eligible participants, 45,169 (41.1%) responded to the 2018–2019 survey, 35,902 respondents met study inclusion criteria, 13,107 deployed to the GW theater. GWI phenotypes were derived from Kansas (KS) and Centers for Disease Control and Prevention (CDC) GWI definitions: (a) KS Symptoms (KS Sym+), (b) KS GWI (met symptom criteria and without exclusionary health conditions) [KS GWI: Sym+/Dx−], (c) CDC GWI and (d) CDC GWI Severe. The prevalence of each phenotype was 67.1% KS Sym+, 21.5% KS Sym+/Dx−, 81.1% CDC GWI, and 18.6% CDC GWI severe. These findings affirm the persistent presence of GWI among GW veterans providing a foundation for further exploration of biological and environmental underpinnings of this condition.

International audience; No abstract available

Background Health literacy is a determinant of health. Few studies characterize its association with surgical outcomes. Methods Retrospective cohort study of patients undergoing elective colorectal surgery 2015-2020. Health literacy assessed using Brief Health Literacy Screening Tool. Outcomes were postoperative complications, LOS, readmissions, mortality. Results Of 552 patients, 46 (8.3%) had limited health literacy, 506 (91.7%) non-limited. Median age 57.7 years, 305 (55.1%) patients were female, 148 (26.8%) were Black. Limited patients had higher rates of overall complications (43.5% vs. 24.3%, p = 0.004), especially surgical site infections (21.7% vs. 11.3%, p = 0.04). Limited patients had longer LOS (5 vs 3.5 days, p = 0.006). Readmissions and mortality did not differ. On multivariable analysis, limited health literacy was independently associated with increased risk of complications (OR 2.03, p = 0.046), not LOS (IRR 1.05, p = 0.67). Conclusion Limited health literacy is associated with increased likelihood of complications after colorectal surgery. Opportunities exist for health literate surgical care to improve outcomes for limited health literacy patients.

The E6 protein of the human papillomavirus (HPV) underpins important protein interaction networks between the virus and host to promote viral infection. Through its interaction with E6AP, a host E3 ubiquitin (UB) ligase, E6 stirs the protein ubiquitination pathways toward the oncogenic transformation of the infected cells. For a systematic measurement of E6 reprogramming of the substrate pool of E6AP, we performed a proteomic screen based on "orthogonal UB transfer (OUT)" that allowed us to identify the ubiquitination targets of E6AP dependent on the E6 protein of HPV-16, a high-risk viral subtype for the development of cervical cancer. The OUT screen identified more than 200 potential substrates of the E6-E6AP pair based on the transfer of UB from E6AP to the substrate proteins. Among them, we verified that E6 would induce E6AP-catalyzed ubiquitination of importin proteins KPNA1-3, protein phosphatase PGAM5, and arginine methyltransferases CARM1 to trigger their degradation by the proteasome. We further found that E6 could significantly reduce the cellular level of KPNA1 that resulted in the suppression of nuclear transport of phosphorylated STAT1 and the inhibition of interferon-γ-induced apoptosis in cervical cancer cells. Overall, our work demonstrates OUT as a powerful proteomic platform to probe the interaction of E6 and host cells through protein ubiquitination and reveals a new role of E6 in down-regulating nuclear transport proteins to attenuate tumor-suppressive signaling.

High-utility itemset mining (HUIM) in transaction databases has been extensively studied to discover interesting itemsets from users' purchase behaviors. With this, business managers can adjust their sale strategies appropriately to increase profit. HUIM approaches usually focus on the utility values of itemsets, but rarely evaluate the correlation of items in itemsets. Many high-utility itemsets are weakly correlated and have no real meaning. To address this issue, we suggest an algorithm, called CoHUI-Miner, to efficiently find correlated high-utility itemsets. In the proposed algorithm, we use the database projection mechanism to reduce the database size and present a new concept, called the prefix utility of projected transactions, to eliminate itemsets which do not satisfy the minimum threshold in the mining process. Experimental evaluation on two types of datasets from sparse to dense ones shows that CoHUI-Miner can efficiently mine correlated high-utility itemsets with regard to both execution time and memory usage.

