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Phages and non-phage derived bacteria have evolved many anti-CRISPR proteins (Acrs) to escape the adaptive immune system of prokaryotes. Thus Acrs can be applied as a regulatory tool for gene edition by CRISPR system. Recently, a non-phage derived AcrVIA2 has been identified as an inhibitor that blocks the editing activity of Cas13a in vitro by binding to Cas13a. Here, we solved the crystal structure of AcrVIA2 at a resolution of 2.59 Å and confirmed that AcrVIA2 can bind to Helical-I domain in LshCas13a. Structural analysis show that the V-shaped acidic groove formed by β3-β3 hairpin of AcrVIA2 dimer is the key region that mediates the interaction between AcrVIA2 and Helical-I domain. In addition, we also reveal that Asp37 of AcrVIA2 plays an essential role in the functioning of the V-shaped acidic groove, and the functional dimer conformation of AcrVIA2 is stabilized by hydrogen bonds formed between Tyr41 of one monomer with Glu35 and Asp37 of the other monomer. These data expand the current understanding of the diverse interaction mechanisms between Acrs and Cas proteins, and also provide new ideas for the development of CRISPR-Cas13a regulatory tool.

High prevalence of obesity is attributable in part to consumption of highly palatable, fat-rich foods. However, the mechanism controlling dietary fat intake is largely unknown. In this study we investigated the role of brain-derived neurotrophic factor (BDNF) in the control of dietary fat intake in a mouse model that mimics the common human Val-to-Met (Val66Met) polymorphism that impairs BDNF release via the regulated secretory pathway. BdnfMet/Met mice gained weight much faster than wild-type (WT) mice and developed severe obesity due to marked hyperphagia when they were fed HFD. Hyperphagia in these mice worsened when the fat content in their diet was increased. Conversely, mice lacking leptin exhibited similar hyperphagia on chow and HFD. When 2 diets were provided simultaneously, WT and BdnfMet/Met mice showed a comparable preference for the more palatable diet rich in either fat or sucrose, indicating that increased hyperphagia on fat-rich diets in BdnfMet/Met mice is not due to enhanced hedonic drive. In support of this interpretation, WT and BdnfMet/Met mice increased calorie intake to a similar extent during the first day after chow was switched to HFD; however, WT mice decreased HFD intake faster than BdnfMet/Met mice in subsequent days. Furthermore, we found that refeeding after fasting or nocturnal feeding with HFD activated TrkB more strongly than with chow in the hypothalamus of WT mice, whereas TrkB activation under these 2 conditions was greatly attenuated in BdnfMet/Met mice. These results indicate that satiety factors generated during HFD feeding induce BDNF release to suppress excess dietary fat intake.

The newly defined Carboniferous Meishan Group, along the northern margin of the Dabie orogenic belt, provides unique opportunities to document the poorly understood Paleozoic tectonic evolution of the Dabie orogenic belt and the Paleozoic convergence between the North and South China blocks. We apply sandstone petrology, geochemistry, and U-Pb detrital-zircon geochronology to constrain the provenance of the Carboniferous Meishan Group and to document its potential tectonic significance. We conclude that the Meishan Group received most sediment directly from early Paleozoic continental island arc rocks that are currently missing in the Dabie orogenic belt, with minor contributions from middle Neoproterozoic magmatic rocks of the South China Block and recycling of Archean to Proterozoic basement rocks of both the North and South China blocks. Compilation and comparison of detrital zircons and geochemistry data of the Silurian–Devonian and Carboniferous units suggests that all of them share similar source areas, but that individual contributions from each source were different. These results support the hypothesis that the Dabie orogenic belt developed a similar Paleozoic accretionary system, and shares a similar tectonic history, with the Qinling orogenic belt. These provenance patterns can be explained by a model of oblique convergence between the North and South China blocks during the Paleozoic. The South China Block was obliquely subducted beneath the North China Block with its opening to the east, forming an eastward-widening sedimentary basin. As a result, the eastern part of the basin received more sediment from the northern passive margin of the South China Block, while the western part of the basin received more material from the southern active margin of the North China Block.

