Aß42 and ROS dual-targeted multifunctional nanocomposite for combination therapy of Alzheimer's disease.

Amyloid-ß (Aß) readily misfolds into neurotoxic aggregates, generating high levels of reactive oxygen species (ROS), leading to progressive oxidative damage and ultimately cell death. Therefore, simultaneous inhibition of Aß aggregation and scavenging of ROS may be a promising therapeutic strategy to alleviate Alzheimer's disease pathology. Based on the previously developed antibody 1F12 that targets all forms of Aß42, we developed an Aß42 and ROS dual-targeting nanocomposite using biodegradable mesoporous silica nanoparticles as carriers to load ultra-small cerium oxide nanocrystals (bMSNs@Ce-1F12). By modifying the brain-targeted rabies virus glycoprotein 29 (RVG29-bMSNs@Ce-1F12), this intelligent nanocomposite can efficiently target brain Aß-rich regions. Combined with peripheral and central nervous system treatments, RVG29-bMSNs@Ce-1F12 can significantly alleviate AD symptoms by inhibiting Aß42 misfolding, accelerating Aß42 clearance, and scavenging ROS. Furthermore, this synergistic effect of ROS scavenging and Aß clearance exhibited by this Aß42 and ROS dual-targeted strategy also reduced the burden of hyperphosphorylated tau, alleviated glial cell activation, and ultimately improved cognitive function in APP/PS1 mice. Our findings indicate that RVG29-bMSNs@Ce-1F12 is a promising nanodrug that can facilitate multi-target treatment of AD.

SUPPRESSOR of MAX2 1 (SMAX1) and SMAX1-LIKE2 (SMXL2) Negatively Regulate Drought Resistance in Arabidopsis thaliana.

Recent investigations in Arabidopsis thaliana suggest that SUPPRESSOR of MORE AXILLARY GROWTH 2 1 (SMAX1) and SMAX1-LIKE2 (SMXL2) are negative regulators of karrikin (KAR) and strigolactone (SL) signaling during plant growth and development, but their functions in drought resistance and related mechanisms of action remain unclear. To understand the roles and mechanisms of SMAX1 and SMXL2 in drought resistance, we investigated the drought-resistance phenotypes and transcriptome profiles of smax1 smxl2 (s1,2) double-mutant plants in response to drought stress. The s1,2 mutant plants showed enhanced drought-resistance and lower leaf water loss when compared with wild-type (WT) plants. Transcriptome comparison of rosette leaves from the s1,2 mutant and the WT under normal and dehydration conditions suggested that the mechanism related to cuticle formation was involved in drought resistance. This possibility was supported by enhanced cuticle formation in the rosette leaves of the s1,2 mutant. We also found that the s1,2 mutant plants were more sensitive to abscisic acid in assays of stomatal closure, cotyledon opening, chlorophyll degradation and growth inhibition, and they showed a higher reactive oxygen species detoxification capacity than WT plants. In addition, the s1,2 mutant plants had longer root hairs and a higher root-to-shoot ratio than the WT plants, suggesting that the mutant had a greater capacity for water absorption than the WT. Taken together, our results indicate that SMAX1 and SMXL2 negatively regulate drought resistance, and disruption of these KAR- and SL-signaling-related genes may therefore provide a novel means for improving crop drought resistance.

KARRIKIN UPREGULATED F-BOX 1 negatively regulates drought tolerance in Arabidopsis.

