Cartilage-Inspired, High-Strength, and Heat-Tolerant Lubricating Hydrogels by Macrophase Separation.

Hydrogels are considered as a potential cartilage replacement material based on their structure being similar to natural cartilage, which are of great significance in repairing cartilage defects. However, it is difficult for the existing hydrogels to combine the high load bearing and low friction properties (37 °C) of cartilage through sample methods. Herein, we report a facile and new fabrication strategy to construct the PNIPAm/EYL hydrogel by using the macrophase separation of supersaturated N-isopropylacrylamide (NIPAm) monomer solution to promote the formation of liposomes from egg yolk lecithin (EYL) and asymmetric template method. The PNIPAm/EYL hydrogels possess a relatively high compressive strength (more than 12 MPa), fracture energy (9820 J/m2), good fatigue resistance, lubricating properties, and excellent biocompatibility. Compared with the PNIPAm hydrogel, the friction coefficient (COF 0.046) of PNIPAm/EYL hydrogel is reduced by 50%. More importantly, the COF (0.056) of PNIPAm/EYL hydrogel above lower critical solution temperature (LCST) does not increase significantly, exhibiting heat-tolerant lubricity. The finite element analysis further proves that PNIPAm/EYL hydrogel can effectively disperse the applied stress and dissipate energy under load conditions. This work not only provides new insights for the design of high-strength lubricating hydrogels but also lays a foundation for the treatment of cartilage injury as a substitute material.

AddaVax Formulated with PolyI:C as a Potential Adjuvant of MDCK-based Influenza Vaccine Enhances Local, Cellular, and Antibody Protective Immune Response in Mice.

Poor immune responses to inactivated influenza vaccine can be improved by effective and safe adjuvants to increase antibody titers and cellular protective response. In our study, AddaVax and PolyI:C combined adjuvant (AP adjuvant) were used for influenza vaccine development. After immunizing BALB/c mice and Wistar rats intramuscularly, Split inactivated H3N2 vaccine adjuvanted with AP elicited higher serum hemagglutination-inhibition antibodies and IgG titers. We demonstrated that AP induced a transient innate immune cytokines production at the injection site, induced H3N2 uptake by DCs, increased recruitment of monocytes and DCs in LNs, and promoted H3N2 vaccine migration; AP facilitated vaccines to induce a vigorous adaptive immune response. Besides, AP showed good safety as shown by lymph nodes (LNs) size, spleens index of BALB/c mice, and weight changes and C-reaction protein level of BALB/c mice and Wistar rats after repeated administration of high-dose vaccine with or without adjuvant. These findings indicate that AP is a potential novel adjuvant and can be used as a safe and effective adjuvant for MDCK-based influenza inactivated vaccine to induce cellular and antibody protective response.

Monodisperse and Polydisperse PEGylation of Peptides and Proteins: A Comparative Study.

Although PEGylation is widely used in biomedicine with great success, it suffers from many drawbacks, such as polydispersity, nonbiodegradability, and loss of precursor potency. Recently, the search for polyethylene glycol (PEG) substitutes has attracted considerable attention. Some of the substitutes partially address the drawbacks of PEGs, but sacrifice the "stealth" effect of PEGs and bring in new issues. Herein, we developed monodisperse oligoethylene glycol (M-OEG) polyamides over 5000 Da as biodegradable and monodisperse PEGylation (M-PEGylation) agents, which provided M-PEGylated peptides and proteins with high monodispersity and a biodegradable PEG moiety. Compared to regular PEGylated proteins with a complex "stealth" cloud of PEG, the hydrogen bond interactions between the M-OEG polyamides and proteins provided the M-PEGylated protein with a biodegradable "stealth" cloak. The monodisperse and biodegradable M-PEGylation strategy as well as the peculiar protein-M-OEG polyamide interactions may shed light on many long-lasting issues during the development of PEGylated biologic drugs, such as monodispersity, biodegradability, and tunable conformation.

Bubble-Enabled Underwater Motion of a Light-Driven Motor.