Distributary channels in large deltas can form a channel pattern similar to braided fluvial system or anastomosed fluvial system that have multichannel systems. Although both systems are of generally comparable platforms, their geometry, sedimentology, and facies associations may exhibit unique characteristics. Many ancient multichannel systems have been interpreted as braided patterns, but some are certainly anastomosed patterns. A reevaluation of ancient multichannel architectures and sedimentology patterns is needed to improve discrimination of braided and anastomosed patterns of multichannel systems. This study examines the characteristics of two modern anastomosed pattern channel systems. Those modern systems are compared to ancient examples in the lower Yanchang Formation, southwest Ordos Basin. This comparison indicates that the multichannel systems of the delta, southwest Ordos Basin, exhibit greater similarity to modern anastomosed channel systems of shallow-water deltas. Systems of low-sinuosity distributary channels and interdistributary bays or swamp islands are developed mainly between the channels, and there are no mouth bar deposits. Both modern and ancient multichannel systems suggest that low gradient slope is a significant controlling factor in the formation of anastomosed pattern channels in river-dominated deltas. The identification of anastomosed patterns plays a significant role in reservoir characterization and hydrocarbon exploration and production in delta systems.

The controlled release of anticancer drugs at the tumor site is a central challenge in treating cancer. To achieve this goal, our strategy was based on tumor-specific targeting and ultrasound-triggered release of an anticancer agent from liposomal nanocarriers. To enhance the ultrasound-triggered drug release, we incorporated a lipophilic sonosensitizer, chlorin e6 (Ce6) ester, into the lipid bilayer of liposomes. Additionally, asparagine-glycine-arginine (NGR) that binds to CD13, which is overexpressed in tumor cells, was introduced into these liposomes. Under the navigation effects of the NGR, the novel ultrasound-triggerable NGR-modified liposomal nanocarrier (NGR/UT-L) accumulates in tumor sites. Once irradiated by ultrasound in tumor tissues, the sonodynamic effect produced by Ce6 could create more efficient disruptions of the lipid bilayer of the liposomal nanocarriers. After encapsulating doxorubicin (DOX) as the model drug, the ultrasound triggered lipid bilayer breakdown can spring the immediate release of DOX, making it possible for ultrasound-responsive chemotherapy with great selectivity. By combining tumor-specific targeting and stimuli-responsive controlled release into one system, NGR/UT-L demonstrated a perfect antitumor effect. Moreover, this report provides an example of controlled-release by means of a novel class of ultrasound triggering systems.

By using data such as lithology, thin sections, sedimentary structure, particle size, logging facies signs, mercury intrusion, porosity and permeability from 34 wells, 11 types of sedimentary microfacies were divided in this study. Upon analysis, sedimentary microfacies exert significant control on reservoirs, and high quality reservoirs are primarily developed with the following sedimentary microfacies: gray sandy conglomerate in underwater distributary channels microfacies of fan delta fronts sub-facies, river-estuary dams and gray sandstones of distal bars on the front edge of the fan delta that have strong hydrodynamic conditions and good stability. Relatively good reservoirs are primarily distributed in the braided channel in fan-delta plains with brown sandy conglomerates, main channel of underwater distributary channels on the front edge of the fan delta with gray conglomerates and underwater distributary channel ends on the front edge of the fan delta with gray fine sandstones. With the stable tectonic background, Triassic sedimentary microfacies in the Mahu sag control the distribution and development of reservoirs. Therefore, sites of high quality reservoirs can be predicted by sedimentary microfacies, and this study provides guidance for oil and gas exploration. Keywords: Microfacies, Reservoir, Mahu sag, Junggar Basin

Since the outbreak of coronavirus disease (COVID-19) that was discovered in 2019 in Wuhan, China, no standard therapy guideline has been set despite the severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its high infectivity. The globally pandemic outbreak suggests that COVID-19 is highly infectious and difficult to control. A dual-combination of ribavirin and interferon-α has been the widely used regimen for the treatment of this disease in China. However, due to the varying results of treatment with these drugs, a novel antiviral combination therapy is urgently needed. This case reports the usage of lopinavir/ritonavir-based combination antiviral regimen for a patient with SARS-CoV-2 infection.

