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Osteoporosis is majorly caused by an imbalance between osteoclastic and osteogenic niches. Despite the development of nationally recognized first-line anti-osteoporosis drugs, including alendronate (AL), their low bioavailability, poor uptake rate, and dose-related side effects present significant challenges in treatment. This calls for an urgent need for more effective bone-affinity drug delivery systems. In this study, we produced hybrid structures with bioactive components and stable fluffy topological morphology by cross-linking calcium and phosphorus precursors based on mesoporous silica to fabricate nanoadjuvants for AL delivery. The subsequent grafting of -PEG-DAsp8 ensured superior biocompatibility and bone targeting capacity. RNA sequencing revealed that these fluffy nanoadjuvants effectively activated adhesion pathways through CARD11 and CD34 molecular mechanisms, hence promoting cellular uptake and intracellular delivery of AL. Experiments showed that small-dose AL nanoadjuvants effectively suppress osteoclast formation and potentially promote osteogenesis. In vivo results restored the balance between osteogenic and osteoclastic niches against osteoporosis as well as the consequent significant recovery of bone mass. Therefore, this study constructed a drug nanoadjuvant with peculiar topological structures and high bone targeting capacities, efficient intracellular drug delivery as well as bone bioactivity. This provides a novel perspective on drug delivery for osteoporosis and treatment strategies for other bone diseases.

Abstract Tissue engineering has demonstrated its efficacy in promoting tissue regeneration, and extensive research has explored its application in rotator cuff (RC) tears. However, there remains a paucity of research translating from bench to clinic. A key challenge in RC repair is the healing of tendon–bone interface (TBI), for which bioactive materials suitable for interface repair are still lacking. The umbilical cord (UC), which serves as a vital repository of bioactive components in nature, is emerging as an important source of tissue engineering materials. A minimally manipulated approach is used to fabricate UC scaffolds that retain a wealth of bioactive components and cytokines. The scaffold demonstrates the ability to modulate the TBI healing microenvironment by facilitating cell proliferation, migration, suppressing inflammation, and inducing chondrogenic differentiation. This foundation sets the stage for in vivo validation and clinical translation. Following implantation of UC scaffolds in the canine model, comprehensive assessments, including MRI and histological analysis confirm their efficacy in inducing TBI reconstruction. Encouraging short‐term clinical results further suggest the ability of UC scaffolds to effectively enhance RC repair. This investigation explores the mechanisms underlying the promotion of TBI repair by UC scaffolds, providing key insights for clinical application and translational research.

Facilitating regeneration of the tendon-to-bone interface can reduce the risk of postoperative retear after rotator cuff repair. Unfortunately, undesirable inflammatory responses following injury, difficulties in fibrocartilage regeneration, and bone loss in the surrounding area are major contributors to suboptimal tendon-bone healing. Thus, the development of biomaterials capable of regulating macrophage polarization to a favorable phenotype and promoting the synchronous regeneration of the tendon-to-bone interface is currently a top priority. Here, strontium-doped mesoporous bioglass nanoparticles (Sr-MBG) were synthesized through a modulated sol-gel method and Bi-lineage Inducible and Immunoregulatory Electrospun Fibers Scaffolds (BIIEFS) containing Sr-MBG were fabricated. The BIIEFS were biocompatible, showed sustained release of multiple types of bioactive ions, enhanced osteogenic and chondrogenic differentiation of mesenchymal stem cells (MSCs), and facilitated macrophage polarization towards the M2 phenotype in vitro. The implantation of BIIEFS at the torn rotator cuff resulted in greater numbers of M2 macrophages and the synchronous regeneration of tendon, fibrocartilage, and bone at the tendon-to-bone interface, leading to a significant improvement in the biomechanical strength of the supraspinatus tendon-humerus complexes. Our research offers a feasible strategy to fabricate immunoregulatory and multi-lineage inducible electrospun fibers scaffolds incorporating bioglass nanoparticles for the regeneration of soft-to-hard tissue interfaces.

