Implantable Patch of Oxidized Nanofibrillated Cellulose and Lysozyme Amyloid Nanofibrils for the Regeneration of Infarcted Myocardium Tissue and Local Delivery of RNA-Loaded Nanoparticles.

Biopolymeric implantable patches are popular scaffolds for myocardial regeneration applications. Besides being biocompatible, they can be tailored to have required properties and functionalities for this application. Recently, fibrillar biobased nanostructures prove to be valuable in the development of functional biomaterials for tissue regeneration applications. Here, periodate-oxidized nanofibrillated cellulose (OxNFC) is blended with lysozyme amyloid nanofibrils (LNFs) to prepare a self-crosslinkable patch for myocardial implantation. The OxNFC:LNFs patch shows superior wet mechanical properties (60 MPa for Young's modulus and 1.5 MPa for tensile stress at tensile strength), antioxidant activity (70% scavenging activity under 24 h), and bioresorbability ratio (80% under 91 days), when compared to the patches composed solely of NFC or OxNFC. These improvements are achieved while preserving the morphology, required thermal stability for sterilization, and biocompatibility toward rat cardiomyoblast cells. Additionally, both OxNFC and OxNFC:LNFs patches reveal the ability to act as efficient vehicles to deliver spermine modified acetalated dextran nanoparticles, loaded with small interfering RNA, with 80% of delivery after 5 days. This study highlights the value of simply blending OxNFC and LNFs, synergistically combining their key properties and functionalities, resulting in a biopolymeric patch that comprises valuable characteristics for myocardial regeneration applications.

Long-term application of silver nanoparticles in dental restoration materials: potential toxic injury to the CNS.

Silver nanoparticles (AgNPs) have durable and remarkable antimicrobial effects on pathogenic microorganisms, such as bacteria and fungi, in dental plaques. As such, they are widely added to dental restoration materials, including composite resins, denture bases, adhesives, and implants, to solve the problems of denture stomatitis, peri-implant inflammation, and oral infection caused by the long-term use of these dental restoration materials. However, AgNPs can be absorbed into the blood circulatory system through the nasal/oral mucosa, lungs, gastrointestinal tract, skin, and other pathways and then distributed into the lungs, kidneys, liver, spleen, and testes, thereby causing toxic injury to these tissues and organs. It can even be transported across the blood-brain barrier (BBB) and continuously accumulate in brain tissues, causing injury and dysfunction of neurons and glial cells; consequently, neurotoxicity occurs. Other nanomaterials with antibacterial or remineralization properties are added to dental restoration materials with AgNPs. However, studies have yet to reveal the neurotoxicity caused by dental restoration materials containing AgNPs. In this review, we summarize the application of AgNPs in dental restoration materials, the mechanism of AgNPs in cytotoxicity and toxic injury to the BBB, and the related research on the accumulation of AgNPs to cause changes of neurotoxicity. We also discuss the mechanisms of neurotoxicity caused by AgNPs and the mode and rate of AgNPs released from dental restorative materials added with AgNPs to evaluate the probability of neurotoxic injury to the central nervous system (CNS), and then provide a theoretical basis for developing new composite dental restoration materials. Mechanism of neurotoxicity caused by AgNPs: AgNPs in the blood circulation enter the brain tissue after being transported across the BBB through transendothelial cell pathway and paracellular transport pathway, and continuously accumulate in brain tissue, causing damage and dysfunction of neurons and glial cells which ultimately leads to neurotoxicity. The uptake of AgNPs by neurons, astrocytes and microglia causes damage to these cells. AgNPs with non-neurotoxic level often increases the secretion of a variety of cytokines, up-regulates the expression of metallothionein in glial cells, even up-regulates autophagy and inflammation response to protect neurons from the toxic damage of AgNPs. However, the protective effect of glial cells induced by AgNPs exposure to neurotoxic levels is insufficient, which leads to neuronal damage and dysfunction and even neuronal programmed cell death, eventually cause neurotoxicity.

Repair mechanism of Yishen Tongluo formula on mouse sperm DNA fragmentation caused by polystyrene microplastics.

