Exosomal MicroRNAs modulate the cognitive function in fasudil treated APPswe/PSEN1dE9 transgenic (APP/PS1) mice model of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by cognitive decline stemming from the accumulation of beta-amyloid (Aß) plaques and the propagation of tau pathology through synapses. Exosomes, crucial mediators in neuronal development, maintenance, and intercellular communication, have gained attention in AD research. Yet, the molecular mechanisms involving exosomal miRNAs in AD remain elusive. In this study, we treated APPswe/PSEN1dE9 transgenic (APP/PS1) mice, a model for AD, with either vehicle (ADNS) or fasudil (ADF), while C57BL/6 (control) mice received vehicle (WT). Cognitive function was evaluated using the Y-maze test, and AD pathology was confirmed through immunostaining and western blot analysis of Aß plaques and phosphorylated tau. Exosomal RNAs were extracted, sequenced, and analyzed from each mouse group. Our findings revealed that fasudil treatment improved cognitive function in AD mice, as evidenced by increased spontaneous alternation in the Y-maze test and reduced Aß plaque load and phosphorylated tau protein expression in the hippocampus. Analysis of exosomal miRNAs identified three miRNAs (mmu-let-7i-5p, mmu-miR-19a-3p, mmu-miR-451a) common to both ADNS vs ADF and WT vs ADNS groups. Utilizing miRTarBase software, we predicted and analyzed target genes associated with these miRNAs. Gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of miRNA target genes indicated that mmu-miR-19a-3p and mmu-miR-451a are implicated in signal transduction, immune response, cellular communication, and nervous system pathways. Specifically, mmu-miR-19a-3p targeted genes involved in the sphingolipid signaling pathway, such as Pten and Tnf, while mmu-miR-451a targeted Nsmaf, Gnai3, and Akt3. Moreover, mmu-miR-451a targeted Myc in signaling pathways regulating the pluripotency of stem cells. In conclusion, fasudil treatment enhanced cognitive function by modulating exosomal MicroRNAs, particularly mmu-miR-451a and mmu-miR-19a-3p. These miRNAs hold promise as potential biomarkers and therapeutic targets for novel AD treatments.

Catalytic asymmetric construction of bridged bicyclo[m.3.1] rings using an intramolecular Diels-Alder reaction.

Herein, we presented an enantioselective intramolecular Diels-Alder (IMDA) reaction with vinyl branched vinylidene ortho-quinone methide (VQM). The control of site selectivity in the IMDA reaction led to both chiral bridged bicyclo[4.3.1] and [5.3.1] architectures with high isolated yields (up to 85%) and excellent enantioselectivities (up to 97% ee).

Catalytic asymmetric functionalization and dearomatization of thiophenes.

The asymmetric synthesis of thiophene-derived compounds, including catalytic asymmetric dearomatization of thiophene and atroposelective synthesis of benzothiophene derivatives, has rarely been reported. In this work, the asymmetric transformation of the thiophene motif is investigated. Through the rational design of substrates with a thiophene structure, by using the vinylidene ortho-quinone methide (VQM) intermediate as a versatile tool, axially chiral naphthyl-benzothiophene derivatives and thiophene-dearomatized chiral spiranes were obtained in high yields with excellent enantioselectivities.

Porous VN nanosheet arrays on MXene carbon fibers for flexible supercapacitors.

VN usually has poor rate performance and cycle stability. In this work, porous VN nanosheet arrays were prepared on carbon nanofibers embedded with Ti3C2Tx nanosheets by electrospinning and chemical vapor deposition. The 3D network accelerates the transfer of electrons and electrolyte ions, prevents the aggregation of VN and the self-stacking of MXene, and enhances cycle stability. The solid-state flexible device comprising Co3O4, MXCF@VN, and KOH/PVA exhibits exceptional energy densities of 83.95 W h kg-1 and robust cycling stability (82.8% retention after 20 000 cycles).

[Clinical Features and Prognosis of Patients with CD5+ Diffuse Large B-Cell Lymphoma].