The karrikin (KAR) receptor and several related signaling components have been identified by forward genetic screening, but only a few studies have reported on upstream and downstream KAR signaling components and their roles in drought tolerance. Here, we characterized the functions of KAR UPREGULATED F-BOX 1 (KUF1) in drought tolerance using a reverse genetics approach in Arabidopsis (Arabidopsis thaliana). We observed that kuf1 mutant plants were more tolerant to drought stress than wild-type (WT) plants. To clarify the mechanisms by which KUF1 negatively regulates drought tolerance, we performed physiological, transcriptome, and morphological analyses. We found that kuf1 plants limited leaf water loss by reducing stomatal aperture and cuticular permeability. In addition, kuf1 plants showed increased sensitivity of stomatal closure, seed germination, primary root growth, and leaf senescence to abscisic acid (ABA). Genome-wide transcriptome comparisons of kuf1 and WT rosette leaves before and after dehydration showed that the differences in various drought tolerance-related traits were accompanied by differences in the expression of genes associated with stomatal closure (e.g. OPEN STOMATA 1), lipid and fatty acid metabolism (e.g. WAX ESTER SYNTHASE), and ABA responsiveness (e.g. ABA-RESPONSIVE ELEMENT 3). The kuf1 mutant plants had higher root/shoot ratios and root hair densities than WT plants, suggesting that they could absorb more water than WT plants. Together, these results demonstrate that KUF1 negatively regulates drought tolerance by modulating various physiological traits, morphological adjustments, and ABA responses and that the genetic manipulation of KUF1 in crops is a potential means of enhancing their drought tolerance.

The beta subunit of AMP-activated protein kinase is critical for cell cycle progression and parasite development in Toxoplasma gondii.

Toxoplasma gondii is a widespread eukaryotic pathogen that causes life-threatening diseases in humans and diverse animals. It has a complex life cycle with multiple developmental stages, which are timely adjusted according to growth conditions. But the regulatory mechanisms are largely unknown. Here we show that the AMP-activated protein kinase (AMPK), a key regulator of energy homeostasis in eukaryotes, plays crucial roles in controlling the cell cycle progression and bradyzoite development in Toxoplasma. Deleting the ß regulatory subunit of AMPK in the type II strain ME49 caused massive DNA damage and increased spontaneous conversion to bradyzoites (parasites at chronic infection stage), leading to severe growth arrest and reduced virulence of the parasites. Under alkaline stress, all Δampkß mutants converted to a bradyzoite-like state but the cell division pattern was significantly impaired, resulting in compromised parasite viability. Moreover, we found that phosphorylation of the catalytic subunit AMPKα was greatly increased in alkaline stressed parasites, whereas AMPKß deletion mutants failed to do so. Phosphoproteomics found that many proteins with predicted roles in cell cycle and cell division regulation were differentially phosphorylated after AMPKß deletion, under both normal and alkaline stress conditions. Together, these results suggest that the parasite AMPK has critical roles in safeguarding cell cycle progression, and guiding the proper exist of the cell cycle to form mature bradyzoites when the parasites are stressed. Consistent with this model, growth of parasites was not significantly altered when AMPKß was deleted in a strain that was naturally reluctant to bradyzoite development.

Mesoporous silica nanoparticle-encapsulated Bifidobacterium attenuates brain Aß burden and improves olfactory dysfunction of APP/PS1 mice by nasal delivery.

BACKGROUND: Dysbiosis or imbalance of gut microbiota in Alzheimer's disease (AD) affects the production of short-chain fatty acids (SCFAs), whereas exogenous SCFAs supplementation exacerbates brain Aß burden in APP/PS1 mice. Bifidobacterium is the main producer of SCFAs in the gut flora, but oral administration of Bifidobacterium is ineffective due to strong acids and bile salts in the gastrointestinal tract. Therefore, regulating the levels of SCFAs in the gut is of great significance for AD treatment. METHODS: We investigated the feasibility of intranasal delivery of MSNs-Bifidobacterium (MSNs-Bi) to the gut and their effect on behavior and brain pathology in APP/PS1 mice. RESULTS: Mesoporous silica nanospheres (MSNs) were efficiently immobilized on the surface of Bifidobacterium. After intranasal administration, fluorescence imaging of MSNs-Bi in the abdominal cavity and gastrointestinal tract revealed that intranasally delivered MSNs-Bi could be transported through the brain to the peripheral intestine. Intranasal administration of MSNs-Bi not only inhibited intestinal inflammation and reduced brain Aß burden but also improved olfactory sensitivity in APP/PS1 mice. CONCLUSIONS: These findings suggested that restoring the balance of the gut microbiome contributes to ameliorating cognitive impairment in AD, and that intranasal administration of MSNs-Bi may be an effective therapeutic strategy for the prevention of AD and intestinal disease.

Acquisition of exogenous fatty acids renders apicoplast-based biosynthesis dispensable in tachyzoites of Toxoplasma.