CONTEXT: Plastics can break down into millions of microplastic (MPs, < 5 mm) particles in the soil and ocean. These MPs can then affect the function of the reproductive system. There is currently no effective solution to this problem aside from traditional Chinese medicine. We have previously used Yishen Tongluo formula (YSTL) to treat sperm DNA damage caused by some toxic substances. OBJECTIVE: To investigate the mechanism underlying the repair of mouse sperm DNA fragmentation caused by polystyrene microplastics by YSTL. MATERIALS AND METHODS: An animal model of polystyrene microplastic (PS-MP)-induced sperm DNA damage was replicated by gavage of SPF ICR (CD1) mice PS-MPs at 1 mg/d and treated with YSTL at 11.89, 23.78 and 47.56 g/kg, respectively, for 60 days. The Sperm DNA fragmentation index (DFI) of each group was detected and compared. The target genes of YSTL identified by transcriptomic and proteomic analyses were validated by qRT-PCR and western blotting. RESULTS: The DFI of the PS group (20.66%) was significantly higher than that of the control group (4.23%). The medium and high doses of the YSTL group (12.8% and 11.31%) exhibited a significant repairing effect. The most enriched pathway was PI3K/Akt. TBL1X, SPARC, hnRNP0, Map7D1, Eps8 and Mrpl27 were screened and SPARC was validated. DISCUSSION AND CONCLUSIONS: The precise mechanism by which YSTL inhibits PD-MPs DNA damage may be associated with the PI3K/Akt pathway and SPARC. It provides a new direction for using traditional Chinese medicine to prevent and repair reproductive system injury caused by MPs.

Synthesis of Starch-Based Amphiphilic Fluorescent Nanoparticles and Their Application in Biological Imaging.

Due to the extensive source, good biocompatibility and biodegradability, the starch of carbohydrates has been extensively investigated for application in biological field. Recently, the development of fluorescent organic nanoparticles (FONs) on the basis of aggregation induced emission (AIE) dyes has attracted great research interest. In this article, novel starch-based S-TPEV polymers with AIE property were successfully fabricated by atom transfer radical polymerization (ATRP) of TPEV dye into water-soluble starch for the first time, subsequently, their structure and properties were detailedly investigated by 1H NMR, TEM, UV-vis, FL and FTIR. The characterization results confirmed the successful synthesis of S-TPEV polymers, and the molar fraction of TPEV and C6H10O5 ring in the starch polymers could be respectively calculated as approximate 5.8% and 94.2%. In aqueous solution, the as-prepared S-TPEV polymers will tend to self-assemble into FONs with 100-200 nm diameters, and their fluorescence intensity increased with the increase of the concentration of water in the mixed solution of water and DMSO, indicative of the obvious AIE property. More importantly, owing to their high water dispersity, good fluorescence and excellent biocompatibility, the S-TPEV FONs can be uptaken by HepG2 cells and show promising application in biological imaging field.

New materials of plesiacerathere (Perissodactyla, Rhinocerotidae) from the late Early Miocene of Northern China.

As a member of Aceratheriinae, the genus Plesiaceratherium in Europe is widely distributed and highly diverse. However, only one species of Plesiaceratherium (i.e., P. gracile) exists in China with a discontinuous distribution range. Recently, we have discovered new materials of Plesiaceratherium in the lower layers of the Zhang'enbao Formation exposed in Miaoerling in Tongxin County, China. The new materials are well-preserved and can be separated from other Plesiaceratherium species by the following combination of features: the long and generally flat skull, with closed frontoparietal crests; the deep nasal notch at the level of P4; the high supraorbital margin, with its anterior margin at the level of the M1/M2 boundary; the medium-sized upper I1, with an oval abraded surface; the semi-molarized upper premolars with the protocone and hypocone joined by a lingual bridge; the strong constrictions of protocone on the upper molars; the absent buccal cingulum on upper cheek teeth; the cheek teeth are covered by cement on the buccal walls; the convex base of mandibular corpus; the inclined backward ramus; and the mandibular foramen above the teeth neck. Based on the combination of characteristics and phylogenetic analysis, we herein establish the new species as Plesiaceratherium tongxinense sp. nov. living in the late Early Miocene. Phylogenetic analysis reveals that P. tongxinense is in the basal position of the genus Plesiaceratherium, providing more detailed morphological characteristics of the plesiaceratheres.