OBJECTIVE: To analyze the clinical characteristics and prognosis of patients with CD5+ diffuse large B-cell lymphoma (DLBCL). METHODS: The clinical data of 161 newly treated DLBCL patients in Gansu Provincial Hospital from January 2013 to January 2020 were retrospectively analyzed. According to CD5 expression, the patients were divided into CD5+ group and CD5- group. The clinical characteristics and prognosis of the two groups were statistically analyzed. RESULTS: The median age of patients in CD5+ group was 62 years, which was higher than 56 years in CD5- group (P =0.048). The proportion of women in CD5+ group was 62.96%, which was significantly higher than 41.79% in CD5- group (P =0.043). The proportion of patients with IPI score > 2 in CD5+ group was 62.96%, which was higher than 40.30% in CD5- group (P =0.031). Survival analysis showed that the median overall survival and progression-free survival time of patients in CD5+ group were 27(3-77) and 31(3-76) months, respectively, which were both shorter than 30(5-84) and 32.5(4-83) months in CD5- group (P =0.047, P =0.026). Univariate analysis showed that advanced age, positive CD5 expression, triple or double hit at initial diagnosis, high IPI score and no use of rituximab during chemotherapy were risk factors for the prognosis of DLBCL patients. Further Cox multivariate regression analysis showed that these factors were also independent risk factors except for advanced age. CONCLUSION: CD5+ DLBCL patients have a worse prognosis than CD5- DLBCL patients. Such patients are more common in females, with advanced age and high IPI score, which is a special subtype of DLBCL.

Eu3+-Doped Anionic Zinc-Based Organic Framework Ratio Fluorescence Sensing Platform: Supersensitive Visual Identification of Prescription Drugs.

Advanced techniques for both environmental and biological prescription drug monitoring are of ongoing interest. In this work, a fluorescent sensor based on an Eu3+-doped anionic zinc-based metal-organic framework (Eu3+@Zn-MOF) was constructed for rapid visual analysis of the prescription drug molecule demecycline (DEM), achieving both high sensitivity and selectivity. The ligand 2-amino-[1,1'-biphenyl]-4,4'-dicarboxylic acid (bpdc-NH2) not only provides stable cyan fluorescence (467 nm) for the framework through intramolecular charge transfer of bpdc-NH2 infinitesimal disturbanced by Zn2+ but also chelates Eu3+, resulting in red (617 nm) fluorescence. Through the synergy of photoinduced electron transfer and the antenna effect, a bidirectional response to DEM is achieved, enabling concentration quantification. The Eu3+@Zn-MOF platform exhibits a wide linear range (0.25-2.5 µM) to DEM and a detection limit (LOD) of 10.9 nM. Further, we integrated the DEM sensing platform into a paper-based system and utilized a smartphone for the visual detection of DEM in water samples and milk products, demonstrating the potential for large-scale, low-cost utilization of the technology.

Ti3C2Tx MXene-embedded MnO2-based hydrophilic electrospun carbon nanofibers as a freestanding electrode for supercapacitors.

Herein, MnO2 nanoflowers are electrodeposited on a self-supported and electroconductive electrode in which 2D Ti3C2Tx nanosheets are encased in carbon nanofibers (MnO2@Ti3C2Tx/CNFs). This improves the conductivity and hydrophilicity of the MnO2 composite electrode. The asymmetric supercapacitor shows a high energy density of 46.4 W h kg-1 and a power density of 4 kW kg-1.

Sensitive quantification of mercury ions in real water systems based on an aggregation-collision electrochemical detection.