Electrospun fibers, with proven ability to promote tissue regeneration, are widely being explored for rotator cuff repairing. However, without post treatment, the microstructure of the electrospun scaffold is vastly different from that of natural extracellular matrix (ECM). Moreover, during mechanical loading, the nanofibers slip that hampers the proliferation and differentiation of migrating stem cells. Here, electrospun nanofiber scaffolds, with crimped nanofibers and welded joints to biomimic the intricate natural microstructure of tendon-to-bone insertion, were prepared using poly(ester-urethane)urea and gelatin via electrospinning and double crosslinking by a multi-bonding network densification strategy. The crimped nanofiber scaffold (CNS) features bionic tensile stress and induces chondrogenic differentiation, laying credible basis for in vivo experimentation. After repairing a rabbit massive rotator cuff tear using a CNS for 3 months, the continuous translational tendon-to-bone interface was fully regenerated, and fatty infiltration was simultaneously inhibited. Instead of micro-CT, μCT was employed to visualize the integrity and intricateness of the three-dimensional microstructure of the CNS-induced-healed tendon-to-bone interface at an ultra-high resolution of less than 1 μm. This study sheds light on the correlation between nanofiber post treatment and massive rotator cuff repair and provides a general strategy for crimped nanofiber preparation and tendon-to-bone interface imaging characterization.

Ligament regeneration is a complicated process that requires dynamic mechanical properties and allowable space to regulate collagen remodeling. Poor strength and limited space of currently available grafts hinder tissue regeneration, yielding a disappointing success rate in ligament reconstruction. Matching the scaffold retreat rate with the mechanical and spatial properties of the regeneration process remains challenging. Herein, a scaffold matching the regeneration process was designed via regulating the trajectories of fibers with different degradation rates to provide dynamic mechanical properties and spatial adaptability for collagen infiltration. This core-shell structured scaffold exhibited biomimetic fiber orientation, having tri-phasic mechanical behavior and excellent strength. Besides, by the sequential material degradation, the available space of the scaffold increased from day 6 and remained stable on day 24, consistent with the proliferation and deposition phase of the native ligament regeneration process. Furthermore, mature collagen infiltration and increased bone integration in vivo confirmed the promotion of tissue regeneration by the adaptive space, maintaining an excellent failure load of 67.65% of the native ligament at 16 weeks. This study proved the synergistic effects of dynamic strength and adaptive space. The scaffold matching the regeneration process is expected to open new approaches in ligament reconstruction.

Based on the published animal studies, we systematically evaluated the outcomes of various materials for rotator cuff repair in animal models and the potentials of their clinical translation. 74 animal studies were finally included, of which naturally derived biomaterials were applied the most widely (50.0%), rats were the most commonly used animal model (47.0%), and autologous tissue demonstrated the best outcomes in all animal models. The biomechanical properties of naturally derived biomaterials (maximum failure load: WMD 18.68 [95%CI 7.71–29.66]; P = 0.001, and stiffness: WMD 1.30 [95%CI 0.01–2.60]; P = 0.048) was statistically significant in the rabbit model. The rabbit model showed better outcomes even though the injury was severer compared with the rat model.

Posterosuperior rotator cuff tear (PSRCT) is one of the most common shoulder disorders in elderly people’s daily life; however, the biomechanical relationship between PSRCT and shoulder abduction function is still controversial. In this study, a total of twelve freshly frozen cadaveric shoulders were included and tested in five conditions: intact rotator cuff, 1/3 PSRCT, 2/3 PSRCT, entire PSRCT, and global RCT. In each condition, extra load (0%, 45%, and 90% failure load) was sequentially added to the distal humerus, and the function of the remaining rotator cuff was mainly evaluated via the middle deltoid force (MDF) required for abduction. It is found that the peak MDF is required for abduction did not differ among the three PSRCT conditions (1/3 PSRCT: 29.30 ± 5.03 N, p = 0.96; 2/3 PSRCT: 29.13 ± 9.09 N, p = 0.98; entire PSRCT: 28.85 ± 7.12 N, p = 0.90) and the intact condition (29.18 ± 4.99 N). However, the peak MDF significantly differed between the global RCT (76.27 ± 4.94 N, p < 0.01) and all PSRCT and intact conditions. Under 45% failure load, the MDF of the entire PSRCT and global tear conditions were significantly increased compared with another status. With the 90% failure load, only the 1/3 PSRCT condition maintained the same shoulder function as the intact rotator cuff. These biomechanical testing jointly suggested that the weight-bearing ability of the shoulder significantly decreased as PSRCT progressed.