The trunk replaces the longer mandible as the main feeding organ in elephant evolution.

The long-trunked elephantids underwent a significant evolutionary stage characterized by an exceptionally elongated mandible. The initial elongation and subsequent regression of the long mandible, along with its co-evolution with the trunk, present an intriguing issue that remains incompletely understood. Through comparative functional and eco-morphological investigations, as well as feeding preference analysis, we reconstructed the feeding behavior of major groups of longirostrine elephantiforms. In the Platybelodon clade, the rapid evolutionary changes observed in the narial region, strongly correlated with mandible and tusk characteristics, suggest a crucial evolutionary transition where feeding function shifted from the mandible to the trunk, allowing proboscideans to expand their niches to more open regions. This functional shift further resulted in elephantids relying solely on their trunks for feeding. Our research provides insights into how unique environmental pressures shape the extreme evolution of organs, particularly in large mammals that developed various peculiar adaptations during the late Cenozoic global cooling trends.

The elephant's trunk is one of the most efficient food-gathering organs in the animal kingdom. From large branches to thin blades of grass, it can coil around and bring many types of vegetation to the animals' strong, short mandibles. This versatility allows elephants to thrive in a range of environments, including grasslands. Trunks are not the only spectacular feature to emerge in Proboscideans, the family of which elephants are the only surviving group. During the early and middle Miocene (between 23 to 11.6 million years ago), many of these species had dramatically elongated lower jaws; how and why this trait emerged then disappeared is poorly understood. The role that lengthened mandibles and trunks played during feeding also remains unclear. To address these questions, Li et al. focused on Platybelodon, Choerolophodon and Gomphotherium, which belong to three Proboscidean families that roamed Northern China between 17 and 15 million years ago. Each had elongated lower jaws, but with strikingly distinct lengths and morphologies. Chemical analyses on enamel samples helped determine which habitat the families occupied, while mathematical modelling revealed how their mandibles tackled different types of plants. Trunk shape was assessed via analyses of the nasal region. The results suggest that Choerolophodon had mandibles better suited for processing branches and a short, 'primitive' trunk. Gomphotherium sported a versatile jaw that could handle both grass and trees, as well as a rather 'elephant-like' trunk. The jaw of Platybelodon seemed well-adapted to cut grass, and remarkable bone structures point towards a long, strong and flexible trunk. While modern elephants fully depend on their trunks to eat, morphological constraints suggest that, in these species, the appendage only served to assist feeding (e.g., by pressing down on branches). All families shared an environment that included grasslands and forests, but analyses suggest that, for a period, Choerolophodon favored relatively closed habitats while Platybelodon spread into grasslands and Gomphotherium navigated both landscapes. This suggests that the evolution of long, strong and flexible trunks is tightly associated with grazing. About 14 million years ago, a global cooling event led to grasslands expanding worldwide. The fossil record shows the mandibles of Proboscideans starting to shorten after this period, including in the descendants of Gomphotherium that would give rise to modern elephants. The work by Li et al. sheds light onto these evolutionary processes, and the environmental pressures which helped shape the trunk.

Co-delivery of camptothecin and MiR-145 by lipid nanoparticles for MRI-visible targeted therapy of hepatocellular carcinoma.