Permian carbon isotopic and clay mineralogical records were recovered from the carbonates in the Xikou section, a complete and uninterrupted Upper Carboniferous to Lower Triassic carbonate-dominated succession exposed in Zhen'an, Shaanxi Province, central China, which were used to document carbon isotopic signatures and climatic changes affecting the easternmost Paleo-Tethys region during the Permian. Both carbon isotope and clay mineralogical data suggest fluctuating climatic conditions and trends that can be approximately correlated with eastern Australian glaciations and North American craton during the Artinskian to Capitanian Stages. Two global carbon isotopic anomalies across the Permian-Triassic boundary and the Guadalupian-Lopingian Series boundary were detected for the first time in the stratigraphic record of the South Qinling micro-continental block. The Capitanian Stage comprises an early phase of climatic warming followed by a later phase of climatic cooling. The Kungurian Stage represents a climatic warming interval and the main phase of deglaciation during the Late Paleozoic Ice Age (LPIA). A δ13C positive shift across the boundary of the Artinskian to Kungurian Stages, together with the following negative excursion recorded in the early Kungurian Stage can be used as an indicator for the boundary between the Artinskian and Kungurian Stage.

The Songliao Basin, northeastern China, is one of the few ultra-large petroleum basins in the world. Fault superposition, linkage, and stratigraphic architecture have produced a complicated basin evolutionary history. In this study, we report the boundary fault linkage and associated Upper Jurassic and Lower Cretaceous stratigraphic record using 3D seismic reflection data and well data. Our results show that the geometry of the boundary Gudian fault was originally controlled by six shorter fault segments, which grew and were linked during a syn-rift stage, then frictionally weakened and inverted in a post-rift stage. This boundary fault has variably controlled coeval syn-rift sedimentation. Fault segments in the middle section controlled the development of the limited, but thickest, Huoshiling and the first member of Shahezi Formations in the early syn-rift stage (ca. 150–133.9 Ma). Later, that control gradually weakened and vanished on succeeding the second member of Shahezi and Yingcheng Formations in the late syn-rift stage (ca. 133.9–105 Ma). The processes and the diverse syn-rift sedimentation response to Gudian fault growth and linkage have further implications for graben evolution and can guide hydrocarbon exploration in the Songliao Basin. This study will help elucidate the different controls of boundary fault linkage on associated sedimentation, as well as rift basins development in eastern China and similar areas throughout the world.

Detrital zircon U–Pb geochronology, and Hf isotope compositional data for Permian strata near Xikou, Zhen’an in the South Qinling belt help constrain the tectonic evolutionary history of the Qinlin...

Early Pennsylvanian sediment dispersal across the Laurentian supercontinent reflects the growth of the Appalachian–Ouachita Orogen that was formed by its collision with Gondwana. Occupying a key position within the Laurentian foreland of the Appalachian–Ouachita Orogen, the middle Bloyd sandstone member of the Bloyd Formation (Early Pennsylvanian) preserves evidence of Morrowan-age fluvio-deltaic depocenters in the southern Laurentian continental margin. The middle Bloyd sandstone provides direct constraints on provenance and dispersal paths of detritus shed from the Appalachian–Ouachita Orogen and other sediment sources on the North American craton during the Early Pennsylvanian. Eight outcrop samples of the middle Bloyd sandstone were collected and analyzed by U-Pb laser ablation ICP-MS detrital-zircon geochronology, producing a total of 850 concordant individual detrital-zircon ages with age ranging from 3.15 Ga to 374 Ma. Detrital-zircon age spectra of the eight middle Bloyd sandstone samples are characterized by a prominent Grenvillian age group (∼ 1350–900 Ma) with two discrete age peaks at ∼ 1070 and ∼ 1169 Ma. The remaining zircon fractions are interpreted as being sourced from the Archean Superior Province (> ∼ 2500 Ma), the Penokean and Trans-Hudson Proterozoic terranes (∼ 1900–1800 Ma), the Yavapai–Mazatzal terrane (∼ 1800–1600 Ma), the Granite–Rhyolite Province (∼ 1600–1350 Ma), and a minor Paleozoic age population (∼ 500–350 Ma) that likely reflects mixed Appalachian and Gondwanan sources. Overall, detrital-zircon age populations of the middle Bloyd sandstone share great similarity with Lower Pennsylvanian sandstones from the Michigan Basin and the central and southern Appalachian foreland, except that the Bloyd sandstone shows greater enrichment in the Yavapai–Mazatzal age population. These new age data provide additional constraints on multiple dispersal paths for fundamentally Laurentian-derived sediment that are ultimately directed southward toward the Ouachita foreland shelf during the Early Pennsylvanian. The Early Pennsylvanian (Morrowan) sediment dispersal in this part of Laurentia was accomplished by a regional-scale drainage system that integrated intracratonic and Appalachian–Ouachita foreland basin depocenters, all recording a recycled orogenic provenance. The new detrital-zircon data indicate that the middle Bloyd sandstone also incorporated significant contributions from Precambrian-age basement uplifts, possibly Ancestral Rocky Mountain uplifts to the west, indicating a complex geography of the Laurentian supercontinent at this time.

