Cerebrospinal fluid amyloid-ß and cerebral microbleed are associated with distinct neuropsychiatric sub-syndromes in cognitively impaired patients.

BACKGROUND: Neuropsychiatric symptoms (NPS) are prevalent in cognitively impaired individuals including Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI). Whereas several studies have reported the associations between NPS with AD pathologic biomarkers and cerebral small vessel disease (SVD), but it remains unknown whether AD pathology and SVD contribute to different sub-syndromes independently or aggravate same symptoms synergistically. METHOD: We included 445 cognitively impaired individuals (including 316 MCI and 129 AD) with neuropsychiatric, cerebrospinal fluid (CSF) biomarkers (Aß42, p-tau, and t-tau) and multi-model MRI data. Psychiatric symptoms were accessed by using the Neuropsychiatric Inventory (NPI). Visual assessment of SVD (white matter hyperintensity, microbleed, perivascular space, lacune) on MRI images was performed by experienced radiologist. Linear regression analyses were conducted to test the association between neuropsychiatric symptoms with AD pathology and CSVD burden after adjustment for age, sex, education, apolipoprotein E (APOE) ε4 carrier status, and clinical diagnosis. RESULTS: The NPI total scores were related to microbleed (estimate 2.424; 95% CI [0.749, 4.099]; P =0.005). Considering the sub-syndromes, the hyperactivity was associated with microbleed (estimate 0.925; 95% CI [0.115, 1.735]; P =0.025), whereas the affective symptoms were correlated to CSF level of Aß42 (estimate -0.006; 95% CI [-0.011, -0.002]; P =0.005). Furthermore, we found the apathy sub-syndrome was associated with CSF t-tau/Aß42 (estimate 0.636; 95% CI [0.078, 1.194]; P =0.041) and microbleed (estimate 0.693; 95% CI [0.046, 1.340]; P =0.036). In addition, we found a significant interactive effect between CSF t-tau/Aß42 and microbleed (estimate 0.993; 95% CI [0.360, 1.626]; P =0.019) on severity of apathy sub-syndrome. CONCLUSION: Our study showed that CSF Aß42 was associated with affective symptoms, but microbleed was correlated with hyperactivity and apathy, suggesting the effect of AD pathology and SVD on different neuropsychiatric sub-syndromes.

Alteration of functional connectivity network in population of objectively-defined subtle cognitive decline.

The objectively-defined subtle cognitive decline individuals had higher progression rates of cognitive decline and pathological deposition than healthy elderly, indicating a higher risk of progressing to Alzheimer's disease. However, little is known about the brain functional alterations during this stage. Thus, we aimed to investigate the functional network patterns in objectively-defined subtle cognitive decline cohort. Forty-two cognitive normal, 29 objectively-defined subtle cognitive decline and 55 mild cognitive impairment subjects were included based on neuropsychological measures from the Alzheimer's disease Neuroimaging Initiative dataset. Thirty cognitive normal, 22 objectively-defined subtle cognitive declines and 48 mild cognitive impairment had longitudinal MRI data. The degree centrality and eigenvector centrality for each participant were calculated by using resting-state functional MRI. For cross-sectional data, analysis of covariance was performed to detect between-group differences in degree centrality and eigenvector centrality after controlling age, sex and education. For longitudinal data, repeated measurement analysis of covariance was used for comparing the alterations during follow-up period among three groups. In order to classify the clinical significance, we correlated degree centrality and eigenvector centrality values to Alzheimer's disease biomarkers and cognitive function. The results of analysis of covariance showed significant between-group differences in eigenvector centrality and degree centrality in left superior temporal gyrus and left precuneus, respectively. Across groups, the eigenvector centrality value of left superior temporal gyrus was positively related to recognition scores in auditory verbal learning test, whereas the degree centrality value of left precuneus was positively associated with mini-mental state examination total score. For longitudinal data, the results of repeated measurement analysis of covariance indicated objectively-defined subtle cognitive decline group had the highest declined rate of both eigenvector centrality and degree centrality values than other groups. Our study showed an increased brain functional connectivity in objectively-defined subtle cognitive decline individuals at both local and global level, which were associated with Alzheimer's disease pathology and neuropsychological assessment. Moreover, we also observed a faster declined rate of functional network matrix in objectively-defined subtle cognitive decline individuals during the follow-ups.