Toxoplasma gondii is a common protozoan parasite that infects a wide range of hosts, including livestock and humans. Previous studies have suggested that the type 2 fatty acid synthesis (FAS2) pathway, located in the apicoplast (a nonphotosynthetic plastid relict), is crucial for the parasite's survival. Here we examined the physiological relevance of fatty acid synthesis in T. gondii by focusing on the pyruvate dehydrogenase complex and malonyl-CoA-[acyl carrier protein] transacylase (FabD), which are located in the apicoplast to drive de novo fatty acid biosynthesis. Our results disclosed unexpected metabolic resilience of T. gondii tachyzoites, revealing that they can tolerate CRISPR/Cas9-assisted genetic deletions of three pyruvate dehydrogenase subunits or FabD. All mutants were fully viable in prolonged cultures, albeit with impaired growth and concurrent loss of the apicoplast. Even more surprisingly, these mutants displayed normal virulence in mice, suggesting an expendable role of the FAS2 pathway in vivo Metabolic labeling of the Δpdh-e1α mutant showed reduced incorporation of glucose-derived carbon into fatty acids with medium chain lengths (C14:0 and C16:0), revealing that FAS2 activity was indeed compromised. Moreover, supplementation of exogenous C14:0 or C16:0 significantly reversed the growth defect in the Δpdh-e1α mutant, indicating salvage of these fatty acids. Together, these results demonstrate that the FAS2 pathway is dispensable during the lytic cycle of Toxoplasma because of its remarkable flexibility in acquiring fatty acids. Our findings question the long-held assumption that targeting this pathway has significant therapeutic potential for managing Toxoplasma infections.

The Sec1/Munc18-like proteins TgSec1 and TgVps45 play pivotal roles in assembly of the pellicle and sub-pellicle network in Toxoplasma gondii.

Post-Golgi vesicle trafficking is indispensable for precise movement of proteins to the pellicle, the sub-pellicle network and apical secretory organelles in Apicomplexa. However, only a small number of molecular complexes involved in trafficking, tethering and fusion of vesicles have been identified in Toxoplasma gondii. Consequently, it is unclear how complicated vesicle trafficking is accomplished in this parasite. Sec1/Munc18-like (SM) proteins are essential components of protein complexes involved in vesicle fusion. Here, we found that depletion of the SM protein TgSec1 using an auxin-inducible degron-based conditional knockout strategy led to mislocalization of plasma membrane proteins. By contrast, conditional depletion of the SM protein TgVps45 led to morphological changes, asymmetrical loss of the inner membrane complex and defects in nucleation of sub-pellicular microtubules, polarization and symmetrical assembly of daughter parasites during repeated endodyogeny. TgVps45 interacts with the SNARE protein TgStx16 and TgVAMP4-1. Conditional ablation of TgStx16 causes the similar growth defect like TgVps45 deficiency suggested they work together for the vesicle fusion at TGN. These findings indicate that these two SM proteins are crucial for assembly of pellicle and sub-pellicle network in T. gondii respectively.

Quantitative assessment of AD markers using naked eyes: point-of-care testing with paper-based lateral flow immunoassay.

Aß42 is one of the most extensively studied blood and Cerebrospinal fluid (CSF) biomarkers for the diagnosis of symptomatic and prodromal Alzheimer's disease (AD). Because of the heterogeneity and transient nature of Aß42 oligomers (Aß42Os), the development of technologies for dynamically detecting changes in the blood or CSF levels of Aß42 monomers (Aß42Ms) and Aß42Os is essential for the accurate diagnosis of AD. The currently commonly used Aß42 ELISA test kits usually mis-detected the elevated Aß42Os, leading to incomplete analysis and underestimation of soluble Aß42, resulting in a comprised performance in AD diagnosis. Herein, we developed a dual-target lateral flow immunoassay (dLFI) using anti-Aß42 monoclonal antibodies 1F12 and 2C6 for the rapid and point-of-care detection of Aß42Ms and Aß42Os in blood samples within 30 min for AD diagnosis. By naked eye observation, the visual detection limit of Aß42Ms or/and Aß42Os in dLFI was 154 pg/mL. The test results for dLFI were similar to those observed in the enzyme-linked immunosorbent assay (ELISA). Therefore, this paper-based dLFI provides a practical and rapid method for the on-site detection of two biomarkers in blood or CSF samples without the need for additional expertise or equipment.

