Identification, characterization and application of M16AT, a new organic solvent-tolerant (R)-enantio-selective type IV amine transaminase from Mycobacterium sp. ACS1612.

Biocatalysis has emerged as a powerful alternative to traditional chemical methods, especially for asymmetric synthesis. As biocatalysts usually exhibit excellent chemical, regio- and enantioselectivity, they facilitate and simplify many chemical processes for the production of a broad range of products. Here, a new biocatalyst called, R-selective amine transaminases (R-ATAs), was obtained from Mycobacterium sp. ACS1612 (M16AT) using in-silico prediction combined with a genome and protein database. A two-step simple purification process could yield a high concentration of pure enzyme, suggesting that industrial application would be inexpensive. Additionally, the newly identified and characterized R-ATAs displayed a broad substrate spectrum and strong tolerance to organic solvents. Moreover, the synthetic applicability of M16AT has been demonstrated by the asymmetric synthesis of (R)-fendiline from of (R)-1-phenylethan-1-amine.

Composition analysis of Compound Shenhua Tablet, a seven-herb Chinese medicine for IgA nephropathy: evaluation of analyte-capacity of the assays.

Compound Shenhua Tablet, a medicine comprising seven herbs, is employed in treating IgA nephropathy. This study aimed to meticulously analyze its chemical composition. Based on a list of candidate compounds, identified through extensive literature review pertinent to the tablet's herbal components, the composition analysis entailed the systematic identification, characterization, and quantification of the constituents. The analyte-capacity of LC/ESI-MS-based and GC/EI-MS-based assays was evaluated. The identified and characterized constituents were quantified to determine their content levels and were ranked based on the constituents' daily doses. A total of 283 constituents, classified into 12 distinct categories, were identified and characterized in the Compound Shenhua Tablet. These constituents exhibited content levels of 1-10 982 µg·g-1, with daily doses of 0.01-395 µmol·d-1. The predominant constituents, with daily doses of ≥ 10 µmol·d-1, include nine organic acids (citric acid, quinic acid, chlorogenic acid, cryptochlorogenic acid, gallic acid, neochlorogenic acid, isochlorogenic acid C, isochlorogenic acid B, and linoleic acid), five iridoids (specnuezhenide, nuezhenoside G13, nuezhenidic acid, secoxyloganin, and secologanoside), two monoterpene glycosides (paeoniflorin and albiflorin), a sesquiterpenoid (curzerenone), a triterpenoid (oleanolic acid), and a phenylethanoid (salidroside). Additionally, there were 83, 126, and 55 constituents detected in the medicine with daily doses of 1-10, 0.1-1, and 0.01-0.1 µmol·d-1, respectively. The combination of the LC/ESI-MS-based and GC/EI-MS-based assays demonstrated a complementary relationship in their analyte-capacity for detecting the constituents present in the medicine. This comprehensive composition analysis establishes a solid foundation for further pharmacological research on Compound Shenhua Tablet and facilitates the quality evaluation of this complex herbal medicine.

Construction of universal equations for knot attributes of three coniferous species.

We constructed base model, dummy variable model, and mixture model with three variables including knot diameter, loose knot length, and sound knot length with three typical coniferous species, Pinus koraiensis, Larix olgensis, and Pinus sylvestris var. mongolica, from the Linkou Forestry Bureau and Mengjiagang forest farm in Heilongjiang Province in 2020. We analyzed the differences in knot properties among different tree species and simplified the modeling work. Firstly, we collected relevant knot property data through the sectioning method based on relevant literature, transformation of the model form and substitution of related variables to conduct a base model. We transformed the species into dummy variables as qualitative factors, and introduced the dummy variable model of the relevant attributes into the base model. We introduced the random effects of sample trees and sample plots when constructing the mixture model. By comparing evaluation indicators, such as Akaike Information Criterion (AIC) and Bayesian Information Criterion (BIC), the mixture model with the best fitting effect was selected. We selected the optimal universal equation by comparing the fitting accuracy of the base model, dummy variable model and mixture model. The fitting accuracy of the dummy variable model and mixture model was higher than that of the basic model. The evaluation indicators (AIC and BIC) showed that the mixture model had a better fitting effect on knot properties than the dummy variable model. In the model comparison results, R2 of mixture models for sound knot length, the loose knot length, and knot diameter increased by 13.2%, 84.8% and 40.3%, respectively. The predictive accuracy of the three base models for different tree species' knot attributes was above 90%, and both the prediction accuracy of the dummy variable model and mixture model were above 94%, indicating that the constructed models could well predict knot-related properties. From the perspective of tree species, the sound knot length, knot diameter, and loose knot length was in order of P. sylvestris var. mongolica > P. koraiensis > L. olgensis. Fitted results of the dummy variable model and the mixture model were superior to the basic model, with higher accuracy.