Leveraging Cas13a's trans-cleavage on RNA G-quadruplexes for amplification-free RNA detection.

In this study, we investigated Cas13a's efficacy in trans-cleaving RNA G-quadruplexes (rG4s) as an alternative to ssRNA reporters in CRISPR-Cas13a diagnostics. Our findings demonstrate enhanced efficiency due to the structural arrangement of rG4s. Implementing a simplified CRISPR-Cas13a system based on rG4, we identified SARS-CoV-2 infections in 25 patient samples within 1 hour without target pre-amplification.

A TeZla micromixer for interrogating the early and broad folding landscape of G-quadruplex via multistage velocity descending.

Biomacromolecular folding kinetics involves fast folding events and broad timescales. Current techniques face limitations in either the required time resolution or the observation window. In this study, we developed the TeZla micromixer, integrating Tesla and Zigzag microstructures with a multistage velocity descending strategy. TeZla achieves a significant short mixing dead time (40 µs) and a wide time window covering four orders of magnitude (up to 300 ms). Using this unique micromixer, we explored the folding landscape of c-Myc G4 and its noncanonical-G4 derivatives with different loop lengths or G-vacancy sites. Our findings revealed that c-Myc can bypass folding intermediates and directly adopt a G4 structure in the cation-deficient buffer. Moreover, we found that the loop length and specific G-vacancy site could affect the folding pathway and significantly slow down the folding rates. These results were also cross-validated with real-time NMR and circular dichroism. In conclusion, TeZla represents a versatile tool for studying biomolecular folding kinetics, and our findings may ultimately contribute to the design of drugs targeting G4 structures.

Interferon Regulatory Factor 5 Regulates the Phagocytosis of Microglia and Alleviate Alzheimer's Pathology.

Microglia play a critical role in the pathophysiology of Alzheimer's disease. They are involved in Aß-induced neuroinflammatory responses, regulating the production of inflammatory mediators. Interferon regulatory factor 5 (IRF5) plays a central role in inflammatory diseases in the periphery, the role of which in central nervous system remains elusive. This study aimed to investigate the role of IRF5 in Aß-induced neuroinflammation and the progression of Aß pathology. We found that Aß1-42 oligomers significantly increased the level of IRF5 in BV2 microglia. The levels of proinflammatory cytokines TNF-α, IL-1ß, and IL-6 were significantly upregulated with Aß treatment. IRF5 knockdown with siRNA in microglia significantly reduced the expression of these proinflammatory factors induced by Aß and promoted Aß phagocytosis. Besides, LC3 upregulation and p62 downregulation were observed in IRF5 knockdown microglia. This was also validated in APP/PS1 mice with IRF5 knockdown, leading to reduced Aß levels in the brain. We conclude that IRF5 mediates Aß-induced microglial inflammatory responses. IRF5 knockdown attenuated Aß-induced inflammatory responses and promoted the phagocytosis and autophagy of Aß by microglia.

Multiple Energy Transfer Channels in Rare Earth Doped Multi-Exciton Emissive Perovskites.

Revealing the energy transfer (ET) process from excitons to rare earth ions in halide perovskites has great guiding value for designing optoelectronic materials. Here, the multiple ET channels in multi-exciton emissive Sb3+ /Nd3+ co-doped Cs2 ZrCl6 are explored to comprehend the ET processes. Förster-Dexter ET theory reveals that the sensitizer concentration rather than the overlap integral of the spectra plays the leading function in the comparison of the ET efficiency among multiple ET channels from the host self-trapped excitons (STEs) and dopant triplet STEs to Nd3+ ions. Besides, Sb3+ /Nd3+ co-doped Cs2 ZrCl6 enables varied color delivery and has great potential as anti-counterfeiting material. Under X-ray irradiation, Sb3+ /Nd3+ co-doped Cs2 ZrCl6 presents a high light yield of ≈13300 photons MeV-1 and promising X-ray imaging ability. This work provides new insight for investigating the ET efficiency among multiple ET processes and presents great potentiality of multi-exciton emissive perovskites in the fields of anti-counterfeiting and X-ray imaging.