Recent trends in treatment strategies for Alzheimer's disease and the challenges: A topical advancement.

Alzheimer's Disease (AD) is an irreversible and progressive neurological disease that has affected at least 50 million people around the globe. Considering the severity of the disease and the continuous increase in the number of patients, the development of new effective drugs or intervention strategies for AD has become urgent. AD is caused by a combination of genetic, environmental, and lifestyle factors, but its exact cause has not yet been clarified. Given the current challenges being faced in the clinical treatment of AD, such as complex AD pathological network and insufficient early diagnosis, herein, we have focused on the three core pathological features of AD, including amyloid-ß (Aß) aggregation, tau phosphorylation and tangles, and activation of inflammatory factors. In this review, we have briefly underscored the primary evidence supporting each pathology and discuss AD pathological network among Aß, tau, and inflammation. We have also comprehensively summarized the most instructive drugs and their treatment strategies against Aß, tau, or neuroinflammation used in basic research and clinical trials. Finally, we have discussed and outlined the pros and cons of each pathological approach and looked forward to potential personalized diagnosis and treatment strategies that are beneficial to AD patients.

Identification of the Maize PP2C Gene Family and Functional Studies on the Role of ZmPP2C15 in Drought Tolerance.

The protein phosphatase PP2C plays an important role in plant responses to stress. Therefore, the identification of maize PP2C genes that respond to drought stress is particularly important for the improvement and creation of new drought-resistant assortments of maize. In this study, we identified 102 ZmPP2C genes in maize at the genome-wide level. We analyzed the physicochemical properties of 102 ZmPP2Cs and constructed a phylogenetic tree with Arabidopsis. By analyzing the gene structure, conserved protein motifs, and synteny, the ZmPP2Cs were found to be strongly conserved during evolution. Sixteen core genes involved in drought stress and rewatering were screened using gene co-expression network mapping and expression profiling. The qRT-PCR results showed 16 genes were induced by abscisic acid (ABA), drought, and NaCl treatments. Notably, ZmPP2C15 exhibited a substantial expression difference. Through genetic transformation, we overexpressed ZmPP2C15 and generated the CRISPR/Cas9 knockout maize mutant zmpp2c15. Overexpressing ZmPP2C15 in Arabidopsis under drought stress enhanced growth and survival compared with WT plants. The leaves exhibited heightened superoxide dismutase (SOD), peroxidase (POD), ascorbate peroxidase (APX), and catalase (CAT) activities, elevated proline (Pro) content, and reduced malondialdehyde (MDA) content. Conversely, zmpp2c15 mutant plants displayed severe leaf dryness, curling, and wilting under drought stress. Their leaf activities of SOD, POD, APX, and CAT were lower than those in B104, while MDA was higher. This suggests that ZmPP2C15 positively regulates drought tolerance in maize by affecting the antioxidant enzyme activity and osmoregulatory substance content. Subcellular localization revealed that ZmPP2C15 was localized in the nucleus and cytoplasm. Yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) experiments demonstrated ZmPP2C15's interaction with ZmWIN1, ZmADT2, ZmsodC, Zmcab, and ZmLHC2. These findings establish a foundation for understanding maize PP2C gene functions, offering genetic resources and insights for molecular design breeding for drought tolerance.

Sensitive detection of multiple blood biomarkers via immunomagnetic exosomal PCR for the diagnosis of Alzheimer's disease.