Millions of tons of plastic are produced annually, but less than 10% are reported to be recycled. This work sets out to transform environmental plastic (polyethylene terephthalate – PET) waste into aerogels for high-value engineering applications, primarily to enhance the monetary incentive in recycling plastics. Coating techniques, using silicone ceramic (SCC) and (3-aminopropyl)triethoxysilane (APS, or APTES) solutions, are successfully devised to enhance the thermal stability and CO2 adsorption capability of rPET aerogel. The rPET/SCC aerogel exhibits improved thermal stability (up to 600 °C), enhanced thermal insulation (thermal conductivity Kavg = [31.8–34.9] mW/m·K), hydrophobic characteristics (up to 144.7° in contact angle) and enhanced rigidity (Young modulus Eavg = [4.5–124.8] kPa), while maintaining an ultra-low density (ρa = [14–62] g/cm3) and a high porosity (Φavg = [95.6–99.0]%). Moreover, the amine-functionalised rPET aerogel achieves a CO2 adsorption capacity of up to 0.44 mmol CO2/g, superior to several commercial physio-sorbents. These promising results obtained demonstrate that the rPET aerogel is a versatile material suitable for a wide variety of high-value engineering applications, including thermal insulation and direct CO2 capture applications.

Over twenty million tons of pineapples have been produced annually worldwide, but their waste is mostly discarded or burnt after harvesting. In this work, the high-value added aerogels from the pin...

The objective of the study was to identify some of common ornamental plants functioned as medicinal plants. The study was carried out in the Ho Chi Minh City, from September 2016 to June 2018 using some methods such as survey, identification, statistics, and applying these plants in garden design with site analysis, computer-aided design and drafting base on main idea. One hundred and twenty popular species belonging to 69 families with medicinal values were identified. Two cases for concept design, instant tree list, shrub and cover list were also proposed. The completed design drawings included function layout plan, master plan, sections and some details of garden, master perspective, detailed perspectives.

Amorphous molybdenum sulfide is an attractive electrode material for Li/Mg batteries and an efficient Pt-free catalyst for the hydrogen evolution reaction in water. By using the electrochemical quartz crystal microbalance (EQCM) analysis, new insights were gained into the electrochemical polymerization of the [Mo3 S13 ]2- cluster, which generates amorphous molybdenum sulfide thin films. In this work, it is shown that, at the anodic potential, a two-electron oxidative elimination of the terminal disulfide ligand within the [Mo3 S13 ]2- cluster induces the polymerization. A reductive elimination of the terminal disulfide ligand also occurs at the cathodic potential, inducing the polymerization. However, in sharp contrast to the anodic polymerization, according to which the film growth is rapid, the cathodic polymerization competes with the electrochemical reductive corrosion of the readily grown film, therefore occurring at a significant lower growth rate.

For the first time, recycled car tire fibers (RCTF) shredded from car tire waste are developed successfully into a novel material, a rubber aerogel, using polyvinyl alcohol (PVA) and glutaraldehyde (GA) as crosslinkers through a cost-effective freeze-drying method. Its structure and main physical properties are investigated comprehensively for high-value applications, such as heat and sound insulation of buildings and oil spill spilling clean up. The rubber aerogel has ultra-low density (ρa = 0.035 – 0.145 g/cm3) and high porosity (Φavg = 84.31–96.20 %). With a simple but effective coating method with methoxytrimethylsilane (MTMS), both the interior and exterior of the whole rubber aerogel surface can be well coated, and the coated aerogel exhibits a super-hydrophobicity with a water contact angle of up to 134.4°. The rubber aerogel exhibits excellent heat insulation properties (Kavg = 0.035 – 0.047 W/m.K), very good thermal stability up to 500 °C, and significantly-enhanced rigidity up to a Young modulus of Eavg = 458.12 kPa, much larger than that of commercial Styrofoam. The rubber aerogel shows very good durability as it springs back to its original shape after compression tests. The rubber aerogel has a noise reduction coefficient (NRC) of 0.41 and performs approximately 10% better than commercial sound foam absorber at 2000–3000 Hz. The maximum oil absorbtion capacity of the rubber aerogel in this work is 19.3 g/g, very competitive to commercial sorbents. The fabrication method can also be scaled up for several other industrial applications, not limited to sound, heat and sorbent applications.