Knockdown of lncRNA MALAT1 induces pyroptosis by regulating the miR­124/SIRT1 axis in cervical cancer cells.

The aim of the present study was to elucidate the role and downstream mechanism of long non­coding RNA (lncRNA) metastasis­associated lung adenocarcinoma transcript 1 (MALAT1) in the process of cervical cancer cell pyroptosis. The effect of inhibiting lncRNA MALAT1 on cervical cancer cells was determined using primary cells isolated from patients and U14 cervical tumor­bearing nude mice. The level of lncRNA MALAT1 expression and cell viability were determined for relationship analysis. Pyroptosis was then investigated in HeLa cells with lncRNA MALAT1 knockdown or overexpression with or without lipopolysaccharide (LPS) treatment. Bioinformatics tools were used to identify downstream factors of lncRNA MALAT1, which were subsequently verified by gain­ or loss­of­function analyses in the process of cervical cancer cell pyroptosis. It was observed that the level of lncRNA MALAT1 was markedly higher in cervical carcinoma cells compared with expression in paracarcinoma cells, and knockdown of lncRNA MALAT1 induced cervical cancer cell death through pyroptosis. By contrast, overexpression of lncRNA MALAT1 blocked LPS­induced pyroptosis. These results, combined with bioinformatics statistical tools, demonstrated that the microRNA (miR)­124/sirtuin 1 (SIRT1) axis may affect the progression of cervical cancer at least partly by mediating the effect of lncRNA MALAT1 on the pyroptosis of cervical cancer cells. In conclusion, the lncRNA MALAT1/miR­124/SIRT1 regulatory axis in cervical cancer cells may mediate pyroptosis and may provide potential targets against the progression of cervical cancer.

Paeoniflorin alleviates AngII-induced cardiac hypertrophy in H9c2 cells by regulating oxidative stress and Nrf2 signaling pathway.

Cardiac hypertrophy is frequently associated with ventricular dysfunction and heart failure. Paeoniflorin, has been widely used to treat cardiovascular dysfunction-related diseases. However, the underlying mechanism has been unclear. Here, we investigated the potential inhibitory effects and mechanism of paeoniflorin on oxidative stress of cardiac hypertrophy induced by angiotensin II (AngII) in vitro. Using MTS assay, qRT-PCR, WGA staining assay, and western blot, different dosages (50-400 µM) of paeoniflorin were utilized to examine the antihypertrophy effects on H9c2 cells. Western blot examination revealed the presence of apoptosis-related proteins Bax, Bcl2, and Cytc, antioxidative stress-related proteins Nrf2, HO-1, SOD, and CAT, and mitophagy-related proteins PINK1 and Parkin. qRT-PCR was used to detect the mRNA expression of Bax, Bcl2, Nrf2, and HO-1. TUNEL, caspase3/9 enzyme viability, and MDA, T-AOC, and superoxide levels were all evaluated using commercial kits.The fluorescent probes DCFH-DA and JC-1 were employed to measure cellular ROS and MMP levels. Nrf2 siRNA was utilized to investigate Nrf2's role in paeoniflorin-treated cardiac hypertrophy. Paeoniflorin dramatically reduced cell section area (CSA) and hypertrophic marker (ANP, BNP) expression while inhibiting oxidative stress by modulating ROS and MDA, CAT, SOD, and T-AOC levels. Furthermore, in AngII-induced cardiomyocyte hypertrophy, paeoniflorin restores H9c2 apoptosis by restoring Bax, Bcl-2 Cyt-C, Caspase 3, and Caspase 9 levels. Paeoniflorin also restored Nrf2/HO-1 and PINK1/Parkin expression, and its anti-AngII activities were mediated by Nrf2, which was regulated by Nrf2 knockdown. In conclusion, Our data confirm that paeoniflorin alleviates cardiac hypertrophy through modulating oxidative stress and Nrf2 signaling pathway in vitro.