Blood exosomes are emerging as potential biomarkers for diagnosing brain diseases such as Alzheimer's disease (AD). There is currently a lack of an ultrasensitive technology for identifying core AD biomarkers in blood exosomes to optimize the utility of biomarkers in clinical practice. Here, an immunomagnetic exosomal polymerase chain reaction (iMEP) platform was developed using DNA-conjugated antibodies for the rapid detection of amyloid-ß (Aß1-40 and Aß1-42) and phosphorylated tau (p-tau396,404 and p-tau181) in clinical blood exosomes. The toehold shift-mediated DNA affinity pulldown eliminates the high detection background, which allows the detection of biomarkers at concentrations down to 10 femtograms per milliliter. With the iMEP assay, exosomal Aß1-42 was more accurate in differentiating patients with AD from healthy individuals compared with exosomal p-tau181 and p-tau396,404, with a sensitivity of 95.0% and a specificity of 95.0%. The iMEP technique is also adept at quantifying the levels of different exosomal biomarkers associated with disease pathogenesis.

Characterization of Chitin Synthase B Gene (HvChsb) and the Effects on Feeding Behavior in Heortia vitessoides Moore.

The chitin synthase B gene is a key enzyme in the chitin synthesis of insect peritrophic matrix (PM), which affects insects' feeding behavior. The chitin synthase B gene was cloned from the transcription library of Heortia vitessoides Moore. RT-qPCR showed that HvChsb was highly expressed in the larval stage of H. vitessoides, especially on the first day of the pre-pupal stage, as well as in the midgut of larvae and the abdomen of adults. After starvation treatment, HvChsb was found to be significantly inhibited over time. After 48 h of starvation, the feeding experiment showed that HvChsb increased with the prolongation of the re-feeding time. The experimental data showed that feeding affected the expression of HvChsb. HvChsb was effectively silenced via RNA interference; thus, its function was lost, significantly decreasing the survival rate of H. vitessoides. The survival rate from larval-to-pupal stages was only 43.33%, and this rate was accompanied by abnormal phenotypes. It can be seen that HvChsb plays a key role in the average growth and development of H. vitessoides.

Ultrasensitive and point-of-care detection of plasma phosphorylated tau in Alzheimer's disease using colorimetric and surface-enhanced Raman scattering dual-readout lateral flow assay.

Phosphorylation of tau at Ser (396, 404) (p-tau396,404) is one of the earliest phosphorylation events, and plasma p-tau396,404 level appears to be a potentially promising biomarker of Alzheimer's disease (AD). The low abundance and easy degradation of p-tau in the plasma make the lateral flow assay (LFA) a suitable choice for point-of-care detection of plasma p-tau396,404 levels. Herein, based on our screening of a pair of p-tau396,404-specific antibodies, we developed a colorimetric and surface-enhanced Raman scattering (SERS) dual-readout LFA for the rapid, highly sensitive, and robust detection of plasma p-tau396,404 levels. This LFA realized a detection limit of 60 pg/mL by the naked eye or 3.8 pg/mL by SERS without cross-reacting with other tau species. More importantly, LFA rapidly and accurately differentiated AD patients from healthy controls, suggesting that it has the potential for clinical point-of-care application in AD diagnosis. This dual-readout LFA has the advantages of simple operation, rapid, and ultra-sensitive detection, providing a new way for early AD diagnosis and intervention, especially in primary and community AD screening. Electronic Supplementary Material: Supplementary material (characterization of AuNPs and 4-MBA@AuNP probe; the optimal 4-MBA load for AuNPs; the optimal K2CO3 volumes for 4-MBA@AuNP-3G5 conjugates; the optimal 3G5 load for 4-MBA@AuNP conjugates; effect of NaCl concentration on 4-MBA@AuNP-3G5 stability; the linear curve of T-line color and SERS intensity versus different p-tau396,404 concentrations; the comparison of colorimetric-based LFA test results and the diagnosis results; Raman intensities and antibody activity of 4-MBA@AuNP-3G5 before and after storage; colorimetric intensity of dual-readout LFA detecting different concentrations of p-tau396,404 protein; sequence of synthesized peptides used in this study; information of the participants in this study; the information of antibodies used in this study) is available in the online version of this article at 10.1007/s12274-022-5354-4.

Colorimetric and surface-enhanced Raman scattering dual-mode magnetic immunosensor for ultrasensitive detection of blood phosphorylated tau in Alzheimer's disease.