Background Baby boomers are at increased risk for hepatitis C virus (HCV) infection and related cancer; therefore, one‐time HCV screening is recommended. Methods To assess prevalence of, and factors associated with providers ordering HCV screening, we examined a retrospective cohort of electronic medical records for patient visits from 01 August 2015 until 31 July 2017 in a large health system. HCV screening ordered was examined by patient age, gender, race/ethnicity, provider specialty, and number of clinical visits, stratified by birth cohort: born ≤1945, 1945‐1965 (baby boomers), 1966‐1985, and ≥1985. Multivariable regression identified factors independently associated with HCV screening ordered among average risk baby boomers. Results A total of 65 114 patients ages ≥18 years were evaluated. Among baby boomers HCV screening test order increased threefold between the two study years (4.0%‐12.9%). Odds of screening test ordered were significantly higher for non‐Hispanic Blacks (multivariable adjusted odds ratio [aOR]=1.36; 95% CI = 1.19‐1.55), males (aOR = 1.44; 95% CI = 1.33‐1.57), and having a clinic visit with a primary care provider alone or with specialty care (aOR = 3.25‐4.16). Medicare (aOR = 0.89; 95% CI = 0.80‐0.99), Medicaid (aOR 0.89; 95% CI 0.80‐0.99), and an unknown provider type (aOR = 0.16; 95% CI = 0.08‐0.33), were associated with lower odds of screening tests ordered. Conclusions While the proportion of baby boomers with an HCV screening test ordered increased during the study, the rate of screening remains far below national goals. Data from this study indicate that providers are not ordering HCV screening universally for all of their baby boomer patients. Continued efforts to increase HCV screening are needed to reduce the incidence of HCV‐related morbidity and mortality.

BACKGROUND: 50% of liver cancer is caused by hepatitis C virus (HCV). Baby boomers are at increased risk and are recommended for one-time HCV screening. However

The hippocampus is well established as an essential brain center for learning and memory. Within the hippocampus, recent studies show that area CA2 is important for social memory, and is an anomaly compared to its better understood neighboring region, CA1. Unlike CA1, CA2 displays a lack of typical synaptic plasticity, enhanced calcium buffering and extrusion, and resilience to cell death following injury. Although recent studies have identified multiple molecular markers of area CA2, the proteins that mediate the unique physiology, signaling, and resilience of this region are unknown. Using a transgenic GFP-reporter mouse line that expresses eGFP in CA2, we were able to perform targeted dissections of area CA2 and CA1 for proteomic analysis. We identified over 100 proteins with robustly enriched expression in area CA2 compared to CA1. Many of these proteins, including RGS14 and NECAB2 have already been shown to be enriched in CA2 and important for its function, while many more merit further study in the context of enhanced expression in this enigmatic brain region. Furthermore, we performed a comprehensive analysis of the entire data set (>2300 proteins) using a weighted protein co-expression network analysis (WPCNA). This identified eight distinct co-expressed patterns of protein co-enrichment associated with increased expression in area CA2 tissue (compared to CA1). The novel data set we present here reveals a specific CA2 hippocampal proteome, laying the groundwork for future studies and a deeper understanding of area CA2 and the proteins mediating its unique physiology and signaling.

Amorphous molybdenum selenide nanoparticles were synthesized by the solvothermal treatment of Mo(CO) 6 and Se in dimethylformamide. By varying the Mo(CO) 6 over Se molar ratio, we obtained a family of MoSe nanoparticles having comparable morphology but different chemical composition. Using a combination of experimental analyses ( e.g. XRD, ICP-MS, Raman, XPS) and DFT theoretical calculation, we found that the structure of MoSe was close to that of the amorphous molybdenum sulfide analogous but not that of MoSe 2 layers. The MoSe was found to consist of [Mo 3 Se 13 ] 2- cluster within its structure together with some structural defects. Thanks to its less ordered structure, the MoSe can be activated by several chemical and electrochemical treatment resulting in a catalytic enhancement. A treatment with fuming HCl resulted in generation of a novel catalyst displaying 1.4 time higher catalytic current. Remarkably, a treatment with reflux NaOH solution resulted in generation of a component being soluble in water and displaying catalytic H 2 -evolving activity at a moderate onset overpotential of ca. 200 mV, being one of the most attractives homogeneous catalysts in water.

Here, we report a method for the generation of complementary tryptic (CompTryp) isotope-labeled peptide standards for the relative and absolute quantification of proteins by mass spectrometry (MS). These standards can be digested in parallel with either trypsin (Tryp-C) or trypsin-N (Tryp-N), to generate peptides that significantly overlap in primary sequence having C- and N-terminal arginine and lysine residues, respectively. As a proof of concept, an isotope-labeled CompTryp standard was synthesized for Tau, a well-established biomarker in Alzheimer's disease (AD), which included both N- and C-terminal heavy isotope-labeled (15N and 13C) arginine residues and flanking amino acid sequences to monitor proteolytic digestion. Despite having the exact same mass, the N- and C-terminal heavy Tau peptides are distinguishable by retention time and MS/MS fragmentation profiles. The isotope-labeled Tau CompTryp standard was added to human cerebrospinal fluid (CSF) followed by parallel digestion with Tryp-N and Tryp-C. The native and isotope-labeled peptide pairs were quantified by parallel reaction monitoring (PRM) in a single assay. Notably, both tryptic peptides were effective at quantifying Tau in human CSF, and both showed a significant difference in CSF Tau levels between AD and controls. Treating these CompTryp Tau peptide measurements as independent replicates also improved the coefficient of variation and correlation with Tau immunoassays. More broadly, we propose that CompTryp standards can be generated for any protein of interest, providing an efficient method to improve the robustness and reproducibility for MS analysis of clinical and research samples.