Transition-Metal-Free Electrochemical Selenylative Cyclization of Alkynyl Phosphonates.

Unprecedented regioselective electrochemical tandem selenation/cyclization of alkynyl phosphonates with diselenide is described here. These obtained selenoether products can be chemo-selectively converted into halogen-functionalized cyclic enol phosphonates under our electrochemical conditions. These protocols provide straightforward access to valuable cyclic enol phosphonate or phosphaisocoumarins under the electrochemical and transition-metal-free conditions. The robustness of these transformations was illustrated by their compatibility with various complex natural products and bioactive molecules. The selenoether and halogen functional groups allow the further diversification of the phosphorus heterocycles thus obtained.

Discovery of Novel Mono-Carbonyl Curcumin Derivatives as Potential Anti-Hepatoma Agents.

Curcumin possesses a wide spectrum of liver cancer inhibition effects, yet it has chemical instability and poor metabolic properties as a drug candidate. To alleviate these problems, a series of new mono-carbonyl curcumin derivatives G1-G7 were designed, synthesized, and evaluated by in vitro and in vivo studies. Compound G2 was found to be the most potent derivative (IC50 = 15.39 µM) compared to curcumin (IC50 = 40.56 µM) by anti-proliferation assay. Subsequently, molecular docking, wound healing, transwell, JC-1 staining, and Western blotting experiments were performed, and it was found that compound G2 could suppress cell migration and induce cell apoptosis by inhibiting the phosphorylation of AKT and affecting the expression of apoptosis-related proteins. Moreover, the HepG2 cell xenograft model and H&E staining results confirmed that compound G2 was more effective than curcumin in inhibiting tumor growth. Hence, G2 is a promising leading compound with the potential to be developed as a chemotherapy agent for hepatocellular carcinoma.

Predicting functional consequences of SNPs on mRNA translation via machine learning.

The functional impact of single nucleotide polymorphisms (SNPs) on translation has yet to be considered when prioritizing disease-causing SNPs from genome-wide association studies (GWAS). Here we apply machine learning models to genome-wide ribosome profiling data to predict SNP function by forecasting ribosome collisions during mRNA translation. SNPs causing remarkable ribosome occupancy changes are named RibOc-SNPs (Ribosome-Occupancy-SNPs). We found that disease-related SNPs tend to cause notable changes in ribosome occupancy, suggesting translational regulation as an essential pathogenesis step. Nucleotide conversions, such as 'G → T', 'T → G' and 'C → A', are enriched in RibOc-SNPs, with the most significant impact on ribosome occupancy, while 'A → G' (or 'A→ I' RNA editing) and 'G → A' are less deterministic. Among amino acid conversions, 'Glu → stop (codon)' shows the most significant enrichment in RibOc-SNPs. Interestingly, there is selection pressure on stop codons with a lower collision likelihood. RibOc-SNPs are enriched at the 5'-coding sequence regions, implying hot spots of translation initiation regulation. Strikingly, ∼22.1% of the RibOc-SNPs lead to opposite changes in ribosome occupancy on alternative transcript isoforms, suggesting that SNPs can amplify the differences between splicing isoforms by oppositely regulating their translation efficiency.

Distinct cerebral small vessel disease impairment in early- and late-onset Alzheimer's disease.

OBJECTIVE: This study investigated cerebral small vessel disease (CSVD) damage patterns in early-onset and late-onset Alzheimer's disease (EOAD and LOAD) and their effects on cognitive function. METHODS: This study included 93 participants, 45 AD patients (14 EOAD and 31 LOAD), and 48 normal controls (13 YNC and 35 ONC) from the ADNI database. All participants had diffusion tensor imaging data; some had amyloid PET and plasma p-tau181 data. The study used peak width of skeletonized mean diffusivity (PSMD) to measure CSVD severity and compared PSMD between patients and age-matched controls. The effect of age on the relationship between PSMD and cognition was also examined. The study also repeated the analysis in amyloid-positive AD patients and amyloid-negative controls in another independent database (31 EOAD and 38 LOAD), and the merged database. RESULTS: EOAD and LOAD showed similar cognitive function and disease severity. PSMD was validated as a reliable correlate of cognitive function. In the ADNI database, PSMD was significantly higher for LOAD and showed a tendency to increase for EOAD; in the independent and merged databases, PSMD was significantly higher for both LOAD and EOAD. The impact of PSMD on cognitive function was notably greater in the younger group (YNC and EOAD) than in the older group (ONC and LOAD), as supported by the ADNI and merged databases. INTERPRETATION: EOAD has less CSVD burden than LOAD, but has a greater impact on cognition. Proactive cerebrovascular prevention strategies may have potential clinical value for younger older adults with cognitive decline.