This work reports the photothermally driven horizontal motion of a motor as well as the suspending and vertical movements underwater. A motor is designed by attaching two polydimethylsiloxane-coated oxidized copper foams (POCF) to the two opposite sides of an oxidized copper foam (OCF). When the hydrophobic POCF is immersed in water, it serves as both an air bubble trapper and a light-to-heat conversion center. As bubbles grow under photothermal heating, they provide lifting force and result in the revolving motion of the motor. With removal of light illumination, bubbles are cooled by the surrounding water and shrink, and the buoyance is lowered. The resultant force of gravitational force, buoyance, and fluid resistance drives the motor to move forward horizontally. Furthermore, the motors are utilized as oil collectors and oil/water separation is achieved successfully. To effectively control the suspending motion, a polydimethylsiloxane foam doped with carbon black (C-foam) is designed under the photothermal principle. It is maintained at a certain position underwater by controlling the on/off of light. The vertical motion is also studied and utilized to generate electricity. It is expected that different types of underwater motion will open up new opportunities for various applications including drug delivery, collection of heavy oil underwater, and electricity generation.

Monodisperse oligoethylene glycols modified Propofol prodrugs.

The low water solubility of Propofol resulted in complicated formulation and adverse effects during its clinical application. To improve its water solubility and maintain its anesthetic effects, Propofol prodrugs with monodisperse oligoethylene glycols as solubility enhancer were designed and synthesized. Monodisperse oligoethylene glycols enable the concise manipulation of water solubility, biocompatibility and anesthetic effects. Through the physicochemical and biological assay, a few water soluble prodrugs of Propofol were identified as promising anesthetic to overcome the drawbacks associated with Propofol.

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.

A newly discovered Hystrix primigenia specimen from the Kemiklitepe collection at Ege University Natural History Museum: insights into paleobiogeography in Eurasia.

Porcupines, members of the Hystricidae family, represent a unique group of herbivorous mammals. This study details the identification of a newly discovered mandible fragment of Hystrix primigenia, along with a right cheek tooth series from the middle Turolian Kemiklitepe-A fossil locality. While Hystrix fossils are found in numerous localities, the materials are often limited to a few dental fragments or isolated teeth, posing challenges to systematic investigations. The examination of this lower tooth series prompted a comprehensive review of all H. primigenia findings across Eurasia, shedding light on its adaptive characteristics over time and space. Our paleobiogeographical analysis indicates the absence of H. depereti in Late Miocene Türkiye, while the dispersal range of H. primigenia is broader than that of H. depereti in Eurasia. Additionally, the study delves into the discussion of H. primigenia and H. depereti findings in Eurasia, ultimately refining the categorization of Late Miocene Hystrix discoveries in Türkiye to two species: H. primigenia and H. kayae. Our review suggests the possibility of an additional H. kayae finding from Samos, Greece.

Stochastic lattice-based porous implant design for improving the stress transfer in unicompartmental knee arthroplasty.

BACKGROUND: Unicompartmental knee arthroplasty (UKA) has been proved to be a successful treatment for osteoarthritis patients. However, the stress shielding caused by mismatch in mechanical properties between human bones and artificial implants remains as a challenging issue. This study aimed to properly design a bionic porous tibial implant and evaluate its biomechanical effect in reconstructing stress transfer pathway after UKA surgery. METHODS: Voronoi structures with different strut sizes and porosities were designed and manufactured with Ti6Al4V through additive manufacturing and subjected to quasi-static compression tests. The Gibson-Ashby model was used to relate mechanical properties with design parameters. Subsequently, finite element models were developed for porous UKA, conventional UKA, and native knee to evaluate the biomechanical effect of tibial implant with designed structures during the stance phase. RESULTS: The internal stress distribution on the tibia plateau in the medial compartment of the porous UKA knee was found to closely resemble that of the native knee. Furthermore, the mean stress values in the medial regions of the tibial plateau of the porous UKA knee were at least 44.7% higher than that of the conventional UKA knee for all subjects during the most loading conditions. The strain shielding reduction effect of the porous UKA knee model was significant under the implant and near the load contact sites. For subject 1 to 3, the average percentages of nodes in bone preserving and building region (strain values range from 400 to 3000 µm/m) of the porous UKA knee model, ranging from 68.7 to 80.5%, were higher than that of the conventional UKA knee model, ranging from 61.6 to 68.6%. CONCLUSIONS: The comparison results indicated that the tibial implant with designed Voronoi structure offered better biomechanical functionality on the tibial plateau after UKA. Additionally, the model and associated analysis provide a well-defined design process and dependable selection criteria for design parameters of UKA implants with Voronoi structures.

Mucoadhesive liposomal delivery system synergizing anti-inflammation and anti-oxidation for enhanced treatment against dry eye disease.