Nanoparticle impact electrochemistry (NIE) is an emerging electroanalytical technique that has been utilized to the sensitive detection of a wide range of biological species. So far, the NIE based trace ion detection is largely unexplored due to the lack of effective signal amplification strategies. We herein develop an NIE-based electrochemical sensing platform that utilizes T-Hg2+-T coordination induced AgNP aggregation to detect Hg2+ in aqueous solution. The proposed aggregation-collision strategy enables highly sensitive and selective detection. A dual-mode analysis based on the change in impact frequency and oxidative charge of the anodic oxidation of the AgNPs in NIE allows for more accurate self-validated quantification. Furthermore, the current NIE-based sensor demonstrates reliable analysis of Hg2+ of real water samples, showing great potential for practical environmental monitoring and point-of-care testing (POCT) applications.

Mitogenome analysis reveals predominantly ancient Yellow River origin of population inhabiting Datong agro-pastoral ecotone along Great Wall.

The Datong Basin was an important arena for population movement and admixture between the Yellow River Valley and Eastern Steppe. In historical materials, the region was often the setting for a tug-of-war between Han farmers and non-Han nomads. The genetic makeup and population history of this Datong population has, however, remained uncertain. In this study, we analysed 289 mitogenomes from Datong individuals. Our primary findings were: (1) population summary statistics analysis revealed a high level of genetic diversity and strong signals of population expansion in the Datong population; (2) inter-population comparisons (PCA and Fst heatmap) exhibited a close clustering between the Datong population and Northern Han, especially northern frontier groups, such as the Inner Mongolia Han, Heilongjiang Han, Liaoning Han and Tianjin Han; (3) phylogeographic analysis of complete mitogenomes revealed the presence of different components in the maternal gene pools of Datong population-the northern East Asian component was dominant (66.44%), whereas the southern East Asians were the second largest component with 31.49%. We also observed a much reduced west Eurasian (2.07%) component; (4) direct comparisons with ancient groups showed closer relationship between Datong and Yellow River farmers than Eastern Steppe nomads. Despite, therefore, centuries of Eastern Steppe nomadic control over the Datong area, Yellow River farmers had a much more significant impact on the Datong population.

Folate-mediated one-carbon metabolism as a potential antifungal target for the sustainable cultivation of microalga Haematococcus pluvialis.

BACKGROUND: Microalgae are widely considered as multifunctional cell factories that are able to transform the photo-synthetically fixed CO2 to numerous high-value compounds, including lipids, carbohydrates, proteins and pigments. However, contamination of the algal mass culture with fungal parasites continues to threaten the production of algal biomass, which dramatically highlights the importance of developing effective measures to control the fungal infection. One viable solution is to identify potential metabolic pathways that are essential for fungal pathogenicity but are not obligate for algal growth, and to use inhibitors targeting such pathways to restrain the infection. However, such targets remain largely unknown, making it challenging to develop effective measures to mitigate the infection in algal mass culture. RESULTS: In the present study, we conducted RNA-Seq analysis for the fungus Paraphysoderma sedebokerense, which can infect the astaxanthin-producing microalga Haematococcus pluvialis. It was found that many differentially expressed genes (DEGs) related to folate-mediated one-carbon metabolism (FOCM) were enriched in P. sedebokerense, which was assumed to produce metabolites required for the fungal parasitism. To verify this hypothesis, antifolate that hampered FOCM was applied to the culture systems. Results showed that when 20 ppm of the antifolate co-trimoxazole were added, the infection ratio decreased to ~ 10% after 9 days inoculation (for the control, the infection ratio was 100% after 5 days inoculation). Moreover, application of co-trimoxazole to H. pluvialis mono-culture showed no obvious differences in the biomass and pigment accumulation compared with the control, suggesting that this is a potentially algae-safe, fungi-targeted treatment. CONCLUSIONS: This study demonstrated that applying antifolate to H. pluvialis culturing systems can abolish the infection of the fungus P. sedebokerense and the treatment shows no obvious disturbance to the algal culture, suggesting FOCM is a potential target for antifungal drug design in the microalgal mass culture industry.

Regiodivergent catalytic asymmetric dearomative cycloaddition of bicyclic heteroaromatics.