In advanced age, some individuals maintain a stable cognitive trajectory while others experience a rapid decline. Such variation in cognitive trajectory is only partially explained by traditional neurodegenerative pathologies. Hence, to identify new processes underlying variation in cognitive trajectory, we perform an unbiased proteome-wide association study of cognitive trajectory in a discovery (n = 104) and replication cohort (n = 39) of initially cognitively unimpaired, longitudinally assessed older-adult brain donors. We find 579 proteins associated with cognitive trajectory after meta-analysis. Notably, we present evidence for increased neuronal mitochondrial activities in cognitive stability regardless of the burden of traditional neuropathologies. Furthermore, we provide additional evidence for increased synaptic abundance and decreased inflammation and apoptosis in cognitive stability. Importantly, we nominate proteins associated with cognitive trajectory, particularly the 38 proteins that act independently of neuropathologies and are also hub proteins of protein co-expression networks, as promising targets for future mechanistic studies of cognitive trajectory., Cognitive abilities tend to decline over time in advanced age, yet some individuals experience stable abilities or rapid decline. Here the authors present a proteome-wide association study of cognitive trajectory, and identify 38 proteins associated with cognitive resilience.

Sirtuin 2 (SIRT2) is a NAD+-dependent deacetylase, which regulates multiple biological processes, including genome maintenance, aging, tumor suppression, and metabolism. While a number of substrates involved in these processes have been identified, the global landscape of the SIRT2 acetylome remains unclear. Using a label-free quantitative proteomic approach following enrichment for acetylated peptides from SIRT2-depleted and SIRT2-overexpressing HCT116 human colorectal cancer cells, we identified a total of 2,846 unique acetylation sites from 1414 proteins. 896 sites from 610 proteins showed a > 1.5-fold increase in acetylation with SIRT2 knockdown, and 509 sites from 361 proteins showed a > 1.5-fold decrease in acetylation with SIRT2 overexpression, with 184 proteins meeting both criteria. Sequence motif analyses identified several site-specific consensus sequence motifs preferentially recognized by SIRT2, most commonly KxxxxK(ac). Gene Ontology, KEGG, and MetaCore pathway analyses identified SIRT2 substrates involved in diverse pathways, including carbon metabolism, glycolysis, spliceosome, RNA transport, RNA binding, transcription, DNA damage response, the cell cycle, and colorectal cancer. Collectively, our findings expand on the number of known acetylation sites, substrates, and cellular pathways targeted by SIRT2, providing support for SIRT2 in regulating networks of proteins in diverse pathways and opening new avenues of investigation into SIRT2 function.

Isolation and proteomic profiling of brain cell types, particularly neurons, pose several technical challenges which limit our ability to resolve distinct cellular phenotypes in neurological diseases. Therefore, we generated a novel mouse line that enables cell type-specific expression of a biotin ligase, TurboID, via Cre-lox strategy for in vivo proximity-dependent biotinylation of proteins. Using adenoviral-based and transgenic approaches, we show striking protein biotinylation in neuronal cell bodies and axons throughout the mouse brain. We quantified more than 2,000 neuron-derived proteins following enrichment that mapped to numerous subcellular compartments. Synaptic, transmembrane transporters, ion channel subunits, and disease-relevant druggable targets were among the most significantly enriched proteins. Remarkably, we resolved brain region-specific proteomic profiles of Camk2a neurons with distinct functional molecular signatures and disease associations that may underlie regional neuronal vulnerability. Leveraging the neuronal specificity of this in vivo biotinylation strategy, we used an antibody-based approach to uncover regionally unique patterns of neuron-derived signaling phospho-proteins and cytokines, particularly in the cortex and cerebellum. Our work provides a proteomic framework to investigate cell type-specific mechanisms driving physiological and pathological states of the brain as well as complex tissues beyond the brain.