Dry eye disease (DED) is a common and frequent ocular surface disease worldwide, which can cause severe ocular surface discomfort and blurred vision. Inflammation and reactive oxygen species (ROS) play decisive roles in the development of DED. However, existing treatments usually focus on anti-inflammation while ignore the role of ROS in DED. Ever worse, the clinical preparations are easily cleared by nasolacrimal ducts, resulting in poor therapeutic effect. To circumvent these obstacles, here we designed a phenylboronic acid (PBA) modified liposome co-loading immunosuppressant cyclosporin A (CsA) and antioxidant crocin (Cro). The CsA/Cro PBA Lip achieved mucoadhesion through the formation of covalent bonds between PBA and the sialic acid residues on mucin, and consequently improved the retention of drugs on the ocular surface. By inhibiting ROS production and blocking NF-κB inflammatory pathway, CsA/Cro PBA Lip successfully promoted the healing of damaged corneal epithelium, eventually achieving the goal of relieving DED. CsA/Cro PBA Lip is proven a simple yet effective dual-drug delivery system, exhibiting superior antioxidant and anti-inflammatory effects both in vitro and in vivo. This approach holds great potential in the clinical treatment of DED and other related mucosal inflammations.

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.

First report on rhinoceros from the late Neogene Qin Basin of Shanxi, China.

Dihoplus is a rhinoceros distributed across East Asia and Europe from the Late Miocene to Pliocene. This study describes a new skull from the Qin Basin in Shanxi Province, China, referred to as Dihoplus ringstroemi, which has long been debated in taxonomic identity. This skull confirms that D. ringstroemi is an independent species and reveals the presence of the upper incisor and variations in the degree of constriction of the two lingual cusps of upper cheek teeth. In addition, the new skull indicates that the Qin Basin has a late Neogene sediment and fauna comparable to that of the Yushe Basin.

A new Late Miocene Hystrix (Hystricidae, Rodentia) from Turkey.

The Çorakyerler fossil locality in Anatolia reveals unique faunal elements. This study introduces Hystrix kayae sp. nov., a new Late Miocene porcupine initially classified as Hystrix sp. Yavuz et al., 2018. This finding expands our knowledge of Late Miocene Anatolian porcupines, bringing the total number of known species to three. H. kayae sp. nov. is larger than Hystrix aryanensis and exhibits greater upper cheek tooth crown height. Its cheek tooth morphology differs from Hystrix depereti, and it possesses distinctive U-shaped choanae unlike Hystrix primigenia. The Çorakyerler locality may predate sites with H. aryanensis and H. primigenia but aligns temporally with Hystrix parvae localities. This study enhances our understanding of Late Miocene porcupine diversity in Anatolia, emphasizing the importance of Çorakyerler in unraveling the evolutionary history of these fascinating mammals.

Reproduction of a fossil rhinoceros from 18 mya and origin of litter size in perissodactyls.

Reproductive strategy is among the most important characteristics of organism. Here, we report reproductive strategy of singleton pregnancy of a fossil rhinoceros, Plesiaceratherium gracile, from 18 mya of the Shanwang Basin, China. Dental and body development data revealed that after birth, the calf of P. gracile is breastfed for 2-3 years; at approximately 5 years of age, when the M2 tooth is slightly worn, the female has already reached sexual maturity and attained a size close to that of an adult and could give birth to the first calf. Furthermore, given litter size is phylogenetically conservative and closely correlates with body size, we conclude that the litter size of perissodactyls is determined by the singleton pregnancy since the Eocene. By contrast, other reproductive traits are highly variable and have a different pace of evolution, and traits observed in living rhinoceroses have been evolving at least since 18 mya.

Parallelism and lineage replacement of the late Miocene scimitar-toothed cats from the old and New World.

In contrast to large-scale convergence/parallelism, the small-scale convergence/parallelism of sabertooth adaptation within closely related genera and species has been seldom investigated. Here, we describe and analyze the rich material of Nimravides catocopis, and provide evidence using a new phylogenetic analysis that Nimravides was endemic to North America. The late Miocene (10.5-6.5 Ma) Nimravides represents a lineage that shows clearly parallelism with the contemporary Old World lineage of Machairodus-Amphimachairodus.The Old World lineage experienced a higher evolutionary rate of cranial trait than the New World one did. The low density of Amphimachairodus at its first appearance in North America suggests that the derived traits did not provide a direct competitive advantage over Nimravides, but allowed Amphimachairodus to survive the significant faunal change in the early-late Hemphillian (∼6.5 Ma) in North America, a process that probably can be applied to most replacement of closely related lineages.

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.

Biomimetic theranostic strategy for anti-metastasis therapy of breast cancer via the macrophage membrane camouflaged superparticles.