Findings of a videofluoroscopic swallowing study in patients with dysphagia.

Objective: Swallowing examination is crucial in patients with dysphagia. We aimed to compare qualitative and quantitative videofluoroscopic swallowing study (VFSS) results to provide reference for standardizing quantitative parameters. Materials and methods: In total, 117 patients with dysphagia were included, 38 with Parkinson's disease and 39 and 40 in convalescence following cerebral hemorrhage and infarction. VFSS was both qualitatively and quantitatively analyzed. Results: A significant difference of Oral transit time was found between the oral motor function grades (p < 0.001), also was swallowing reaction times found between swallowing reaction duration grades (p < 0.001), and soft palate lift duration between the soft palate lift grades (p < 0.001). Superior hyoid bone movement (p < 0.001), anterior hyoid bone movement (p < 0.001), hyoid pause time (p < 0.001), and hyoid movement duration (p = 0.032) had significant differences between the hyoid laryngeal complex movement grades, as did the pharyngeal cavity transit time among the cricopharyngeal muscle opening duration grades (p < 0.001). The laryngeal vestibule closure duration differed among the glottic closure grades (p < 0.001). No statistically significant difference in upper esophageal sphincter opening diameter (p = 0.682) or duration (p = 0.682) among the cyclopharyngeal muscle opening duration grades. The pharyngeal area at rest did not significantly differ among the different vallecular residue (p = 0.202) and pyriform sinus residue (p = 0.116) grades. Conclusion: Several quantitative parameters can reflect the swallowing assessment process well. Further optimization of quantitative parameters is recommended.

Cytoreductive surgery offers prognostic benefits in metastatic gastrointestinal stromal tumors with generalized progression following imatinib therapy: a single institute retrospective study.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Distant metastasis has been detected in approximately 50% of GIST patients at the first diagnosis. The surgical strategy for metastatic GIST with generalized progression (GP) after imatinib therapy remains unclear. METHODS: We recruited 15 patients with imatinib-resistant metastatic GIST. They received cytoreductive surgery (CRS) for tumor rupture, intestinal obstruction and gastrointestinal bleeding. We collected clinical, pathological and prognostic data for analyses. RESULTS: OS and PFS after R0/1 CRS were 56.88 ± 3.47 and 26.7 ± 4.12 months, respectively, when compared with 26 ± 5.35 and 5 ± 2.78 months after R2 CRS (P = 0.002 and P < 0.001, respectively). The OS of patients from the initiation of imatinib in the R0/1 group was 133.90 ± 15.40 months when compared with 59.80 ± 10.98 months in the R2 CRS group. There were two significant grade III complications after 15 operations (13.3%). No patient underwent reoperation. In addition, no perioperative death occurred. CONCLUSIONS: R0/1 CRS is highly probable to provide prognostic benefits for patients with metastatic GIST who experience GP following imatinib treatment. An aggressive surgical strategy for achieving R0/1 CRS can be deemed safe. If applicable, R0/1 CRS should be carefully considered in imatinib-treated patients with GP metastatic GIST.

Mettl3-m6A-Creb1 forms an intrinsic regulatory axis in maintaining iNKT cell pool and functional differentiation.

N6-methyladenosine (m6A) methyltransferase Mettl3 is involved in conventional T cell immunity; however, its role in innate immune cells remains largely unknown. Here, we show that Mettl3 intrinsically regulates invariant natural killer T (iNKT) cell development and function in an m6A-dependent manner. Conditional ablation of Mettl3 in CD4+CD8+ double-positive (DP) thymocytes impairs iNKT cell proliferation, differentiation, and cytokine secretion, which synergistically causes defects in B16F10 melanoma resistance. Transcriptomic and epi-transcriptomic analyses reveal that Mettl3 deficiency disturbs the expression of iNKT cell-related genes with altered m6A modification. Strikingly, Mettl3 modulates the stability of the Creb1 transcript, which in turn controls the protein and phosphorylation levels of Creb1. Furthermore, conditional targeting of Creb1 in DP thymocytes results in similar phenotypes of iNKT cells lacking Mettl3. Importantly, ectopic expression of Creb1 largely rectifies such developmental defects in Mettl3-deficient iNKT cells. These findings reveal that the Mettl3-m6A-Creb1 axis plays critical roles in regulating iNKT cells at the post-transcriptional layer.