Abstract Most models of the COVID-19 pandemic in the United States do not consider geographic variation and spatial interaction. In this research, we developed a travel-network-based susceptible-exposed-infectious-removed (SEIR) mathematical compartmental model system that characterizes infections by state and incorporates inflows and outflows of interstate travelers. Modeling reveals that curbing interstate travel when the disease is already widespread will make little difference. Meanwhile, increased testing capacity (facilitating early identification of infected people and quick isolation) and strict social-distancing and self-quarantine rules are most effective in abating the outbreak. The modeling has also produced state-specific information. For example, for New York and Michigan, isolation of persons exposed to the virus needs to be imposed within 2 days to prevent a broad outbreak, whereas for other states this period can be 3.6 days. This model could be used to determine resources needed before safely lifting state policies on social distancing.

Abstract Background Data from meta-analysis suggest that robotic radical antegrade modular pancreatosplenectomy (RAMPS) is a safe and effective procedure for treating adenocarcinoma in the body or tail of the pancreas, and is oncologically superior to standard retrograde pancreatosplenectomy (SRPS). RAMPS is an operation that actively expands the scope of resection, and achieves a higher R0 resection rate and lymph nodes acquisition through expanded resection. However, previous studies on RAMPS were conducted under open and laparoscopic surgery. Robotic surgery, on the other hand, plays a role in ergonomics and offers several advantages, including less fatigue, tremor filtering, 7° of wrist-like motion, motion scaling, and three-dimensional vision. At present, there is still a world-wide lack of clinical studies to observe the safety and clinical efficacy of robotic RAMPS. Hence, prospective randomized controlled trials (RCTs) comparing robotic RAMPS and SRPS are required. We begin an RCT to compare short-term surgical and oncological outcomes of robotic RAMPS and SRPS in patients undergoing distal pancreatectomy. Methods This is a randomized, single-center clinical trial. All participants are adult patients with primary pancreatic cancer, who are undergoing RAMPS or SRPS. The primary endpoints are R0 rate (resection margins are classified by a margin to tumor distance ≥ 1 mm). The secondary endpoints are the number of harvested lymph nodes, perioperative complications and perioperative indicators (duration of surgery, blood loss, blood transfusion volume, costs). Discussion We are undertaking a prospective RCT to evaluate the surgical and oncological outcomes of robotic RAMPS. This procedure may become a standard approach to robotic pancreatosplenectomy. Trial registration Chinese Clinical Trial Registry: ChiCTR1900020833 , Registered on 20 January 2019.

With the ubiquitous use of location-based services, large-scale individual-level location data has been widely collected through location-awareness devices. Geoprivacy concerns arise on the issues of user identity de-anonymization and location exposure. In this work, we investigate the effectiveness of geomasking techniques for protecting the geoprivacy of active Twitter users who frequently share geotagged tweets in their home and work locations. By analyzing over 38,000 geotagged tweets of 93 active Twitter users in three U.S. cities, the two-dimensional Gaussian masking technique with proper standard deviation settings is found to be more effective to protect user's location privacy while sacrificing geospatial analytical resolution than the random perturbation masking method and the aggregation on traffic analysis zones. Furthermore, a three-dimensional theoretical framework considering privacy, analytics, and uncertainty factors simultaneously is proposed to assess geomasking techniques. Our research offers insights into geoprivacy concerns of social media users' georeferenced data sharing for future development of location-based applications and services.