Proteomic profiling of brain cell types using isolation-based strategies pose limitations in resolving cellular phenotypes representative of their native state. We describe a mouse line for cell type-specific expression of biotin ligase TurboID, for in vivo biotinylation of proteins. Using adenoviral and transgenic approaches to label neurons, we show robust protein biotinylation in neuronal soma and axons throughout the brain, allowing quantitation of over 2000 neuron-derived proteins spanning synaptic proteins, transporters, ion channels and disease-relevant druggable targets. Next, we contrast Camk2a-neuron and Aldh1l1-astrocyte proteomes and identify brain region-specific proteomic differences within both cell types, some of which might potentially underlie the selective vulnerability to neurological diseases. Leveraging the cellular specificity of proteomic labeling, we apply an antibody-based approach to uncover differences in neuron and astrocyte-derived signaling phospho-proteins and cytokines. This approach will facilitate the characterization of cell-type specific proteomes in a diverse number of tissues under both physiological and pathological states.

Mitochondria are recognized as signaling organelles, because under stress, mitochondria can trigger various signaling pathways to coordinate the cell’s response. The specific pathway(s) engaged by mitochondria in response to mitochondrial energy defects in vivo and in high-energy tissues like the heart are not fully understood. Here, we investigated cardiac pathways activated in response to mitochondrial energy dysfunction by studying mice with cardiomyocyte-specific loss of the mitochondrial phosphate carrier (SLC25A3), an established model that develops cardiomyopathy as a result of defective mitochondrial ATP synthesis. Mitochondrial energy dysfunction induced a striking pattern of acylome remodeling, with significantly increased posttranslational acetylation and malonylation. Mass spectrometry-based proteomics further revealed that energy dysfunction-induced remodeling of the acetylome and malonylome preferentially impacts mitochondrial proteins. Acetylation and malonylation modified a highly interconnected interactome of mitochondrial proteins, and both modifications were present on the enzyme isocitrate dehydrogenase 2 (IDH2). Intriguingly, IDH2 activity was enhanced in SLC25A3-deleted mitochondria, and further study of IDH2 sites targeted by both acetylation and malonylation revealed that these modifications can have site-specific and distinct functional effects. Finally, we uncovered a novel cross talk between the two modifications, whereby mitochondrial energy dysfunction-induced acetylation of sirtuin 5 (SIRT5), inhibited its function. Because SIRT5 is a mitochondrial deacylase with demalonylase activity, this finding suggests that acetylation can modulate the malonylome. Together, our results position acylations as an arm of the mitochondrial response to energy dysfunction and suggest a mechanism by which focal disruption to the energy production machinery can have an expanded impact on global mitochondrial function.

The locus coeruleus is the initial site of Alzheimer’s disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration in dementia. Locus coeruleus dysfunction contributes to Alzheimer’s pathobiology in experimental models, which can be rescued by increasing norepinephrine transmission. To test norepinephrine augmentation as a potential disease-modifying therapy, we performed a biomarker-driven phase II trial of atomoxetine, a clinically-approved norepinephrine transporter inhibitor, in subjects with mild cognitive impairment due to Alzheimer’s disease. The design was a single-centre, 12-month double-blind crossover trial. Thirty-nine participants with mild cognitive impairment and biomarker evidence of Alzheimer’s disease were randomized to atomoxetine or placebo treatment. Assessments were collected at baseline, 6- (crossover) and 12-months (completer). Target engagement was assessed by CSF and plasma measures of norepinephrine and metabolites. Prespecified primary outcomes were CSF levels of IL1α and TECK. Secondary/exploratory outcomes included clinical measures, CSF analyses of amyloid-β42, Tau, and pTau181, mass spectrometry proteomics and immune-based targeted inflammation-related cytokines, as well as brain imaging with MRI and fluorodeoxyglucose-PET. Baseline demographic and clinical measures were similar across trial arms. Dropout rates were 5.1% for atomoxetine and 2.7% for placebo, with no significant differences in adverse events. Atomoxetine robustly increased plasma and CSF norepinephrine levels. IL-1α and TECK were not measurable in most samples. There were no significant treatment effects on cognition and clinical outcomes, as expected given the short trial duration. Atomoxetine was associated with a significant reduction in CSF Tau and pTau181 compared to placebo, but not associated with change in amyloid-β42. Atomoxetine treatment also significantly altered CSF abundances of protein panels linked to brain pathophysiologies, including synaptic, metabolism and glial immunity, as well as inflammation-related CDCP1, CD244, TWEAK and osteoprotegerin proteins. Treatment was also associated with significantly increased brain-derived neurotrophic factor and reduced triglycerides in plasma. Resting state functional MRI showed significantly increased inter-network connectivity due to atomoxetine between the insula and the hippocampus. Fluorodeoxyglucose-PET showed atomoxetine-associated increased uptake in hippocampus, parahippocampal gyrus, middle temporal pole, inferior temporal gyrus and fusiform gyrus, with carry-over effects 6 months after treatment. In summary, atomoxetine treatment was safe, well tolerated and achieved target engagement in prodromal Alzheimer’s disease. Atomoxetine significantly reduced CSF Tau and pTau, normalized CSF protein biomarker panels linked to synaptic function, brain metabolism and glial immunity, and increased brain activity and metabolism in key temporal lobe circuits. Further study of atomoxetine is warranted for repurposing the drug to slow Alzheimer’s disease progression.