In contrast to typical intracratonic basins, the Ordos Basin comprises marginal deformation belts and complex fault systems. This study uses 3D seismic data tied to sonic and stratigraphic data from exploration wells, to document the geographic extend of the Porjianghaizi fault and its control on sedimentation and gas accumulation in the northern Ordos Basin. Our results show that the geometry of large Porjianghaizi fault is controlled by five small fault segments. The growth history of the Porjianghaizi fault composes four stages: (1) an initiation stage (Late Carboniferous to Early Permian); (2) a reactivation stage during the Late Triassic; (3) an inversion stage during the Middle Jurassic; and (4) an interaction and linkage stage during the Late Jurassic. Detailed studies show that the Porjianghaizi fault had significant control on sedimentation and gas accumulation. During the initiation stage (Late Carboniferous to Early Permian), five fault segments and associated relay ramps controlled the sedimentation in the study area. The relay ramps formed transport pathways in which sediment extended from north basin margin to the basin center. In contrast, sedimentation along the fault was more localized. Based on Shale Gouge Ratios (SGR) and formation water salinity, the fault sealing capacity of the Porjianghaizi fault is characterised by “horizontal segmentation”, which means the fault composes laterally sealed areas and laterally connected areas along the fault strike. As a corollary, we propose that gas resources were mainly generated from the south where there are thick source rocks, migrating vertically through interbedded open fractures first, and then laterally through the junction zone of fault (relay ramps). It eventually accumulated in structural traps found in the northern areas. Understanding the evolution of the Porjianghaizi fault is important for predicting the distribution of sedimentary facies in Upper Carboniferous and Lower Permian units. As well as understanding the migration and distribution of gas resources in the north Ordos Basin, these results can further help in hydrocarbon exploration in the north Ordos Basin.

Therapeutic outcome for the treatment of glioma was often limited due to the non-targeted nature and low permeability of drugs across the blood-brain barrier (BBB). An ideal glioma-targeted delivery system need to traverse the BBB and then target glioma cells with adequate optimized physiochemical properties and biocompatibility. However, it is an enormous challenge to the researchers to engineer the above-mentioned features into a single nanocarrier particle. New frontiers in nanomedicine are advancing the research of new biomaterials. In this study, we demonstrate a strategy for glioma targeting by encapsulating vincristine sulfate (VCR) into a naturally available low-density lipoprotein particles (LDL)-based drug delivery system with the modification of T7 peptide ligand (T7-LDL). LDL, endogenous lipid transporters, can specifically bind to brain endothelial cells and glioma cells via interacting with the low-density lipoprotein receptors (LDLR). T7 is a seven-peptide ligand of transferrin receptors (TfR) capable of circumventing the BBB and then targeting glioma. By combining the dual-targeting delivery effect of T7 peptide and parent LDL, T7-LDL displayed higher glioma localization than that of parent LDL. After loading with VCR, T7-LDL showed the most favorable antiglioma effect in vitro and in vivo. These results demonstrated that T7-LDL is an important potential drug delivery system for glioma-targeted therapy.

To construct an artificial low-density lipoprotein (aLDL) that highly mimics low-density lipoprotein (LDL) in vivo, and deliver vincristine (VCR) - doxorubicin (DOX) simultaneously, the 100 nm and 35 nm DOX-VCR-aLDLs (DV-aLDLs) were constructed, then the physicochemical characteristics were evaluated. Through in vitro inverse gravity diffusion experiment, the tumour cake and sphere model experiment, draw a conclusion that the diffusion of 35 nm DV-aLDLs was stronger than 100 nm DV-aLDLs, and the tumour retention of 35 nm DV-aLDLs was better than the DV-solution. In addition, the three-dimension (3D) in vivo distribution imaging of aLDLs was performed on HepG-2 tumour-bearing nude mice, followed by the biodistribution and therapeutic efficacy on these xenograft models. Taking advantage of better diffusion capacity in tumour tissue, as well as the synergistic effect of VCR and DOX, the 35 nm DV-aLDL had the strongest efficacy and the lowest toxicity. High entrapment efficiency and stability, both active and passive targeting, making aLDL a potential carrier for tumour-targeted therapy at the same time.