Phosphorylation of tau at Ser 396, 404 (p-tau396,404) is the earliest phosphorylation event and a promising biomarker for the early diagnosis of Alzheimer's disease (AD). However, the detection of blood p-tau is challenging because of its low abundance, easy degradation, and complex formation with various blood proteins or cells, often leading to the underestimation of p-tau levels in conventional plasma-based assays. Herein, we developed a colorimetric and surface-enhanced Raman scattering (SERS) dual-mode magnetic immunosensor for highly sensitive, specific, and robust detection of p-tau396,404 in whole blood samples. The detection assay was based on an immunoreaction between p-tau396,404 proteins, wherein antibody-modified superparamagnetic iron oxide nanoparticles act as recognition elements to capture p-tau396,404 in blood, and then horseradish peroxidase- and Raman tags label the corresponding paired antibody as a reporter to provide high signal-to-noise ratios for the immunosensor. This dual-mode immunosensor achieved identified as low as 1.5 pg/mL of p-tau396,404 in the blood in SERS mode and 24 pg/mL in colorimetric mode by the naked eye. More importantly, this immunosensor rapidly and accurately distinguished AD patients from healthy individuals based on blood p-tau396,404 levels, and also had the potential to distinguish AD patients of different severities. Therefore, the dual-mode immunosensor is promising for rapid clinical diagnosis of AD, especially in large-scale AD screening.

Synthesis vs. salvage of ester- and ether-linked phosphatidylethanolamine in the intracellular protozoan pathogen Toxoplasma gondii.

Toxoplasma gondii is a prevalent zoonotic pathogen infecting livestock as well as humans. The exceptional ability of this parasite to reproduce in several types of nucleated host cells necessitates a coordinated usage of endogenous and host-derived nutritional resources for membrane biogenesis. Phosphatidylethanolamine is the second most common glycerophospholipid in T. gondii, but how its requirement in the acutely-infectious fast-dividing tachyzoite stage is satisfied remains enigmatic. This work reveals that the parasite deploys de novo synthesis and salvage pathways to meet its demand for ester- and ether-linked PtdEtn. Auxin-mediated depletion of the phosphoethanolamine cytidylyltransferase (ECT) caused a lethal phenotype in tachyzoites due to impaired invasion and cell division, disclosing a vital role of the CDP-ethanolamine pathway during the lytic cycle. In accord, the inner membrane complex appeared disrupted concurrent with a decline in its length, parasite width and major phospholipids. Integrated lipidomics and isotope analyses of the TgECT mutant unveiled the endogenous synthesis of ester-PtdEtn, and salvage of ether-linked lipids from host cells. In brief, this study demonstrates how T. gondii operates various means to produce distinct forms of PtdEtn while featuring the therapeutic relevance of its de novo synthesis.

Elevated Plasma Oligomeric Amyloid ß-42 Is Associated with Cognitive Impairments in Cerebral Small Vessel Disease.

Due to the heterogeneity of amyloid ß-42 (Aß42) species, the potential correlation between plasma oligomeric Aß42 (oAß42) and cognitive impairments in cerebral small vessel disease (CSVD) remains unclear. Herein, a sandwich ELISA for the specific detection of Aß42 oligomers (oAß42) and total Aß42 (tAß42) was developed based on sequence- and conformation-specific antibody pairs for the evaluation of plasma samples from a Chinese CSVD community cohort. After age and gender matching, 3-Tesla magnetic resonance imaging and multidimensional cognitive assessment were conducted in 134 CSVD patients and equal controls. The results showed that plasma tAß42 and oAß42 levels were significantly elevated in CSVD patients. By regression analysis, these elevations were correlated with the presence of CSVD and its imaging markers (i.e., white matter hyperintensities). Plasma Aß42 tests further strengthened the predictive power of vascular risk factors for the presence of CSVD. Relative to tAß42, oAß42 showed a closer correlation with memory domains evaluated by neuropsychological tests. In conclusion, this sensitive ELISA protocol facilitated the detection of plasma Aß42; Aß42, especially its oligomeric form, can serve as a biosensor for the presence of CSVD and associated cognitive impairments represented by memory domains.

Rapid metabolic reprogramming mediated by the AMP-activated protein kinase during the lytic cycle of Toxoplasma gondii.