The catalytic dearomative cycloaddition of bicyclic heteroaromatics including benzofurans and indoles provides rapid access to functionalized heterocyclic molecules. Because of the inherent stereoelectronic differences, the furan or pyrrole nucleus is more prone to dearomative cycloaddition than the benzene ring. Here, we realized a geometry-based differentiation approach for achieving C6-C7 and C7-C7a regioselectivity. The rotationally restricted σ bond at C7 position respectively placed the C6-C7 and C7-C7a sites of benzofurans or indoles in an optimal spatial orientation toward the axially chiral heterodiene, thus affording two enantioenriched polycyclic compounds from a single racemic heterobiaryl atropisomers. Calculation results of density functional theory interpreted the mechanism of this parallel kinetic resolution. The bioactivity of the dearomatized products was evaluated in cancer cell lines with certain compounds exhibiting interesting biological activities.

A versatile and tunable bio-patterning platform for the construction of various cell array biochips.

In this work, we report a versatile and tunable platform for the construction of various cell array biochips using a simple soft lithographic approach to pattern polydopamine (PDA) arrays via microcontact printing (µCP). Instead of direct polymerization of PDA on the polydimethylsiloxane (PDMS) tips, dopamine monomers were first printed on the substrate followed by a self-oxidative polymerization step facilitated by ammonia vapor to grow PDA in situ, which greatly reduced the reaction time and prevented the PDMS tips from damaging. The improved robustness and utility of the PDMS tips allows the formation of tunable PDA array chips with controllable PDA feature size and shape. As a result, single cell, multi-cells and cell line arrays can be constructed. The obtained cell array chips showed high single cell capture efficiency, providing a standardized single cell array analysis platform. Meanwhile, the adhered cells can maintain excellent viability and proliferation ability on the PDA chips. Moreover, a cytotoxicity sensor with single cell resolution was enabled on the single cell array chip. This work provides a promising cell array biochip platform for high-throughput cellular analysis and cell screening.

Homogeneous Electrochemical Immunoassay Using an Aggregation-Collision Strategy for Alpha-Fetoprotein Detection.

Homogeneous immunoassays represent an attractive alternative to traditional heterogeneous assays due to their simplicity and high efficiency. Homogeneous electrochemical assays, however, are not commonly accessed due to the requirement of electrode immobilization of the recognition elements. Herein, we demonstrate a new homogeneous electrochemical immunoassay based on the aggregation-collision strategy for the quantification of tumor protein biomarker alpha-fetoprotein (AFP). The detection principle relies on the aggregation of AgNPs induced by the molecular biorecognition between AFP and AgNPs-anti-AFP probes, which leads to an increased AgNP size and decreased AgNP concentration, allowing an accurate self-validated dual-mode immunoassay by performing nanoimpact electrochemistry (NIE) of the oxidation of AgNPs. The intrinsic one-by-one analytical capability of NIE as well as the participation of all of the atoms of the AgNPs in signal transduction greatly elevates the detection sensitivity. Accordingly, the current sensor enables a limit of detection (LOD) of 5 pg/mL for AFP analysis with high specificity and efficiency. More importantly, reliable detection of AFP in diluted human sera of hepatocellular carcinoma (HCC) patients is successfully achieved, indicating that the NIE-based homogeneous immunoassay shows great potential in HCC liquid biopsy.

Organocatalytic asymmetric deoxygenation of sulfones to access chiral sulfinyl compounds.

Over the past decades, many efficient methodologies have been developed that allow for the enantioselective synthesis of chiral sulfinyl compounds. However, the enantioselective deoxygenation of hexavalent sulfones for the formation of chiral sulfinyl compounds still remains one of the major challenges in the fields of asymmetric synthesis and organosulfur chemistry. Here we have demonstrated that a synergistic combination of organocatalysis and the incorporation of a cyano group into the sulfone generates a chiral sulfinic species as an active intermediate. A wide range of chiral sulfinates with high enantioselectivities could then be acquired using alcohols as nucleophiles, and the subsequent transformations allowed the collective preparation of a variety of chiral sulfinyl compounds. Density functional theory calculations revealed that the catalytic cycle involves a quinuclidine-assisted stepwise 1,2-cyano group transfer, base-assisted intermolecular substitution with alcohol and regeneration of the active catalyst. The enantioselectivity was determined by the cyano migration step.