The rational design of theranostic systems are critical for addressing challenging issues associated with cancers. Toward this objective, the multifunctional biomimetic superparticle, termed as DOX-QDs-Lip@M, which can specifically deliver drug to tumor and synergistically monitor their therapeutic effects, was fabricated. Initially, anticancer drug doxorubicin hydrochloride (DOX) and imaging agent quaternary quantum dots (QDs) were loaded into the hydrophilic core region and hydrophobic chamber of liposome by self-assembly method, respectively. The integrated nanostructure can greatly increase the fluorescence intensity of signal unit and tremendously improve the diagnostic sensitivity. Subsequently, the biomimetic DOX-QDs-Lip@M was constructed by fusing and coating the isolated macrophage membranes on the surface of liposome, which can consequently extend the circulation of the whole blood and effectively target the tumor sites. Moreover, the naturally formed biofilm can stabilize the artificial liposome structure, which can prevent the leakage of the loaded materials in the liposome. These integrated properties endow the biomimetic DOX-QDs-Lip@M with improved tumor imaging and anti-metastasis treatment in living systems.

A natural polysaccharide mediated MOF-based Ce6 delivery system with improved biological properties for photodynamic therapy.

Chlorin e6 (Ce6) is a second generation photosensitizer for photodynamic therapy (PDT). However, free Ce6 still has some defects leading to reduced clinical efficacy, such as easy agglomeration in a physiological environment and poor accumulation in tumor tissue. In order to solve these problems, a hyaluronic acid (HA) modified zeolitic imidazolate framework-8 (ZIF-8) based Ce6 (ZIF-8@Ce6-HA) therapeutic agent is constructed for PDT by one-pot encapsulation and self-assembly. ZIF-8@Ce6-HA exhibits acceptable encapsulation efficiency, effective cell uptake and good biocompatibility. Moreover, the results of in vitro anticancer experiments demonstrated that the ZIF-8@Ce6-HA group exhibited greater cytotoxicity after irradiation than the free Ce6 group, which caused about 88.4% of HepG2 cells to die since ROS is produced by PDT. Additionally, the data of inductively coupled plasma mass spectrometry indicated that modification of HA increased the blood circulation time and reduced the systemic toxicity of ZIF-8@Ce6. In summary, this work created an interesting Ce6 therapeutic agent for PDT and provided the data for HA regarding the improvement in biocompatibility and biological half-life of metal organic frameworks.

Clinical effects of staged joint replacement in patients with septic arthritic knee.

OBJECTIVE: To assess the clinical effect of staged joint replacement for the treatment of septic arthritic knee and the therapeutic differences between antibiotic cement beads and the tibial plateau spacer. METHODS: Twenty-three patients (24 knee joints) treated with a staged joint replacement for septic arthritis knee were retrospectively reviewed between March 2014 and April 2018. At the first stage, thorough debridement and irrigation with self-made antibiotic cement beads or tibial plateau spacer were performed. After that, systemic antibiotic treatment was followed; when the infection was surely eliminated, the second-stage TKA was performed. Knee mobility (range of motion, abbreviated to ROM) and function (HSS scores system) were evaluated before surgery, in the interval period, and after joint replacement. RESULTS: All patients finished follow-up, and the mean follow-up time was 27.3 months (12-54 months). Each group has one patient replaced with a homotypic spacer, and all patients eventually cleared the infection. None of the patients had a recurrent infection. The mobility and HSS scores of the two groups were significantly improved postoperation (p < 0.05). And there was no significant difference in the post-surgery ROM (p = 0.153) and the HSS score (p = 0.054) between the two groups. CONCLUSION: Staged joint replacement is an efficacious way for septic arthritic knees, whether tibial plateau spacer or antibiotic cement beads were used, which can effectively control infection and improve knee function.

Silene sunhangii (Caryophyllaceae), a new species from China.

Silene sunhangii, a new species of Caryophyllaceae known from only three populations in Hubei and Hunan provinces of central China, is described. Both morphological and molecular data were used to assess the taxonomic status and relationships of this species. Morphologically, S. sunhangii is most similar to S. platyphylla Franch. from which it differs most readily in having 3-veined elliptical leaves without pubescence, tasseled catacorolla, pale purple to red petals without a linear lobe or narrow tooth and lanceolate, bifid to one third. A phylogenetic analysis based on nuclear ITS region identified the new species as a well-supported, independent lineage. Our new species is nested within a grade that encompasses species representing a polyphyletic Silene sect. Physolychnis (Benth.) Bocquet. Both the genetic and morphological data support the recognition of Silene sunhangii as a distinct species, although there is inconsistency between these two datasets as to the relationships of the new species.

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.