BACKGROUND: Camptothecin (CPT) is one of the frequently used small chemotherapy drugs for treating hepatocellular carcinoma (HCC), but its clinical application is limited due to severe toxicities and acquired resistance. Combined chemo-gene therapy has been reported to be an effective strategy for counteracting drug resistance while sensitizing cancer cells to cytotoxic agents. Thus, we hypothesized that combining CPT with miR-145 could synergistically suppress tumor proliferation and enhance anti-tumor activity. METHODS: Lactobionic acid (LA) modified lipid nanoparticles (LNPs) were developed to co-deliver CPT and miR-145 into asialoglycoprotein receptors-expressing HCC in vitro and in vivo. We evaluated the synergetic antitumor effect of miR-145 and CPT using CCK8, Western blotting, apoptosis and wound scratch assay in vitro, and the mechanisms underlying the synergetic antitumor effects were further investigated. Tumor inhibitory efficacy, safety evaluation and MRI-visible ability were assessed using diethylnitrosamine (DEN) + CCl4-induced HCC mouse model. RESULTS: The LA modification improved the targeting delivery of cargos to HCC cells and tissues. The LA-CMGL-mediated co-delivery of miR-145 and CPT is more effective on tumor inhibitory than LA-CPT-L or LA-miR-145-L treatment alone, both in vitro and in vivo, with almost no side effects during the treatment period. Mechanistically, miR-145 likely induces apoptosis by targeting SUMO-specific peptidase 1 (SENP1)-mediated hexokinase (HK2) SUMOylation and glycolysis pathways and, in turn, sensitizing the cancer cells to CPT. In vitro and in vivo tests confirmed that the loaded Gd-DOTA served as an effective T1-weighted contrast agent for noninvasive tumor detection as well as real-time monitoring of drug delivery and biodistribution. CONCLUSIONS: The LA-CMGL-mediated co-delivery of miR-145 and CPT displays a synergistic therapy against HCC. The novel MRI-visible, actively targeted chemo-gene co-delivery system for HCC therapy provides a scientific basis and a useful idea for the development of HCC treatment strategies in the future.

Is continuous venovenous hemofiltration effective against severe acute pancreatitis?

Our aim was to investigate the efficacy of continuous venovenous hemofiltration (CVVH) in treating severe acute pancreatitis (SAP). A literature search was performed using PubMed (1992-present), and all studies investigating the efficacy of CVVH in treating SAP were included. Four comparative studies and seven case series comprising a total of 354 patients were included. The overall mortality rate of patients receiving CVVH was 20% (55/275). A decreased mortality rate and decreased serum cytokine levels were reported in the CVVH groups in only two studies. The starting time point, substitution fluid flow rate, filter membrane type, hemofilter change interval, anticoagulation, and sustaining times of CVVH varied among the studies, and the impact of these parameters on the efficacy of CVVH was poorly reported. High-volume CVVH, when started early, was demonstrated to be more effective in eliminating cytokines in only one study. After the application of CVVH, the patient conditions started to improve between the 6th and 72nd hours. In conclusion, no solid clinical evidence has proven the efficacy of CVVH in treating SAP. High-volume CVVH that is started early and sustained for at least 72 h may be adopted to investigate the efficacy of CVVH for treating SAP.

Braided scaffolds with polypyrrole/polydopamine/hydroxyapatite coatings with electrical conductivity and osteogenic properties for bone tissue engineering.

When impaired bones are grafted with bone scaffolds, the behaviors of osteoblast are dependent on the implant materials and surface morphology. To this end, we modulated the surface morphology of scaffolds that promote cell growth. In this study, ice-template and spraying method methods are employed to coat different proportions of PDA and PPy over the PLA/PVA weaving scaffolds, after which HA is Coated over via the electrochemical deposition, forming weaving scaffolds with electrically conductive PDA/PPy/HA coating. The test results indicate that with a PPy/PDA concentration ratio is 30, the PPy particles are more uniformly distributed on the fiber surface. The scaffolds are wrapped in a HA coating layer with a high purity, and calcium and phosphorus elements are evenly dispersed with a Ca/P ratio being 1.69. Owing to the synergistic effect between PDA and PPy coating, the scaffolds demonstrate excellent electrochemical stability and electrochemical activity. The biological activity of the scaffold increased to 274.66% under electrical stimulation. The new thinking proposed by this study extends the worth of applying textile structure to the medical field, the application of which highly increases the prospect of bone tissue engineering.

Quantitative Analysis of Porous Silicon Nanoparticles Functionalization by 1H NMR.