Efficacy and safety of anlotinib plus camrelizumab in treating retroperitoneal soft tissue sarcomas: a single-center retrospective cohort study.

Background: Conventional chemotherapy has limited therapeutic effects in retroperitoneal soft tissue sarcomas (RSTs), while anlotinib emerged as a novel multi-target tyrosine kinase inhibitor (TKI) for sarcomas. TKIs in combination with immunotherapy have demonstrated clinical activity in a variety of solid tumors. This study retrospectively analyzed the efficacy and safety of anlotinib plus camrelizumab for the treatment of RSTs. Methods: Patients with RSTs who received anlotinib plus camrelizumab at Peking University Cancer Hospital Sarcoma Center were enrolled. Response assessment was conducted every 3 cycles of treatment according to response evaluation criteria in solid tumors version 1.1 (RECIST v1.1). Treatment-related adverse events (TRAEs) were evaluated by Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Patients who had at least 1 response evaluation were analyzed. Results: In all, 57 RSTs cases including 35 males and 22 females were analyzed, with a median age of 55 years. The pathological subtypes included 38 cases of L-sarcoma (liposarcoma and leiomyosarcoma), and 19 cases of non-L-sarcoma. Two patients (3.5%) had complete response (CR) and 13 patients (22.8%) had partial response (PR), with an objective response rate (ORR) of 26.3%. There were 31 (54.4%) and 11 (19.3%) patients with stable and progressive disease, respectively, with a disease control rate of 80.7%. Patients with non-L-sarcoma had a significantly better response rate than those with L-sarcoma (ORR: 52.6% vs. 13.2%; P=0.0031). After a median follow-up of 15.8 months, the median progression-free survival (PFS) was 9.1 months, with 3- and 6-month PFS rates of 83.6% and 60.8%, respectively. Patients with non-L-sarcoma had a significantly longer median PFS than did those with L-sarcoma (median PFS: 11.1 vs. 6.3 months; P=0.0256). TRAEs occurred in 28 (49.1%) patients, and 13 (22.8%) patients had grade 3-4 TRAEs. Hypertension (24.6%), hypothyroidism (19.3%), and palmar-plantar erythrodysesthesia syndrome (12.3%) were the most common TRAEs. Conclusions: The combination of anlotinib and camrelizumab demonstrated possible therapeutic efficacy and safety in the treatment of RSTs, especially for non-L-sarcomas.

Model Predictive Control of a Semi-Active Vehicle-Mounted Vibration Isolation Platform.

When conventional delivery vehicles are driven over complex terrain, large vibrations can seriously affect vehicle-loaded equipment and cargo. Semi-active vehicle-mounted vibration isolation control based on road preview can improve the stability of loaded cargo and instruments by enabling them to have lower vertical acceleration. A combined dynamic model including a vehicle and platform is developed first. In order to obtain a non-linear relationship between damping force and input current, a continuous damping control damper model is developed, and the corresponding external characteristic tests are carried out. Because some conventional control algorithms cannot handle complex constraints and preview information, a model predictive control algorithm based on forward road preview and input constraints is designed. Finally, simulations and real tests of the whole vehicle vibration environment are carried out. The results show that the proposed model predictive control based on road preview can effectively improve vibration isolation performance of the vehicle-mounted platform.

Multi-compound and drug-combination pharmacokinetic research on Chinese herbal medicines.

Traditional medicine has provided a basis for health care and disease treatment to Chinese people for millennia, and herbal medicines are regulated as drug products in China. Chinese herbal medicines have two features. They normally possess very complex chemical composition. This makes the identification of the constituents that are together responsible for the therapeutic action of an herbal medicine challenging, because how to select compounds from an herbal medicine for pharmacodynamic study has been a big hurdle in such identification efforts. To this end, a multi-compound pharmacokinetic approach was established to identify potentially important compounds (bioavailable at the action loci with significant exposure levels after dosing an herbal medicine) and to characterize their pharmacokinetics and disposition. Another feature of Chinese herbal medicines is their typical use as or in combination therapies. Coadministration of complex natural products and conventional synthetic drugs is prevalent worldwide, even though it remains very controversial. Natural product-drug interactions have raised wide concerns about reduced drug efficacy or safety. However, growing evidence shows that incorporating Chinese herbal medicines into synthetic drug-based therapies delivers benefits in the treatment of many multifactorial diseases. To address this issue, a drug-combination pharmacokinetic approach was established to assess drug-drug interaction potential of herbal medicines and degree of pharmacokinetic compatibility for multi-herb combination and herbal medicine-synthetic drug combination therapies. In this review we describe the methodology, techniques, requirements, and applications of multi-compound and drug-combination pharmacokinetic research on Chinese herbal medicines and to discuss further development for these two types of pharmacokinetic research.