Post-translational modifications (PTMs) within splicing factor RNA-binding proteins (RBPs), such as phosphorylation, regulate several critical steps in RNA metabolism including spliceosome assembly, alternative splicing and mRNA export. Notably, the arginine-/serine-rich (RS) domains in SR proteins are densely modified by phosphorylation compared with the remainder of the proteome. Previously, we showed that dephosphorylation of SRSF2 regulated increased interactions with similar arginine-rich RBPs U1-70K and LUC7L3. In this work, we dephosphorylated nuclear extracts using phosphatase in vitro and analyzed equal amounts of detergent-soluble and -insoluble fractions by mass spectrometry-based proteomics. Correlation network analysis resolved 27 distinct modules of differentially soluble nucleoplasm proteins. We found classes of arginine-rich RBPs that decrease in solubility following dephosphorylation and enrich to the insoluble pelleted fraction, including the SR protein family and the SR-like LUC7L RBP family. Importantly, increased insolubility was not observed across broad classes of RBPs. Phosphorylation regulated SRSF2 structure, as dephosphorylated SRSF2 formed high molecular weight oligomeric species in vitro. Reciprocally, phosphorylation of SRSF2 by serine-/arginine protein kinase 2 (SRPK2) in vitro prevented high molecular weight SRSF2 species formation. Furthermore, we pharmacologically inhibited SRPKs in mammalian cells and observed increased cytoplasmic granules as well as the formation of cytoplasmic SRSF2 tubular structures that associate with microtubules by immunocytochemical staining. Collectively, these findings demonstrate that phosphorylation may be a critical modification that prevents arginine-rich RBP insolubility and oligomerization.

Graphic Abstract Tons of waste from residential, commercial and manufacturing activities are generated due to the growing population, urbanization and economic development, prompting the need for sustainable measures. Numerous ways of converting waste to aerogels, a novel class of ultra-light and ultra-porous materials, have been researched to tackle the issues of waste. This review provides an overview of the status of aerogels made from agricultural waste, municipal solid, and industrial waste focusing on the fabrication, properties, and applications of such aerogels. The review first introduced common methods to synthesize the aerogels from waste, including dispersion and drying techniques. Following that, numerous works related to aerogels from waste are summarized and compared, mainly focusing on the sustainability aspect of the processes involved and their contributions for environmental applications such as thermal insulation and oil absorption. Next, advantages, and disadvantages of the current approaches are analyzed. Finally, some prospective waste aerogels and its applications are proposed.

Advances in synthetic biology, nanotechnology, and genetic engineering are allowing parallel advances in areas such as drug delivery and rapid diagnostics. Although our current visions of nanobots may be far off, a generation of nanobots synthesized by engineering viruses is approaching. Such tools can be used to solve complex problems where current methods do not meet current demands. Assuring safe drinking water is crucial for minimizing the spread of waterborne illnesses. Although extremely low levels of fecal contamination in drinking water are sufficient to cause a public health risk, it remains challenging to rapidly detect Escherichia coli, the standard fecal indicator organism. Current methods sensitive enough to meet regulatory standards suffer from either prohibitively long incubation times or requirement of expensive, impractical equipment. Bacteriophages, tuned by billions of years of evolution to bind viable bacteria and readily engineered to produce custom proteins, are uniquely suited to bacterial detection. We have developed a biosensor platform based on magnetized phages encoding luminescent reporter enzymes. This system utilizes bio-orthogonally functionalized phages to enable site-specific conjugation to magnetic nanoparticles. The resulting phage-based nanobots, when combined with standard, portable field equipment, allow for detection of