Porous silicon (PSi) nanoparticles have been applied in various fields, such as catalysis, imaging, and biomedical applications, because of their large specific surface area, easily modifiable surface chemistry, biocompatibility, and biodegradability. For biomedical applications, it is important to precisely control the surface modification of PSi-based materials and quantify the functionalization density, which determines the nanoparticle's behavior in the biological system. Therefore, we propose here an optimized solution to quantify the functionalization groups on PSi, based on the nuclear magnetic resonance (NMR) method by combining the hydrolysis with standard 1H NMR experiments. We optimized the hydrolysis conditions to degrade the PSi, providing mobility to the molecules for NMR detection. The NMR parameters were also optimized by relaxation delay and the number of scans to provide reliable NMR spectra. With an internal standard, we quantitatively analyzed the surficial amine groups and their sequential modification of polyethylene glycol. Our investigation provides a reliable, fast, and straightforward method in quantitative analysis of the surficial modification characterization of PSi requiring a small amount of sample.

Sexual selection promotes giraffoid head-neck evolution and ecological adaptation.

The long neck of the giraffe has been held as a classic example of adaptive evolution since Darwin's time. Here we report on an unusual fossil giraffoid, Discokeryx xiezhi, from the early Miocene, which has an unusual disk-shaped headgear and the most complicated head-neck joints in known mammals. The distinctive morphology and our finite element analyses indicate an adaptation for fierce head-butting behavior. Tooth enamel isotope data suggest that D. xiezhi occupied a niche different from that of other herbivores, comparable to the characteristic high-level browsing niche of modern giraffes. The study shows that giraffoids exhibit a higher headgear diversity than other ruminants and that living in specific ecological niches may have fostered various intraspecific combat behaviors that resulted in extreme head-neck morphologies in different giraffoid lineages.

Glucose-responsive microneedle patch for closed-loop dual-hormone delivery in mice and pigs.

Insulin and glucagon secreted from the pancreas with dynamic balance play a vital role in regulating blood glucose levels. Although distinct glucose-responsive insulin delivery systems have been developed, the lack of a self-regulated glucagon release module limits their clinical applications due to the potential risk of hypoglycemia. Here, we describe a transdermal polymeric microneedle patch for glucose-responsive closed-loop insulin and glucagon delivery to achieve glycemic regulation with minimized risk of hypoglycemia. The glucose-responsive phenylboronic acid units can bind to glucose to reversibly shift the net charge (from positive to negative) of the entire polymeric matrix within microneedles. Therefore, the release ratio of the negatively charged insulin and the positively charged glucagon analog from the patch can be dynamically tuned upon the fluctuation of blood glucose levels to realize glycemic homeostasis. In both chemically induced type 1 diabetic mouse and minipig models, this glucose-responsive dual-hormone microneedle patch demonstrated tight long-term regulation in blood glucose levels (>24 hours in minipigs).

A pH-Responsive Cluster Metal-Organic Framework Nanoparticle for Enhanced Tumor Accumulation and Antitumor Effect.

As a result of the deficient tumor-specific antigens, potential off-target effect, and influence of protein corona, metal-organic framework nanoparticles have inadequate accumulation in tumor tissues, limiting their therapeutic effects. In this work, a pH-responsive linker (L) is prepared by covalently modifying oleylamine (OA) with 3-(bromomethyl)-4-methyl-2,5-furandione (MMfu) and poly(ethylene glycol) (PEG). Then, the L is embedded into a solid lipid nanoshell to coat apilimod (Ap)-loaded zeolitic imidazolate framework (Ap-ZIF) to form Ap-ZIF@SLN#L. Under the tumor microenvironment, the hydrophilic PEG and MMfu are removed, exposing the hydrophobic OA on Ap-ZIF@SLN#L, increasing their uptake in cancer cells and accumulation in the tumor. The ZIF@SLN#L nanoparticle induces reactive oxygen species (ROS). Ap released from Ap-ZIF@SLN#L significantly promotes intracellular ROS and lactate dehydrogenase generation. Ap-ZIF@SLN#L inhibits tumor growth, increases the survival rate in mice, activates the tumor microenvironment, and improves the infiltration of macrophages and T cells in the tumor, as demonstrated in two different tumor-bearing mice after injections with Ap-ZIF@SLN#TL. Furthermore, mice show normal tissue structure of the main organs and the normal serum level in alanine aminotransferase and aspartate aminotransferase after treatment with the nanoparticles. Overall, this pH-responsive targeting strategy improves nanoparticle accumulation in tumors with enhanced therapeutic effects.