Effect of Iron Plaque on Gaseous Elemental Mercury Uptake, Translocation, and Volatilization by Paddy Rice.

Paddy rice is a typical wetland plant species, and mercury (Hg) accumulation in this rice has received much attention over the last two decades. The role of root iron plaque on rice Hg accumulation is not well understood. The effects of iron plaque on Hg0 uptake, translocation, and volatilization in rice seedlings were investigated under hydroponic conditions using different rice genotypes. After induction of iron plaque on rice roots with pretreatment solutions containing 0, 15 and 30 mg Fe2+L-1, rice seedlings were transplanted into specially designed airtight culture chambers, where roots were separated from the aerial parts and exposed to saturated Hg0 vapor. The results showed the following: (1) There were significant differences in the amount of iron plaque formed on the rice roots among the three genotypes. (2) A significant correlation was observed between the concentrations of Hg and Fe in the iron plaque of the root surface for the three genotypes (R2 = 0.933, p < 0.01). (3) Iron plaque may act as a barrier for Hg0 behavior, i.e., inhibiting the process of Hg0 uptake and translocation from the rhizosphere.

Mechanistic analysis of resveratrol in cardiac hypertrophy by network pharmacology and animal experiments.

Resveratrol (Res) serves a protective role in hepatic, cardiovascular and autoimmune hypertrophic disease. However, the mechanisms by which Res ameliorates cardiac hypertrophy have not yet been fully elucidated. In the present study, network pharmacology was used to construct a network and perform enrichment analysis to evaluate the effect of Res on cardiac hypertrophy. Experimental validation was performed using 40 Sprague­Dawley rats administered intragastric 80 mg/kg/day Res and 20 mg/kg/day 3­methyladenine (3­MA) for 4 weeks. A total of 444 targets associated with cardiac hypertrophy and 229 potential disease­associated targets of Res were identified, from which 8 overlapping genes were demonstrated. Gene Ontology function and 'Kyoto Encyclopedia of Genes and Genomes' pathway enrichment analysis demonstrated that Res affected STAT3 and was associated with autophagy signaling pathways, including 'negative regulation of autophagy for hypertrophic cardiomyopathy'. Furthermore, Res ameliorated isoprenaline­induced cardiac hypertrophy, significantly improving cardiac dysfunction in vivo experiment (echocardiography, the degree of ventricular hypertrophy, etc.); this effect may be associated with regulation of autophagy and apoptosis. The autophagy inhibitor 3­MA markedly reversed the anti­cardiac hypertrophy effects of Res. In conclusion, Res inhibited cardiac hypertrophy via downregulation of the apoptosis signaling pathway and upregulating the autophagy pathway.

[Mahuang (herbaceous stem of Ephedra spp.): chemistry, pharmacodynamics, and pharmacokinetics].

The Chinese medicinal herb Mahuang is herbaceous stem of Ephedra sinica, E. intermedia, or E. equisetina(Family, Ephedraceae). In China, Mahuang has been used, all the way over a millennium, as a key component herb of many herbal medicines for management of epidemics of acute respiratory illness and is also used in officially recommended herbal medicines for COVID-19. Mahuang is the first-line medicinal herb for cold and wheezing and also an effective diuretic herb for edema. However, Mahuang can also exert significant adverse effects. The key to safety and effectiveness is rational and precise use of the herb. In this review article, we comprehensively summarize chemical composition of Mahuang and associated differences in pharmacognosy, pharmacodynamics and pharmacokinetics of Mahuang compounds, along with the adverse effects of Mahuang compounds and products. Based on full understanding of how Mahuang is used in Chinese traditional medicine, systematic research on Mahuang in line with contemporary standards of pharmaceutical sciences will facilitate promoting Chinese herbal medicines to become more efficient in management of epidemic illnesses, such as COVID-19. To this end, we recommend research on Mahuang of two aspects, i.e., pharmacological investigation for its multicompound-involved therapeutic effects and toxicological investigation for clinical manifestation of the adverse effects, chemicals responsible for the adverse effects, and conditions for safe use of the herb and the herb-containing medicines.