Detection of small sequence variations within the goat GHR gene and its effects on growth traits.

Growth hormone receptor (GHR) gene is considered to be an important candidate gene in growth traits. Therefore, the purpose of this study was to detect whether there were potential indel variations in the GHR gene that were related to the growth traits of the Shaanbei white cashmere goats (SBWC). In this study, genomic DNA from 931 healthy SBWC individuals were used to verify the relationship between the indel of the GHR gene and growth traits. Two indel variants, P49-bp indel in intron 1 and P1410-bp indel in 3'-UTR, were confirmed. Association analyses demonstrated that these two indel polymorphism loci were associated with the chest circumference and chest width of SBWC. Additionally, for the P49-bp and P1410-bp indel loci, the ID and II genotypes were dominant genotypes, respectively. Moreover, the genotypic distributions of these two indel loci in SBWC were significantly different from those in three other Chinese indigenous goat breeds (HNBG, GZDG and IMWC) (p < 0.05). Taken together, two indel loci (P49-bp indel and P1410-bp indel) both significantly affected the growth traits of goats. This illustrated that these two indel loci might be the potential DNA marker for use in improving the selection and breeding of goats.

Clinically Applicable Homogeneous Assay for Serological Diagnosis of Alpha-Fetoprotein by Impact Electrochemistry.

Tumor protein quantification with high specificity, sensitivity, and efficiency is of great significance to enable early diagnosis and effective treatment. The existing methods for protein analysis usually suffer from high cost, time-consuming operation, and insufficient sensitivity, making them not clinically friendly. In this work, a label-free homogeneous sensor based on the nano-impact electroanalytic (NIE) technique was proposed for the detection of tumor protein marker alpha-fetoprotein (AFP). The detection principle is based on the recovery of current of single PtNP catalyzed hydrazine oxidation due to the release of the pre-adsorbed passivating aptamers on PtNPs from the competition of the stronger binding between the specific interaction of the AFP aptamer and AFP. The intrinsic one-by-one analytical ability of NIE allows highly sensitive detection, which can be further improved by reducing the reaction/incubation volume. Meanwhile, the current sensor avoids a laborious labeling procedure as well as the separation and washing steps due to the in situ characteristic of NIE. Accordingly, the current sensor enables efficient, highly sensitive, and specific AFP analysis. More importantly, the reliable detection of AFP in diluted real sera from hepatocellular carcinoma (HCC) patients is successfully achieved, indicating that the impact electrochemistry-based sensing platform has great potential to be applied in point-of-care devices for HCC liquid biopsy.

Enantioselective Synthesis of Atropisomers via Vinylidene ortho-Quinone Methides (VQMs).