Ar-turmerone suppresses Aspergillus flavus growth and aflatoxin accumulation: Finding a new antifungal agent based on stored maize.

Aspergillus flavus (A. flavus) is a common saprophytic pathogenic fungus that produces toxic and carcinogenic aflatoxins prone to contaminate food. Here, we optimized the synthesis method of Ar-turmerone, the main active ingredient in turmeric essential oil, improved its yield and reduced the operation requirements. Moreover, 50.0 µg/mL Ar-turmerone 100.0 % inhibited the colonies growth, spore germination, mycelium biomass and aflatoxin accumulation in 7 days. 2,018 differentially expressed genes (DEGs) such as catA, ppoC, erg7, erg6 and aflO related to the A. flavus growth and aflatoxin product were significantly downregulated including 45 DEGs were 100.0 % suppressed. Besides, Ar-turmerone greatly reduced A. flavus in maize, the optimal storage conditions for maize to avoid A. flavus contamination were determined as 0.940 aw, 400.0 µg/mL Ar-turmerone, and 16.0 °C. Satisfactory odor, luster, taste, and mildew in maize observed after three weeks of storage under the optimal conditions. Thus, Ar-turmerone can be used as a potential food antifungal agent against A. flavus growth and aflatoxin accumulation during food storage.

Computationally efficient adaptive decompression for whole slide image processing.

Whole slide image (WSI) analysis is increasingly being adopted as an important tool in modern pathology. Recent deep learning-based methods have achieved state-of-the-art performance on WSI analysis tasks such as WSI classification, segmentation, and retrieval. However, WSI analysis requires a significant amount of computation resources and computation time due to the large dimensions of WSIs. Most of the existing analysis approaches require the complete decompression of the whole image exhaustively, which limits the practical usage of these methods, especially for deep learning-based workflows. In this paper, we present compression domain processing-based computation efficient analysis workflows for WSIs classification that can be applied to state-of-the-art WSI classification models. The approaches leverage the pyramidal magnification structure of WSI files and compression domain features that are available from the raw code stream. The methods assign different decompression depths to the patches of WSIs based on the features directly retained from compressed patches or partially decompressed patches. Patches from the low-magnification level are screened by attention-based clustering, resulting in different decompression depths assigned to the high-magnification level patches at different locations. A finer-grained selection based on compression domain features from the file code stream is applied to select further a subset of the high-magnification patches that undergo a full decompression. The resulting patches are fed to the downstream attention network for final classification. Computation efficiency is achieved by reducing unnecessary access to the high zoom level and expensive full decompression. With the number of decompressed patches reduced, the time and memory costs of downstream training and inference procedures are also significantly reduced. Our approach achieves a 7.2× overall speedup, and the memory cost is reduced by 1.1 orders of magnitudes, while the resulting model accuracy is comparable to the original workflow.

Acute toxic effects of microcystin-LR on crayfish (Procambarus clarkii): Insights from antioxidant system, histopathology and intestinal flora.