The tendon-to-bone interface is a special structure connecting the tendon and bone and is crucial for mechanical load transfer between dissimilar tissues. After an injury, fibrous scar tissues replace the native tendon-to-bone interface, creating a weak spot that needs to endure extra loading, significantly decreasing the mechanical properties of the motor system. Macrophages play a critical role in tendon-bone healing and can be divided into various phenotypes, according to their inducing stimuli and function. During the early stages of tendon-bone healing, M1 macrophages are predominant, while during the later stages, M2 macrophages replace the M1 macrophages. The two macrophage phenotypes play a significant, yet distinct, role in tendon-bone healing. Growing evidence shows that regulating the macrophage phenotypes is able to promote tendon-bone healing. This review aims to summarize the impact of different macrophages on tendon-bone healing and the current immunomodulatory biomaterials for regulating macrophages, which are used to promote tendon-bone healing. Although macrophages are a promising target for tendon-bone healing, the challenges and limitations of macrophages in tendon-bone healing research are discussed, along with directions for further research.

[This corrects the article DOI: 10.1371/journal.pone.0236347.].

Dynamic and steady-state aspects of wave propagation are deeply connected in lossless open systems in which the scattering matrix is unitary. There is then an equivalence among the energy excited within the medium through all channels, the Wigner time delay, which is the sum of dwell times in all channels coupled to the medium, and the density of states. But these equivalences fall away in the presence of material loss or gain. In this paper, we use microwave measurements, numerical simulations, and theoretical analysis to discover the changing relationships among fundamental wave properties with loss and gain, and their dependence upon dimensionality and spectral overlap. We begin with the demonstrations that the transmission time in random 1D media is equal to the density of states even in the presence of ultrastrong absorption and that its ensemble average is independent of the strengths of scattering and absorption. In contrast, the Wigner time becomes imaginary in the presence of loss, with real and imaginary parts that fall with absorption. In multichannel media, the transmission time remains equal to the density of states and is independent of the scattering strength in unitary systems but falls with absorption to a degree that increases with the strengths of absorption and scattering, and the number of channels coupled to the medium. We show that the relationships between key propagation variables in non-Hermitian systems can be understood in terms of the singularities of the phase of the determinant of the transmission matrix. The poles of the transmission matrix are the same as those of the scattering matrix, but the transmission zeros are fundamentally different. Whereas the zeros of the scattering matrix are the complex conjugates of the poles, the transmission zeros are topological: in unitary systems they occur only singly on the real axis or as conjugate pairs. We follow the evolution and statistics of zeros in the complex plane as random samples are deformed. The sensitivity of the spacing of zeros in the complex plane with deformation of the sample has a square-root singularity at a zero point at which two single zeros and a complex pair interconvert. The transmission time is a sum of Lorentzian functions associated with poles and zeros. The sum over poles is the density of states with an average that is independent of scattering and dissipation. But the sum over zeros changes with loss, gain, scattering strength and the number of channels in ways that make it possible to control ultranarrow spectral features in transmission and transmission time. We show that the field, including the contribution of the still coherent incident wave, is a sum over modal partial fractions with amplitudes that are independent of loss and gain. The energy excited may be expressed in terms of the resonances of the medium and is equal to the dwell time even in the presence of loss or gain.

Measuring the semantic similarity between words is important for natural language processing tasks. The traditional models of semantic similarity perform well in most cases, but when dealing with words that involve geographical context, spatial semantics of implied spatial information are rarely preserved. Geographic information retrieval (GIR) methods have focused on this issue; however, they sometimes fail to solve the problem because the spatial and textual similarities of words are considered and calculated separately. In this paper, from the perspective of spatial context, we consider the two parts as a whole-spatial context semantics, and we propose a method that measures spatial semantic similarity using a sliding geospatial context window for geo-tagged words. The proposed method was first validated with a set of simulated data and then applied to a real-world dataset from Flickr. As a result, a spatial semantic similarity model at different scales is presented. We believe this model is a necessary supplement for traditional textual-language semantic analyses of words obtained by word-embedding technologies. This study has the potential to improve the quality of recommendation systems by considering relevant spatial context semantics, and benefits linguistic semantic research by emphasising the spatial cognition among words.