Molecular Basis Underlying Hepatobiliary and Renal Excretion of Phenolic Acids of Salvia miltiorrhiza Roots (Danshen).

Phenolic acids are cardiovascular constituents (originating from the Chinese medicinal herb Salvia miltiorrhiza root/Danshen) of DanHong and many other Danshen-containing injections. Our earlier pharmacokinetic investigation of DanHong suggested that hepatic and/or renal uptake of the Danshen compounds was the crucial steps in their systemic elimination. This investigation was designed to survey the molecular basis underlying hepatobiliary and renal excretion of the Danshen compounds, i.e., protocatechuic acid, tanshinol, rosmarinic acid, salvianolic acid D, salvianolic acid A, lithospermic acid, and salvianolic acid B. A large battery of human hepatic and renal transporters were screened for transporting the Danshen compounds and then characterized for the uptake kinetics and also compared with associated rat transporters. The samples were analyzed by liquid chromatography/mass spectrometry. Because the Danshen phenolic acids are of poor or fairly good membrane permeability, their elimination via the liver or kidneys necessitates transporter-mediated hepatic or renal uptake from blood. Several human transporters were found to mediate hepatic and/or renal uptake of the Danshen compounds in a compound-molecular-mass-related manner. Lithospermic acid and salvianolic acid B (both >500 Da) underwent systemic elimination, initiated by organic anion-transporting polypeptide (OATP)1B1/OATP1B3-mediated hepatic uptake. Rosmarinic acid and salvianolic acids D (350-450 Da) underwent systemic elimination, initiated by OATP1B1/OATP1B3/organic anion transporter (OAT)2-mediated hepatic uptake and by OAT1/OAT2-mediated renal uptake. Protocatechuic acid and tanshinol (both <200 Da) underwent systemic elimination, initiated by OAT1/OAT2-mediated renal uptake and OAT2-mediated hepatic uptake. A similar scenario was observed with the rat orthologs. The investigation findings advance our understanding of the disposition of the Danshen phenolic acids and could facilitate pharmacokinetic research on other Danshen-containing injections.

Emerging blood exosome-based biomarkers for preclinical and clinical Alzheimer's disease: a meta-analysis and systematic review.

Blood exosomes, which are extracellular vesicles secreted by living cells into the circulating blood, are regarded as a relatively noninvasive novel tool for monitoring brain physiology and disease states. An increasing number of blood cargo-loaded exosomes are emerging as potential biomarkers for preclinical and clinical Alzheimer's disease. Therefore, we conducted a meta-analysis and systematic review of molecular biomarkers derived from blood exosomes to comprehensively analyze their diagnostic performance in preclinical Alzheimer's disease, mild cognitive impairment, and Alzheimer's disease. We performed a literature search in PubMed, Web of Science, Embase, and Cochrane Library from their inception to August 15, 2020. The research subjects mainly included Alzheimer's disease, mild cognitive impairment, and preclinical Alzheimer's disease. We identified 34 observational studies, of which 15 were included in the quantitative analysis (Newcastle-Ottawa Scale score 5.87 points) and 19 were used in the qualitative analysis. The meta-analysis results showed that core biomarkers including Aß1-42, P-T181-tau, P-S396-tau, and T-tau were increased in blood neuron-derived exosomes of preclinical Alzheimer's disease, mild cognitive impairment, and Alzheimer's disease patients. Molecules related to additional risk factors that are involved in neuroinflammation (C1q), metabolism disorder (P-S312-IRS-1), neurotrophic deficiency (HGF), vascular injury (VEGF-D), and autophagy-lysosomal system dysfunction (cathepsin D) were also increased. At the gene level, the differential expression of transcription-related factors (REST) and microRNAs (miR-132) also affects RNA splicing, transport, and translation. These pathological changes contribute to neural loss and synaptic dysfunction. The data confirm that the above-mentioned core molecules and additional risk-related factors in blood exosomes can serve as candidate biomarkers for preclinical and clinical Alzheimer's disease. These findings support further development of exosome biomarkers for a clinical blood test for Alzheimer's disease. This meta-analysis was registered at the International Prospective Register of Systematic Reviews (Registration No. CRD4200173498, 28/04/2020).