To study the toxic effects of microcystin-LR (MC-LR) on crayfish, adult male Procambarus clarkii were exposed to different concentrations of MC-LR for 96 h. In the meantime, the accumulation characteristics of MC-LR and the alternations of antioxidant system, histopathology and intestinal flora of P. clarkii were investigated. The results demonstrated that the hepatopancreas, gills and intestines of P. clarkii could effectively accumulate MC-LR. Antioxidant-related genes such as Mn-sod, cat, gst, gpx, mt and hsp70 showed different expression trends in different organs to respond to MC-LR-induced oxidative stress. MC-LR led to histological changes in the hepatopancreas, gills and intestines, thus affecting their corresponding physiological functions. Additionally, the abundances of bacterial phyla including Firmicutes and Planctomycetes and genera including Dysgonomonas, Brevundimonas and Anaerorhabdus in the intestine were significantly changed after MC-LR exposure, and the disruption of intestinal flora might further cause abnormal intestinal microbial metabolism and genetics in P. clarkii. This study provides novel mechanistic insights into the toxic impacts of microcystins on aquatic crustaceans. HIGHLIGHTS: • MC-LR was significantly accumulated in the hepatopancreas, gills and intestines of P. clarkii. • MC-LR induced the differential expression of antioxidant-related genes of P. clarkii. • MC-LR caused histological alterations in the hepatopancreas, gills and intestines of P. clarkii. • MC-LR affected the intestinal microbial composition and function of P. clarkii.

EEG-based driver states discrimination by noise fraction analysis and novel clustering algorithm.

Driver states are reported as one of the principal factors in driving safety. Distinguishing the driving driver state based on the artifact-free electroencephalogram (EEG) signal is an effective means, but redundant information and noise will inevitably reduce the signal-to-noise ratio of the EEG signal. This study proposes a method to automatically remove electrooculography (EOG) artifacts by noise fraction analysis. Specifically, multi-channel EEG recordings are collected after the driver experiences a long time driving and after a certain period of rest respectively. Noise fraction analysis is then applied to remove EOG artifacts by separating the multichannel EEG into components by optimizing the signal-to-noise quotient. The representation of data characteristics of the EEG after denoising is found in the Fisher ratio space. Additionally, a novel clustering algorithm is designed to identify denoising EEG by combining cluster ensemble and probability mixture model (CEPM). The EEG mapping plot is used to illustrate the effectiveness and efficiency of noise fraction analysis on the denoising of EEG signals. Adjusted rand index (ARI) and accuracy (ACC) are used to demonstrate clustering performance and precision. The results showed that the noise artifacts in the EEG were removed and the clustering accuracy of all participants was above 90%, resulting in a high driver fatigue recognition rate.

Recent advances in microfluidics-based bioNMR analysis.

Nuclear magnetic resonance (NMR) has been used in a variety of fields due to its powerful analytical capability. To facilitate biochemical NMR (bioNMR) analysis for samples with a limited mass, a number of integrated systems have been developed by coupling microfluidics and NMR. However, there are few review papers that summarize the recent advances in the development of microfluidics-based NMR (µNMR) systems. Herein, we review the advancements in µNMR systems built on high-field commercial instruments and low-field compact platforms. Specifically, µNMR platforms with three types of typical microcoils settled in the high-field NMR instruments will be discussed, followed by summarizing compact NMR systems and their applications in biomedical point-of-care testing. Finally, a conclusion and future prospects in the field of µNMR were given.

Salivary Aß1-42 may be a quick-tested biomarker for clinical use in Alzheimer's disease: a meta-analysis.

OBJECTIVE: Alzheimer's disease (AD) is the most prevalent form of dementia among the aging population. Cumulative studies aim to find non-invasive biomarkers in the early stages of AD. Saliva can be obtained easily, and salivary biomarkers have been proven effective in detecting neurodegenerative diseases. To find effective biomarkers in saliva and to help the diagnosis of AD, we performed a meta-analysis focusing on the salivary biomarkers (ß-amyloid 1-42 (Aß1-42), total tau (t-tau), phosphorylated tau (p-tau) and acetylcholinesterase (AChE)) in AD. METHODS: We conducted a systematic online search for eligible studies reporting data on salivary biomarkers reflecting Aß1-42, t-tau, p-tau, and AChE in AD cohorts versus controls. Biomarkers' performance was assessed in a random-effects meta-analysis with the ratio of mean (RoM). RESULTS: A total of thirteen studies were included in the meta-analysis, of them seven involved salivary Aß1-42 (271 AD and 489 controls), five involved salivary t-tau (324 AD and 252 controls), four involved salivary p-tau (130 AD and 161 controls), and three involved salivary AChE (81 AD and 54 controls). AD showed significantly higher salivary Aß1-42 levels than control (ROM = 1.90 (95% CI 1.28-2.81, P = 0.001), while AD and control did not differ significantly on salivary t-tau, p-tau and AChE (ROM = 0.94, 95% CI 0.67-1.31, P = 0.72; ROM = 0.91, 95% CI 0.56-1.45, P = 0.68; ROM = 0.83, 95% CI 0.24-2.88, P = 0.77; respectively). CONCLUSION: The pooled results provide evidence that salivary Aß1-42 may serve as a sensitive biomarker for AD; nevertheless, larger AD cohorts are required to further confirm the sensitivity and specificity of salivary Aß1-42 for AD diagnosis.