Controversies over the origin of globally distributed Cretaceous red beds have mainly focused on climate vs. weathering with potential hydrothermal influence. In comparison to Cretaceous Oceanic Red Beds, Cretaceous lacustrine red beds exhibit chronological inconsistencies and their diverse tectonic settings suggest differing genetic mechanisms. In this paper, Early Cretaceous red beds in the North Yellow Sea Basin, one of Mesozoic rift basins in eastern China that are associated with multi-phase magmatic activities, was chosen to document potential hydrothermal impact. Geological and geochemical analyses show that these red beds were syndepositional products developed in shallow to moderately deep lacustrine environments and that they were influenced by hydrothermal activity. Major and trace elements, including enhanced Al 2 O 3 -normalized Fe 2 O 3 and Fe 2 O 3 (total) values, Al/(Al + Fe + Mn) and (Fe + Mn)/Ti ratios, Ni-Co-Zn and Fe-Mn-(Ni + Co + Cu)*10, ∑REE-La/Yb, the concentrations of hydrothermally-related ions, invalid redox indicators of trace elements, abnormally high Fe 2 O 3 (total) content, positive Eu anomaly, correlation of Fe 2 O 3 (total) and Eu anomaly, and vitrinite reflectance (Ro) vs. total organic carbon (TOC), all show strong hydrothermal fluid influence and heating effects. By integrating and comparing data from previous studies, we propose a hydrothermally affected sedimentation model for Cretaceous red beds and associated sediments in magma-activated lacustrine basins, and conclude that the enriched metallic ions introduced by the hydrothermal fluids may be the most significant reason for the deposition of the red beds, and the flushed ferric ions, accompanied by hydrothermal fluid, are the main ions that are hosted inside hematite causing the red sediment. This model can be applied to similar lacustrine basins that experience strong magmatic activity.

A series of Mesozoic rift basins formed in eastern China were associated with magmatic activity and subduction along the Eurasia, Izanagi and Pacific plate margins. The impact of magmatic activity on lacustrine sequence development was documented with well-log and 3-D seismic data from the Jupiter Depression in the North Yellow Sea Basin. We identified key surfaces, retrogradational and progradational parasequence sets, and defined the characteristics of systems tracts and the internal sequence components for the Lower Cretaceous (K1SQ1). A 2-D SEDPAK numerical stratigraphic forward modeling was used to further constrain sequence development in the Jupiter Depression by considering different modeling parameters and the spatial-temporal characteristics of magmatic activity. Modeling results were compared and matched with the sequence architecture observed from seismic and well interpretations. Magmatic activity impacts on the development of the K1SQ1 sequence in the North Yellow Sea Basin include topographic variation, lake level fluctuation, and sediment supply ratios. Results suggest that magmatic upwelling uplifted the northwestern area of the Jupiter Depression and formed its slope break during the late Jurassic or early Cretaceous. Along with uplifting, relative lake level dropped sharply and lake accommodation was reduced, but with increased sediment supply. Therefore, sediment accumulated along the slope break as a lowstand systems tract. Later on, as lake level continuously rose, transgressive and highstand systems tracts were developed. The proposed stacking pattern provides an analog, and a useful model, for lacustrine sequence development in response to magmatic activities in eastern China and other rift basins of similar tectonic setting.

The Fort Worth basin in northcentral Texas is a major shale-gas producer, yet its subsidence history and relationship to the Ouachita fold-thrust belt have not been well understood. We studied the depositional patterns of the basin during the late Paleozoic by correlating well logs and constructing structure and isopach maps. We then modeled the one-dimensional (1-D) and two-dimensional subsidence history of the basin and constrained its relationship to the Ouachita orogen. Because the super-Middle Pennsylvanian strata were largely eroded in the region, adding uncertainty to the subsidence reconstruction, we used PetroMod 1-D to conduct thermal-maturation modeling to constrain the post-Middle Pennsylvanian burial and exhumation history by matching the modeled vitrinite reflectance with measured vitrinite reflectance along five depth profiles. Our results of depositional patterns show that the tectonic uplift of the Muenster uplift to the northeast of the basin influenced subsidence as early as the Middle Mississippian, and the Ouachita orogen became the primary tectonic load by the late Middle Pennsylvanian when the depocenter shifted to the east. Our results show that the basin experienced 3.7–5.2 km (12,100–17,100 ft) of burial during the Pennsylvanian, and the burial depth deepens toward the east. We attributed the causes of deep Pennsylvanian burial and its spatial variation to flexural subsidence that continued into the Late Pennsylvanian in response to the growth of the Ouachita orogen and southeastward suturing of Laurentia and Gondwana. The modeling results also suggest that the Mississippian Barnett Shale reached the gas maturation window during the Middle–Late Pennsylvanian.