Local neural-network-weighted models for occurrence and number of down wood in natural forest ecosystem.

The natural forest ecosystem has been affected by wind storms for years, which have caused several down wood (DW) and dramatically modified the fabric and size. Therefore, it is very important to explain the forest system by quantifying the spatial relationship between DW and environmental parameters. However, the spatial non-stationary characteristics caused by the terrain and stand environmental changes with distinct gradients may lead to an incomplete description of DW, the local neural-network-weighted models of geographically neural-network-weighted (GNNWR) models are introduced here. To verify the validity of models, our DW and environmental factors were applied to investigate of occurrence of DW and number of DW to establish the generalized linear (logistic and Poisson) models, geographically weighted regression (GWLR and GWPR) models and GNNWR (GNNWLR and GNNWPR) models. The results show that the GNNWR models show great advantages in the model-fitting performance, prediction performance, and the spatial Moran's I of model residuals. In addition, GNNWR models can combine the geographic information system technology for accurately expressing the spatial distribution of DW relevant information to provide the key technology that can be used as the basis for human decision-making and management planning.

Enhanced Medial Prefrontal Cortex and Hippocampal Activity Improves Memory Generalization in APP/PS1 Mice: A Multimodal Animal MRI Study.

Memory generalization allows individuals to extend previously learned movement patterns to similar environments, contributing to cognitive flexibility. In Alzheimer's disease (AD), the disturbance of generalization is responsible for the deficits of episodic memory, causing patients with AD to forget or misplace things, even lose track of the way home. Cognitive training can effectively improve the cognition of patients with AD through changing thinking mode and memory flexibility. In this study, a T-shaped maze was utilized to simulate cognitive training in APP/PS1 mice to elucidate the potential mechanisms of beneficial effects after cognitive training. We found that cognitive training conducted by a T-shaped maze for 4 weeks can improve the memory generalization ability of APP/PS1 mice. The results of functional magnetic resonance imaging (fMRI) showed that the functional activity of the medial prefrontal cortex (mPFC) and hippocampus was enhanced after cognitive training, and the results of magnetic resonance spectroscopy (MRS) showed that the neurochemical metabolism of N-acetyl aspartate (NAA) and glutamic acid (Glu) in mPFC, hippocampus and reuniens (Re) thalamic nucleus were escalated. Furthermore, the functional activity of mPFC and hippocampus was negatively correlated with the escape latency in memory generalization test. Therefore, these results suggested that cognitive training might improve memory generalization through enhancing the functional activity of mPFC and hippocampus and increasing the metabolism of NAA and Glu in the brain regions of mPFC, hippocampus and Re nucleus.

Activation of Adenosine Monophosphate-Activated Protein Kinase Drives the Aerobic Glycolysis in Hippocampus for Delaying Cognitive Decline Following Electroacupuncture Treatment in APP/PS1 Mice.

Aerobic glycolysis (AG), an important pathway of glucose metabolism, is dramatically declined in Alzheimer's disease (AD). AMP-activated protein kinase (AMPK) is a key regulator to maintain the stability of energy metabolism by promoting the process of AG and regulating glucose metabolism. Interestingly, it has been previously reported that electroacupuncture (EA) treatment can improve cognitive function in AD through the enhancement of glucose metabolism. In this study, we generated AMPK-knockdown mice to confirm the EA effect on AMPK activation and further clarify the mechanism of EA in regulating energy metabolism and improving cognitive function in APP/PS1 mice. The behavioral results showed that EA treatment can improve the learning and memory abilities in APP/PS1 mice. At the same time, the glucose metabolism in the hippocampus was increased detected by MRI-chemical exchange saturation transfer (MRI-CEST). The expression of proteins associated with AG in the hippocampus was increased simultaneously, including hexokinase II (HK2), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), and pyruvate kinase M2 (PKM2). Moreover, the knockdown of AMPK attenuated AG activated by EA treatment. In conclusion, this study proves that EA can activate AMPK to enhance the process of AG in the early stage of AD.