Dual-Crosslinked Dynamic Hydrogel Incorporating {Mo154 } with pH and NIR Responsiveness for Chemo-Photothermal Therapy.

Polyoxometalates are an emerging class of molecular clusters, with well-defined structures and chemical compositions that are produced through simple, low-cost, and highly reproducible methods. In particular, the wheel-shaped cluster {Mo154 } is a promising photothermal agent due to its intervalence charge transfer transitions. However, its toxicity hinders its systemic administration, being the development of a localized delivery system still incipient. Herein, an injectable and self-healing hydrogel of easy preparation and administration is developed, incorporating both {Mo154 } and doxorubicin for synergistic photothermal and chemotherapy applications. The hydrogel is composed of benzylaldehyde functionalized polyethylene glycol, poly(N-isopropylacrylamide) functionalized chitosan and {Mo154 }. The gelation occurs within 60 s at room temperature, and the dual crosslinking by Schiff base and electrostatic interactions generates a dynamic network, which enables self-healing after injection. Moreover, the hydrogel delivers chemotherapeutic drugs, with a release triggered by dual near infra-red (NIR) radiation and pH changes. This stimuli-responsive release system along with the photothermal conversion ability of the hydrogel allows the simultaneous combination of photothermal and chemotherapy. This synergic system efficiently ablates the cancer tumor in vivo with no systemic toxicity. Overall, this work paves the way for the development of novel {Mo154 }-based systems, incorporated in self-healing and injectable hydrogels for dual chemo-photothermal therapy.

Near-physiological microenvironment simulation on chip to evaluate drug resistance of different loci in tumour mass.

Developing a bio-functional model in vitro to study cancer resistance, which is a big challenge for clinical cancer therapy, is of great interest. Such reliable model requires appropriate drug diffusion kinetics simulation and a microenvironment that allows cell-cell and cell-matrix interactions. In this work, a special hydrogel-based three-dimensional (3D) microfluidic chip was constructed to simulate tumour-vascular microenvironment. The self-healing hydrogel supports long-time cell survival and proliferation, effective cellular metabolism of cancer drugs and cell-cell interaction between different types of cells. In the effective near-physiological tumour-vascular microenvironment, the endothelial and fibroblast cells are spread on different sides of a porous membrane, while sensitive and resistant breast tumour cells are separately cultured in the dynamic hydrogel consisting of glycol chitosan and telechelic difunctional poly (ethylene glycol) in the upper chambers. Nutrients and drugs are introduced through the bottom channel and diffuse into the cancer cells. Doxorubicin molecules pass first through blood vessel endothelial cells and act on the tumour cells surrounded by fibroblasts. Tumour cells respond differently to drug when they are cultured in the microenvironment. Sensitive breast tumour cells have a 47% increase in viability than those cultured without fibroblasts and endothelial cells. Both sensitive and resistant tumour cells can be analysed under the same chemical environment. This work represents a multi-functional in vitro platform that allows near-physiological simulation, effective drug metabolism and cellular response to extracellular stimuli and has great potential to make drug discovery speedy and precise.

Low-intensity pulsed ultrasound repair in mandibular condylar cartilage injury rabbit model.

OBJECTIVES: Beneficial effects of low-intensity pulsed ultrasound(US) have been reported for knee articular cartilage injury. It is unclear whether the same effect could be observed on mandibular condylar cartilage. This study was designed to explore the efficacy of ultrasound cartilage repair via autophagy regulation. METHODS: A total of 18 adult rabbits were divided into a sham operation group (exposure to condylar articular surface only), operation without US group (only cartilage surgery), and operation with US group (received ultrasonic therapy daily on day 4 after cartilage surgery). The rabbits were then sacrificed to construct a temporomandibular joint (TMJ) cartilage injury model and HE staining was conducted to observe pathological changes of cartilage in each group. Expression of FGF18, FGFR4, beclin1, ATG3 and ATG7 in rabbit TMJ cartilage were detected using RT-PCR and western blotting. Finally, protein-protein interaction (PPI) analysis was used to observe the interaction among the network of important biomarkers in this injury model. RESULTS: Compared to the operation without US group, the severity of cartilage injury was decreased in the operation with US group according to HE staining. The expression of autophagy biomarkers, beclin1, ATG3, ATG7, FGF18 and FGFR4, in operation with US group were up-regulated compared with those in sham operation group and operation without US group p < 0.05). In PPI analysis, ATG3, ATG7, PIK3C3, PIK3R4, BECN1 were identified as hub nodes connecting with most proteins network. CONCLUSIONS: Our results suggest US has therapeutic potential for the treatment of mandibular condylar cartilage injury, and may affect chondrocyte autophagy.