Valleys in the photonic band structure provide an additional degree of freedom to engineer topological photonic structures and devices. Here, Kang et al. demonstrate that inter-valley scattering is inhibited at a Y-junction between three sections with different valley topology.

In recent years, with the growing accessibility of abundant contextual emotion information, which is benefited by the numerous georeferenced user-generated content and the maturity of artificial intelligence (AI)-based emotional computing technics, the emotion layer of human–environment relationship is proposed for enriching traditional methods of various related disciplines such as urban planning. This paper proposes the geographic information system (GIS)-based emotional computing concept, which is a novel framework for applying GIS methods to collective human emotion. The methodology presented in this paper consists of three key steps: (1) collecting georeferenced data containing emotion and environment information such as social media and official sites, (2) detecting emotions using AI-based emotional computing technics such as natural language processing (NLP) and computer vision (CV), and (3) visualizing and analyzing the spatiotemporal patterns with GIS tools. This methodology is a great synergy of multidisciplinary cutting-edge techniques, such as GIScience, sociology, and computer science. Moreover, it can effectively and deeply explore the connection between people and their surroundings with the help of GIS methods. Generally, the framework provides a standard workflow to calculate and analyze the new information layer for researchers, in which a measured human-centric perspective onto the environment is possible.

Intracellular membrane fusion is mediated by dynamic assembly and disassembly of soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptors (SNAREs). α-SNAP guides NSF to disassemble SNARE complexes after membrane fusion. Recent experiments showed that α-SNAP also dramatically enhances SNARE assembly and membrane fusion. How α-SNAP is involved in these opposing activities is not known. Here, we examine the effect of α-SNAP on the stepwise assembly of the synaptic SNARE complex using optical tweezers. We found that α-SNAP destabilized the linker domain (LD) of the SNARE complex but stabilized its C-terminal domain (CTD) through a conformational selection mechanism. In contrast, α-SNAP minimally affected assembly of the SNARE N-terminal domain (NTD), indicating that α-SNAP barely bound the partially assembled trans-SNARE complex. Thus, α-SNAP recognizes the folded CTD for SNARE disassembly with NSF and subtly modulates membrane fusion by altering the stabilities of the SNARE CTD and LD.

Topological protection of transmission has been demonstrated in the edge channel in topological insulators in the face of bent paths and on-site randomness in the structure. Microwave measurements and couple-mode theory of a topological medium possessing time-reversal symmetry with a cavity adjacent to the edge channel show that spin is not conserved in scattering from the defect. The transmission time is negative near resonance with the defect.

Synaptic-soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins couple their stage-wise folding/assembly to rapid exocytosis of neurotransmitters in a Munc18-1-dependent manner. The functions of the different assembly stages in exocytosis and the role of Munc18-1 in SNARE assembly are not well understood. Using optical tweezers, we observed four distinct stages of assembly in SNARE N-terminal, middle, C-terminal, and linker domains (or NTD, MD, CTD, and LD, respectively). We found that SNARE layer mutations differentially affect SNARE assembly. Comparison of their effects on SNARE assembly and on exocytosis reveals that NTD and CTD are responsible for vesicle docking and fusion, respectively, whereas MD regulates SNARE assembly and fusion. Munc18-1 initiates SNARE assembly and structures t-SNARE C-terminus independent of syntaxin N-terminal regulatory domain (NRD) and stabilizes the half-zippered SNARE complex dependent upon the NRD. Our observations demonstrate distinct functions of SNARE domains whose assembly is intimately chaperoned by Munc18-1.