Genome-wide association studies (GWAS) have identified several risk loci for post-traumatic stress disorder (PTSD); however, how they confer PTSD risk remains unclear. We aimed to identify genes that confer PTSD risk through their effects on brain protein abundance to provide new insights into PTSD pathogenesis. To that end, we integrated human brain proteomes with PTSD GWAS results to perform a proteome-wide association study (PWAS) of PTSD, followed by Mendelian randomization, using a discovery and confirmatory study design. Brain proteomes (N = 525) were profiled from the dorsolateral prefrontal cortex using mass spectrometry. The Million Veteran Program (MVP) PTSD GWAS (n = 186,689) was used for the discovery PWAS, and the Psychiatric Genomics Consortium PTSD GWAS (n = 174,659) was used for the confirmatory PWAS. To understand whether genes identified at the protein-level were also evident at the transcript-level, we performed a transcriptome-wide association study (TWAS) using human brain transcriptomes (N = 888) and the MVP PTSD GWAS results. We identified 11 genes that contribute to PTSD pathogenesis via their respective cis-regulated brain protein abundance. Seven of 11 genes (64%) replicated in the confirmatory PWAS and 4 of 11 also had their cis-regulated brain mRNA levels associated with PTSD. High confidence level was assigned to 9 of 11 genes after considering evidence from the confirmatory PWAS and TWAS. Most of the identified genes are expressed in other PTSD-relevant brain regions and several are preferentially expressed in excitatory neurons, astrocytes, and oligodendrocyte precursor cells. These genes are novel, promising targets for mechanistic and therapeutic studies to find new treatments for PTSD.

Mitochondrial composition varies by organ and their constituent cell types. This mitochondrial diversity likely determines variations in mitochondrial function. However, the heterogeneity of mitochondria in the brain remains underexplored despite the large diversity of cell types in neuronal tissue. Here, we used molecular systems biology tools to address whether mitochondrial composition varies by brain region and neuronal cell type in mice. We reasoned that proteomics and transcriptomics of microdissected brain regions combined with analysis of single cell mRNA sequencing could reveal the extent of mitochondrial compositional diversity. We selected nuclear encoded gene products forming complexes of fixed stoichiometry, such as the respiratory chain complexes and the mitochondrial ribosome, as well as molecules likely to perform their function as monomers, such as the family of SLC25 transporters. We found that the proteome encompassing these nuclear-encoded mitochondrial genes and obtained from microdissected brain tissue segregated the hippocampus, striatum, and cortex from each other. Nuclear-encoded mitochondrial transcripts could only segregate cell types and brain regions when the analysis was performed at the single cell level. In fact, single cell mitochondrial transcriptomes were able to distinguish glutamatergic and distinct types of GABAergic neurons from one another. Within these cell categories, unique SLC25A transporters were able to identify distinct cell subpopulations. Our results demonstrate heterogeneous mitochondrial composition across brain regions and cell types. We postulate that mitochondrial heterogeneity influences regional and cell type specific mechanisms in health and disease. Significance Statement Mitochondria are important organelles for maintaining brain health. The composition of proteins making up mitochondria is essential for their function. Disturbances to mitochondria are thought to contribute to neurodegeneration and neurodevelopmental disorders. These conditions typically affect specific brain regions or cell types. Despite the link between mitochondria and diseases with distinct anatomical and cellular patterns, how mitochondrial composition varies across brain regions and cell types remains poorly explored. Here, we analyze mitochondrial composition in different brain regions and cell types in adult mice, showing composition differs by region and cell lineage. Our work provides a resource of genes enriched in certain cell types or regions that improves our understanding of how mitochondrial composition influences brain function in health and disease.

We generated an online brain pQTL resource for 7,376 proteins through the analysis of genetic and proteomic data derived from post-mortem samples of the dorsolateral prefrontal cortex of 330 older adults. The identified pQTLs tend to be non-synonymous variation, are over-represented among variants associated with brain diseases, and replicate well (77%) in an independent brain dataset. Comparison to a large study of brain eQTLs revealed that about 75% of pQTLs are also eQTLs. In contrast, about 40% of eQTLs were identified as pQTLs. These results are consistent with lower pQTL mapping power and greater evolutionary constraint on protein abundance. The latter is additionally supported by observations of pQTLs with large effects' tending to be rare, deleterious, and associated with proteins that have evidence for fewer protein-protein interactions. Mediation analyses using matched transcriptomic and proteomic data provided additional evidence that pQTL effects are often, but not always, mediated by mRNA. Specifically, we identified roughly 1.6 times more mRNA-mediated pQTLs than mRNA-independent pQTLs (550 versus 341). Our pQTL resource provides insight into the functional consequences of genetic variation in the human brain and a basis for novel investigations of genetics and disease.

Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging technique called manganese-enhanced magnetic resonance imaging (MEMRI) with quantitative R1 mapping. Surprisingly, these benefits occurred despite unchanged hyperphosphorylated tau levels. To elucidate the mechanism behind these improved cognitive outcomes, we performed quantitative proteomics to determine the altered protein network during this early stage in tauopathy and compare this model with the human Alzheimer&rsquo, s disease (AD) proteome. We identified a cluster of preserved pathways shared with human tauopathy with striking potential for broad multi-target kinase intervention. We further report high confidence candidate proteins as novel therapeutically relevant targets for the treatment of tauopathy. Proteomics data are available via ProteomeXchange with identifier PXD023562.

Background: No evidence currently exists characterising global outcomes following major cancer surgery, including esophageal cancer. Therefore, this study aimed to characterise impact of high income countries (HIC) versus low and middle income countries (LMIC) on the outcomes following esophagectomy for esophageal cancer. Method: This international multi-center prospective study across 137 hospitals in 41 countries included patients who underwent an esophagectomy for esophageal cancer, with 90-day follow-up. The main explanatory variable was country income, defined according to the World Bank Data classification. The primary outcome was 90-day postoperative mortality, and secondary outcomes were composite leaks (anastomotic leak or conduit necrosis) and major complications (Clavien-Dindo Grade III-V). Multivariable generalized estimating equation models were used to produce adjusted odds ratios (ORs) and 95% confidence intervals (CI95%). Results: Between April 2018 to December 2018, 2247 patients were included. Patients from HIC were more significantly older, with higher ASA grade, and more advanced tumors. Patients from LMIC had almost three-fold increase in 90-day mortality, compared to HIC (9.4% vs 3.7%, p < 0.001). On adjusted analysis, LMIC were independently associated with higher 90-day mortality (OR: 2.31, CI95%: 1.17-4.55, p = 0.015). However, LMIC were not independently associated with higher rates of anastomotic leaks (OR: 1.06, CI95%: 0.57-1.99, p = 0.9) or major complications (OR: 0.85, CI95%: 0.54-1.32, p = 0.5), compared to HIC. Conclusion: Resections in LMIC were independently associated with higher 90-day postoperative mortality, likely reflecting a failure to rescue of these patients following esophagectomy, despite similar composite anastomotic leaks and major complication rates to HIC. These findings warrant further research, to identify potential issues and solutions to improve global outcomes following esophagectomy for cancer. (C) 2020 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

The most derived method and realistic way to predict the current stock price is via media resource and trusted new. In this paper, we will apply the current classifier text technique (Based LSTM) and pre-trained model from transfer learning to gain more intuition in financial news and precisely predict stock price. Finally, after using the latest pre-trained word embedding and a classification layer. We have achieved the robust success, and the experiment result shows that our method is able to outperform in accuracy than the previous one and have some advantage in the adaptive dataset.

Background The complexity of oesophageal surgery and the significant risk of morbidity necessitates that oesophagectomy is predominantly performed by a consultant surgeon, or a senior trainee under their supervision. The aim of this study was to determine the impact of trainee involvement in oesophagectomy on postoperative outcomes in an international multicentre setting. Methods Data from the multicentre Oesophago-Gastric Anastomosis Study Group (OGAA) cohort study were analysed, which comprised prospectively collected data from patients undergoing oesophagectomy for oesophageal cancer between April 2018 and December 2018. Procedures were grouped by the level of trainee involvement, and univariable and multivariable analyses were performed to compare patient outcomes across groups. Results Of 2232 oesophagectomies from 137 centres in 41 countries, trainees were involved in 29.1 per cent of them (n = 650), performing only the abdominal phase in 230, only the chest and/or neck phases in 130, and all phases in 315 procedures. For procedures with a chest anastomosis, those with trainee involvement had similar 90-day mortality, complication and reoperation rates to consultant-performed oesophagectomies (P = 0.451, P = 0.318, and P = 0.382, respectively), while anastomotic leak rates were significantly lower in the trainee groups (P = 0.030). Procedures with a neck anastomosis had equivalent complication, anastomotic leak, and reoperation rates (P = 0.150, P = 0.430, and P = 0.632, respectively) in trainee-involved versus consultant-performed oesophagectomies, with significantly lower 90-day mortality in the trainee groups (P = 0.005). Conclusion Trainee involvement was not found to be associated with significantly inferior postoperative outcomes for selected patients undergoing oesophagectomy. The results support continued supervised trainee involvement in oesophageal cancer surgery. The aim of this study was to determine the impact of trainee involvement in oesophagectomy on perioperative outcomes in the international multicentre Oesophago-Gastric Anastomosis Audit (OGAA). Analysis of 2232 oesophagectomies has shown that trainee involvement did not negatively impact perioperative outcomes.