The ubiquitous pathogen Toxoplasma gondii has a complex lifestyle with different metabolic activities at different stages that are intimately linked to the parasitic environments. Here we identified the eukaryotic regulator of cellular homeostasis AMP-activated protein kinase (AMPK) in Toxoplasma and discovered its role in metabolic programming during parasite's lytic cycle. The catalytic subunit AMPKα is quickly phosphorylated after the release of intracellular parasites to extracellular environments, driving energy-producing catabolism to power parasite motility and invasion into host cells. Once inside host cells, AMPKα phosphorylation is reduced to basal level to promote a balance between energy production and biomass synthesis, allowing robust parasite replication. AMPKγ depletion abolishes AMPKα phosphorylation and suppresses parasite growth, which can be partially rescued by overexpressing wildtype AMPKα but not the phosphorylation mutants. Thus, through the cyclic reprogramming by AMPK, the parasites' metabolic needs at each stage are satisfied and the lytic cycle progresses robustly.

Dual-targeted magnetic mesoporous silica nanoparticles reduce brain amyloid-ß burden via depolymerization and intestinal metabolism.

Rationale: Active removal of excess peripheral amyloid-ß (Aß) can potentially treat Alzheimer's disease (AD). However, the peripheral clearance of Aß using an anti-Aß monoclonal antibody (mAb) cannot remove PET-detectable Aß within the brain. This may be due to the inability of mAb to cross the blood-brain barrier (BBB) to degrade insoluble brain Aß plaques and block liver dysfunction. Methods: We developed a dual-targeted magnetic mesoporous silica nanoparticle (HA-MMSN-1F12) through surface-coupled Aß42-targeting antibody 1F12 and CD44-targeting ligand hyaluronic acid (HA). Results: HA-MMSN-1F12 had a high binding affinity toward Aß42 oligomers (Kd = 1.27 ± 0.34 nM) and revealed robust degradation of Aß42 aggregates. After intravenous administration of HA-MMSN-1F12 into ten-month-old APP/PS1 mice for three weeks (4 mg/kg/week), HA-MMSN-1F12 could cross the BBB and depolymerize brain Aß plaques into soluble Aß species. In addition, it also avoided hepatic uptake and excreted captured Aß species through intestinal metabolism, thereby reducing brain Aß load and neuroinflammation and improving memory deficits of APP/PS1 mice. Furthermore, the biochemical analysis showed that HA-MMSN-1F12 did not detect any toxic side effects on the liver and kidney. Thus, the efficacy of HA-MMSN-1F12 is associated with the targeted degradation of insoluble brain Aß plaques, avoidance of non-specific hepatic uptake, and excretion of peripheral Aß through intestinal metabolism. Conclusions: The study provides a new avenue for treating brain diseases by excreting disease-causing biohazards using intestinal metabolism.

Evolution and Expression Patterns of the Fructose 1,6-Bisphosptase Gene Family in a Miracle Tree (Neolamarckia cadamba).

Neolamarckia cadamba (N. cadamba) is a fast-growing tree species with tremendous economic and ecological value; the study of the key genes regulating photosynthesis and sugar accumulation is very important for the breeding of N. cadamba. Fructose 1,6-bisphosptase (FBP) gene has been found to play a key role in plant photosynthesis, sugar accumulation and other growth processes. However, no systemic analysis of FBPs has been reported in N. cadamba. A total of six FBP genes were identifed and cloned based on the N. cadamba genome, and these FBP genes were sorted into four groups. The characteristics of the NcFBP gene family were analyzed such as phylogenetic relationships, gene structures, conserved motifs, and expression patterns. A cis-acting element related to circadian control was first found in the promoter region of FBP gene. Phylogenetic and quantitative real-time PCR analyses showed that NcFBP5 and NcFBP6 may be chloroplast type 1 FBP and cytoplasmic FBP, respectively. FBP proteins from N. cadamba and 22 other plant species were used for phylogenetic analyses, indicating that FBP family may have expanded during the evolution of algae to mosses and differentiated cpFBPase1 proteins in mosses. This work analyzes the internal relationship between the evolution and expression of the six NcFBPs, providing a scientific basis for the evolutionary pattern of plant FBPs, and promoting the functional studies of FBP genes.