Metformin Attenuates Tau Pathology in Tau-Seeded PS19 Mice.

Accumulation of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau is a histopathological hallmark of Alzheimer's disease (AD) and related tauopathies. Growing evidence demonstrated that tau pathology in AD spreads in a prion-like manner. Previous studies showed that metformin might have a positive effect on cognition. However, the underlying mechanisms are still unknown. Therefore, the present study aimed to investigate the effects of metformin on tau propagation. Brain extracts containing tau aggregates were unilaterally injected into the hippocampus and the overlying cerebral cortex of PS19 mice. Metformin was administrated through drinking water for four months, and we observed tau spreading in the brain of tau-seeded PS19 mice. Metformin inhibited the spreading of tau pathology in the ipsilateral hemisphere, attenuated tau pathology in the contralateral hemisphere, and reduced the hyperphosphorylation of tau at Ser202/Thr205, Thr231, and Ser422 sites in the soluble fraction and Ser202/Thr205, Ser262, Thr396, Thr231, and Ser422 sites in the insoluble fraction of tau-seeded PS19 mice brains. Metformin did not affect tau kinases or phosphatase 2A protein levels but reduced mTORC1 protein levels. Additionally, metformin reduced learning and memory deficits of the tau-seeded PS19 mice. These findings indicate that metformin reduced tau hyperphosphorylation, attenuated tau pathology in tau-seeded PS19 mice, and improved learning and memory deficits. These findings highlight the potential mechanisms underlying the beneficial effects of metformin on cognition, implying that metformin could be a promising drug for the prevention and early treatment of AD.

Neuropsychiatric symptoms associated multimodal brain networks in Alzheimer's disease.

Concomitant neuropsychiatric symptoms (NPS) are associated with accelerated Alzheimer's disease (AD) progression. Identifying multimodal brain imaging patterns associated with NPS may help understand pathophysiology correlates AD. Based on the AD continuum, a supervised learning strategy was used to guide four-way multimodal neuroimaging fusion (Amyloid, Tau, gray matter volume, brain function) by using NPS total score as the reference. Loadings of the identified multimodal patterns were compared across the AD continuum. Then, regression analyses were performed to investigate its predictability of longitudinal cognition performance. Furthermore, the fusion analysis was repeated in the four NPS subsyndromes. Here, an NPS-associated pathological-structural-functional covaried pattern was observed in the frontal-subcortical limbic circuit, occipital, and sensor-motor region. Loading of this multimodal pattern showed a progressive increase with the development of AD. The pattern significantly correlates with multiple cognitive domains and could also predict longitudinal cognitive decline. Notably, repeated fusion analysis using subsyndromes as references identified similar patterns with some unique variations associated with different syndromes. Conclusively, NPS was associated with a multimodal imaging pattern involving complex neuropathologies, which could effectively predict longitudinal cognitive decline. These results highlight the possible neural substrate of NPS in AD, which may provide guidance for clinical management.

Redox-neutral rhodium(III)-catalyzed divergent synthesis of tetrasubstituted 1,3-enynes and alkynylated benzofurans.

With the assistance of the acetamido directing group (DG), a rhodium-catalyzed C-H alkenylation/DG migration cascade for the synthesis of tetrasubstituted 1,3-enynes from N-phenoxyacetamides and 1,3-diynes has been achieved in this work. Alternatively, a rhodium-catalyzed [3 + 2] annulation for the synthesis of alkynylated benzofurans from the same set of substrates has also been achieved by simply changing the reaction conditions. This work highlights the tunable divergent synthesis of valuable compounds triggered by C-H activation.