Atropisomers, arising from conformational restriction, are inherently chiral due to the intersecting dissymmetric planes. Since there are numerous applications of enantiopure atropisomers in catalyst design, drug discovery, and material science, the asymmetric preparation of these highly prized molecules has become a flourishing field in synthetic chemistry. A number of catalysts, synthetic procedures, and novel concepts have been developed for the manufacture of the atropisomeric molecules. However, due to the intrinsic properties of different types of atropisomers featuring biaryl, hetero-biaryl, or non-biaryl architectures, only very few methods pass the rigorous inspection and are considered generally applicable. The development of a broadly applicable synthetic strategy for various atropisomers is a challenge. In this Account, we summarize our recent studies on the enantioselective synthesis of atropisomers using the vinylidene ortho-quinone methides (VQMs) as pluripotent intermediates.The most appealing features of VQMs are the disturbed aromaticity and axial chirality of the allene fragment. At the outset, the applications of VQMs in organic synthesis have been neglected due to their principal liabilities: ephemeral nature, extraordinary reactivity, and multireaction sites. The domestication of this transient intermediate was demonstrated by in situ catalytic asymmetric generation of VQMs, and the reactivity and selectivity were fully explored by judiciously modifying precursors and tuning catalytic systems. A variety of axially chiral heterocycles were achieved through five-, six-, seven- and nine-membered ring formation of VQM intermediates with different kinds of branched nucleophilic functional groups. The axially chiral C-N axis could be constructed from VQM intermediates via N-annulation or desymmetrization of preformed C-N scaffolds. We take advantage of the high electrophilicity of VQMs toward a series of sulfur and carbon based nucleophiles leading to atropisomeric vinyl arenes. Furthermore, chiral helical compounds were realized by cycloaddition or consecutive annulation of VQM intermediates. These achievements demonstrated that the VQMs could work as a nuclear parent for the collective synthesis of distinct and complex optically active atropisomers. Recently, we have realized the isolation and structural characterization of the elusive VQMs, which were questioned as putative intermediates for decades. The successful isolation of VQMs provided direct evidence for their existence and an unprecedented opportunity to directly investigate their reactivity. The good thermal stability and reserved reactivity of the isolated VQMs demonstrated their great potential as synthetic reagents and expanded the border of VQM chemistry.

Iron oxide nanoparticles for biomedical applications: an updated patent review (2015-2021).

INTRODUCTION: Iron oxide nanoparticles (IONPs) hold the edges of great magnetic properties and fine nanoparticle characteristics, making them an attractive therapeutic agent. In the past seven years, more in-depth investigations were devoted to the intrinsic structure, magnetic properties, and biological effects of IONPs, expanding the range of their therapeutic application scenes. AREAS COVERED: This review focuses on the development of IONPs for biomedical applications from the angle of the patent literature reported during the period 2015-2021. EXPERT OPINION: While the magnetic properties of IONPs have been extensively explored, the precise control of IONP behavior through external magnetic fields remains a challenge. Further digging into the biological effects of IONPs will facilitate the development of IONP-based immune therapies. Long-term reliable safety evaluations are of necessity and significance to promote the process of clinical translation.

A facile synthesis of CuSe nanosheets for high-performance sodium-ion hybrid capacitors.

Due to the low price and abundant reserves of sodium resources, sodium-ion batteries have become the main candidate for the next generation of energy storage equipment, particularly for large-scale grid storage and low-speed electric vehicles. Transition metal selenides have attracted considerable attention because of their high reversible capacity, superior electrical conductivity and versatile structures. In this study, two-dimensional CuSe nanosheets are synthesized via a simple hydrothermal reaction. When acting as an electrode material for sodium-ion batteries, the CuSe electrode exhibits an initial coulombic efficiency of 96.7% at a current density of 0.1 A g-1 and a specific capacity of 330 mA h g-1 after 100 operation cycles, as well as retains a specific capacity of 211 mA h g-1 even at a high current density of 10 A g-1. Moreover, the anode delivers a specific capacity of 236 mA h g-1 after 3300 cycles at 5 A g-1 with a capacity retention of 91.2%. In sodium-ion hybrid capacitors (SHICs) with the two-dimensional CuSe nanosheets and Ti3C2T x MXene as the negative and positive materials, respectively, the nanosheets without any pre-sodiation present a lifespan of up to 2000 cycles at 2 A g-1 and a capacity retention of about 77.7%.

Organocatalytic Asymmetric Construction of Tetrasubstituted Carbon Stereocenters Bearing Three Heteroatoms via Intramolecular Cyclization of Vinylidene ortho-Quinone Methide with Imidates.

We report herein an organocatalytic asymmetric protocol for the construction of tetrasubstituted carbon stereocenters bearing three heteroatoms. The reaction proceeded via the enantioselective intramolecular cyclization reaction of vinylidene ortho-quinone methide (VQM) with imidates to form pentacyclic heterocycles. The formed tetrasubstituted carbon center was stable under a high temperature and the conditions for further transformations.