Obesity has been an epidemic worldwide over the past decades and significantly increases the risk of developing a variety of deadly diseases including type 2 diabetes, cardiovascular diseases and many cancers. The relationship between obesity and type 2 diabetes and cardiovascular disease has been well documented. The drastically increased frequency of a number of cancers in obesity has attracted growing interest. On one hand, how increased adiposity promotes cancer development remains poorly understood, despite the fact that considerable epidemiological evidence has suggested links between them. On the other hand, however, numerous studies have shown that tumorigenesis leads to substantial weight loss in a large portion of cancer patients. Here, we summarize the recent advances on our understanding of the link between obesity and cancer development with a focus on the molecular mechanisms accounting for the rising cancer incidence in the context of obesity. In addition, we also discuss how cancer-associated anorexia and cachexia causes weight loss. © 2017 IUBMB Life, 69(10):776-784, 2017.

Combination of metolazone (0.5 mg) and valsartan (80 mg) has been verified as a promising therapy treatment for hypertension. In order to facilitate to pharmacokinetic research, it needs a method for the simultaneously determination of metolazone and valsartan in biological samples. However, there are no relative reports so far. In order to facilitate to pharmacokinetic research, an on-line solid phase extraction coupled with liquid chromatography-tandem mass spectrometry method for the simultaneous determination of metolazone and valsartan in beagle dog plasma was developed and validated in this study. An on-line solid phase extraction column Retain PEP Javelin (10 mm × 2.1 mm) was used to remove impurities in plasma samples. The metolazone, valsartan and internal standard (losartan) were separated on a Poroshell 120 SB-C18 column (4.6 mm × 50 mm × 2.7 µm) with a gradient elution procedure. Acidified acetonitrile/water mixture was used as a mobile phase. The selected multiple-reaction monitoring mode in positive ion was performed and the parent to the product transitions m/z 366/259, m/z 436.2/291 and m/z 423.4/207 were used to measure the metolazone, valsartan and losartan. The method was linear over the range of 0.1–100 ng/mL and 1–1000 ng/mL for metolazone and valsartan, respectively. This method was validated in terms of specificity, linearity, sensitivity, precision, accuracy, matrix effect, and stability and then successfully applied to pharmacokinetic studies of the metolazone and valsartan combination tablets in beagle dogs.

Excessive reactive oxygen species (ROS) is highly involved in inflammation and the pathogenesis of infectious diseases As a potent scavenger of ROS, peroxiredo

Additional file 2. Raw data of mitoROS and apoptosis that measured by flow of cytometry.

Additional file 1: Table S1. Real Time PCR Primers and Conditions. Table S2. Characteristics of the biomimetic nanoparticles (NPs). Table S3. Pharmacokinetic parameters of different biomimetic NPs. Table S4. Transendothelial electrical resistance of co-culture cells. Figure S1. Stability of various biomimetic formulations in the presence of 10 % FBS in PBS at 37 °C. The delta transmission (∆T) and backscattering (∆BS) profiles were measured at each time point using a Turbiscan Lab® Expert analyser. Figure S2. Cytotoxicity of PCNP(a), RPCNP (b), T807/RPCNP (c) NPs at different concentrations in HT22 cells. Figure S3. Inhibition of OA-induced cell death of HT22 cells after exposure to 40 nM OA for 12 h and then treated with different concentration of CUR(a), PCNP-CUR(b), RPCNP-CUR(c), T807/RPCNP-CUR(d) and T807/RPCNP(e) for another 12 h. Figure S4. An in vitro blood–brain barrier (BBB) model being composed of co-culture with endothelial (RBMVEC), astrocyte (As) and HT22 cells was established to evaluate the transcytosis of biomimetic formulations. Figure S5. Total p-Tau levels after treatment by different CUR-tagged formulations in OA-induced AD mice. The data are presented as the means ± SD (n = 5). ** indicates p