A New Strategy for Intestinal Drug Delivery via pH-Responsive and Membrane-Active Nanogels.

Oral administration of hydrophobic and poorly intestinal epithelium-permeable drugs is a significant challenge. Herein, we report a new strategy to overcome this problem by using novel, pH-responsive, and membrane-active nanogels as drug carriers. Prepared by simple physical cross-linking of amphiphilic pseudopeptidic polymers with pH-controlled membrane-activity, the size and hydrophobicity-hydrophilicity balance of the nanogels could be well-tuned. Furthermore, the amphiphilic nanogels could release hydrophobic payloads and destabilize cell membranes at duodenum and jejunum pH 5.0-6.0, which suggests their great potential for intestinal drug delivery.

A grazing Gomphotherium in Middle Miocene Central Asia, 10 million years prior to the origin of the Elephantidae.

Feeding preference of fossil herbivorous mammals, concerning the coevolution of mammalian and floral ecosystems, has become of key research interest. In this paper, phytoliths in dental calculus from two gomphotheriid proboscideans of the middle Miocene Junggar Basin, Central Asia, have been identified, suggesting that Gomphotherium connexum was a mixed feeder, while the phytoliths from G. steinheimense indicates grazing preference. This is the earliest-known proboscidean with a predominantly grazing habit. These results are further confirmed by microwear and isotope analyses. Pollen record reveals an open steppic environment with few trees, indicating an early aridity phase in the Asian interior during the Mid-Miocene Climate Optimum, which might urge a diet remodeling of G. steinheimense. Morphological and cladistic analyses show that G. steinheimense comprises the sister taxon of tetralophodont gomphotheres, which were believed to be the general ancestral stock of derived "true elephantids"; whereas G. connexum represents a more conservative lineage in both feeding behavior and tooth morphology, which subsequently became completely extinct. Therefore, grazing by G. steinheimense may have acted as a behavior preadaptive for aridity, and allowing its lineage evolving new morphological features for surviving later in time. This study displays an interesting example of behavioral adaptation prior to morphological modification.

Membrane-Anchoring, Comb-Like Pseudopeptides for Efficient, pH-Mediated Membrane Destabilization and Intracellular Delivery.

Endosomal release has been identified as a rate-limiting step for intracellular delivery of therapeutic agents, in particular macromolecular drugs. Herein, we report a series of synthetic pH-responsive, membrane-anchoring polymers exhibiting dramatic endosomolytic activity for efficient intracellular delivery. The comb-like pseudopeptidic polymers were synthesized by grafting different amounts of decylamine (NDA), which act as hydrophobic membrane anchors, onto the pendant carboxylic acid groups of a pseudopeptide, poly(l-lysine iso-phthalamide). The effects of the hydrophobic relatively long alkyl side chains on aqueous solution properties, cell membrane destabilization activity, and in-vitro cytotoxicity were investigated. The optimal polymer containing 18 mol % NDA exhibited limited hemolysis at pH 7.4 but induced nearly complete membrane destabilization at endosomal pH within only 20 min. The mechanistic investigation of membrane destabilization suggests the polymer-mediated pore formation. It has been demonstrated that the polymer with hydrophobic side chains displayed a considerable endosomolytic ability to release endocytosed materials into the cytoplasm of various cell lines, which is of critical importance for intracellular drug delivery applications.

Surfactant modification of aggregation-induced emission material as biocompatible nanoparticles: facile preparation and cell imaging.

Water soluble and biocompatible fluorescent organic nanoparticles based on aggregation-induced emission (AIE) material were facilely prepared by mixing AIE material and surfactant. The utilization of such fluorescent organic nanoparticles for cell imaging applications was further explored.