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Abstract The intriguing biomineralization process in nature endows the mineralized biological materials with intricate microarchitected structures in a facile and orderly way, which provides an inspiration for processing ceramics. Here, we propose a simple and efficient manufacturing process to fabricate cellular ceramics in programmed cell-based 3D configurations, inspired by the biomineralization process of the diatom frustule. Our approach separates the ingredient synthesis from architecture building, enabling the programmable manufacturing of cellular ceramics with various cell sizes, geometries, densities, metastructures, and constituent elements. Our approach exploits surface tension to capture precursor solutions in the architected cellular lattices, allowing us to control the liquid geometry and manufacture cellular ceramics with high precision. We investigate the geometry parameters for the architected lattices assembled by unit cells and unit columns, both theoretically and experimentally, to guide the 3D fluid interface creation in arranged configurations. We manufacture a series of globally cellular and locally compact piezoceramics, obtaining an enhanced piezoelectric constant and a designed piezoelectric anisotropy. This bioinspired, surface tension-assisted approach has the potential to revolutionize the design and processing of multifarious ceramic materials for structural and functional applications in energy, electronics and biomedicine.

Abstract The transcription and replication processes of non-segmented, negative-strand RNA viruses (nsNSVs) are catalyzed by a multi-functional polymerase complex composed of the large protein (L) and a cofactor protein, such as phosphoprotein (P). Previous studies have shown that the nsNSV polymerase can adopt a dimeric form, however, the structure of the dimer and its function are poorly understood. Here we determine a 2.7 Å cryo-EM structure of human parainfluenza virus type 3 (hPIV3) L–P complex with the connector domain (CD′) of a second L built, while reconstruction of the rest of the second L–P obtains a low-resolution map of the ring-like L core region. This study reveals detailed atomic features of nsNSV polymerase active site and distinct conformation of hPIV3 L with a unique β-strand latch. Furthermore, we report the structural basis of L–L dimerization, with CD′ located at the putative template entry of the adjoining L. Disruption of the L–L interface causes a defect in RNA replication that can be overcome by complementation, demonstrating that L dimerization is necessary for hPIV3 genome replication. These findings provide further insight into how nsNSV polymerases perform their functions, and suggest a new avenue for rational drug design.

Abstract Background Lumbar revision surgery can be performed by simple lumbar nerve decompression or lumbar interbody fusion, including percutaneous endoscopic lumbar discectomy, transforaminal lumbar interbody fusion (TLIF), etc. However, lumbar revision surgery is very difficult in surgical operation. We sought to explore the technique safety and efficacy of microscope-assisted minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) in lumbar revision surgery. Methods Cases of postoperative recurrence following lumbar spine surgery (n = 63) treated from December 2016 to July 2021 were retrospectively analyzed, including 24 cases of microscope-assisted MI-TLIF (microscopic group) and 39 cases of naked-eye MI-TLIF (naked-eye group). The operation time, intraoperative blood loss, incision length, postoperative drainage, length of hospital stay, initial operation, and visual analog score (VAS) of low back and leg pain before and at 7 days and 3 months after the operation and the last follow-up were compared between the two groups. The Oswestry Dysfunction Index (ODI) and the Japanese Orthopaedic Association (JOA) scores before and after the operation and the Bridwell interbody fusion grades at 1 year were compared. The independent t tests, Mann–Whitney U tests, and Chi-square tests were used for analysis. Results All 63 patients were successfully treated by operation and were followed up for an average of 31.5 ± 8.6 months (range 12–48 months). The two groups had no significant difference in sex, age, incision length, initial operation, or operative segment (P > 0.05). There was no significance in operation time, VAS score, ODI score, and JOA score of low back pain or Bridwell interbody fusion grade between the two groups (P > 0.05). Significant differences in intraoperative blood loss, postoperative drainage, and the lengths of hospital stay were observed between the two groups (P

The modeling of the concrete matrix serves as a foundation for mesoscale analysis of concrete, which provides a crucial avenue for investigating the crack propagation and strength characteristics of concrete. However, the primary prerequisite for conducting such analyses is the generation of aggregate models. By combining the advantages of Voronoi diagrams and the random walk algorithm (RWA), a Voronoi–random walk algorithm is proposed in this paper. The algorithm overcomes the limitations of traditional methods, including constraints on aggregate volume fraction, low computational efficiency, and insufficient randomness in aggregate distribution. The meso-structure of a concrete block was modeled by the proposed method, and then its failure behavior under uniaxial compression was simulated using the finite element method. The numerical results agreed well with the experimental observations, indicating the effectiveness and accuracy of the proposed approach.

Background Lupus nephritis (LN) is a complication of SLE characterised by immune dysfunction and oxidative stress (OS). Limited options exist for LN. We aimed to identify LN-related OS, highlighting the need for non-invasive diagnostic and therapeutic approaches.Methods LN-differentially expressed genes (DEGs) were extracted from Gene Expression Omnibus datasets (GSE32591, GSE112943 and GSE104948) and Molecular Signatures Database for OS-associated DEGs (OSEGs). Functional enrichment analysis was performed for OSEGs related to LN. Weighted gene co-expression network analysis identified hub genes related to OS-LN. These hub OSEGs were refined as biomarker candidates via least absolute shrinkage and selection operator. The predictive value was validated using receiver operating characteristic (ROC) curves and nomogram for LN prognosis. We evaluated LN immune cell infiltration using single-sample gene set enrichment analysis and CIBERSORT. Additionally, gene set enrichment analysis explored the functional enrichment of hub OSEGs in LN.Results The study identified four hub genes, namely STAT1, PRODH, TXN2 and SETX, associated with OS related to LN. These genes were validated for their diagnostic potential, and their involvement in LN pathogenesis was elucidated through ROC and nomogram. Additionally, alterations in immune cell composition in LN correlated with hub OSEG expression were observed. Immunohistochemical analysis reveals that the hub gene is most correlated with activated B cells and CD8 T cells. Finally, we uncovered that the enriched pathways of OSEGs were mainly involved in the PI3K-Akt pathway and the Janus kinase-signal transducer and activator of transcription pathway.Conclusion These findings contribute to advancing our understanding of the complex interplay between OS, immune dysregulation and molecular pathways in LN, laying a foundation for the identification of potential diagnostic biomarkers and therapeutic targets.

Abstract Fault maturity has been proposed to exert a first order control on earthquake rupture, yet direct observations linking individual rupture to long‐term fault growth are rare. The 2021 Mw 7.4 Maduo earthquake ruptured the east‐growing end of the slow‐moving (∼1 mm/yr) Jiangcuo fault in north Tibet, providing an opportunity to examine the relation between rupture characteristics and fault structure. Here we combine field and multiple remote sensing techniques to map the surface rupture at cm‐resolution and document comprehensively on‐fault offsets and off‐fault deformation. The 158 km‐long surface rupture consists of misoriented structurally inherited N110°‐striking segments and younger optimally oriented N093°‐striking segments, relative to the regional stress field. Despite being comparatively newly formed, the ∼N093°‐striking fault segments accommodate more localized strain, with up to 3 m on‐fault left‐lateral slip and 25%–50% off‐fault deformation, and possibly faster rupture speed. These results are in contrast with previous findings showing more localized strain and faster rupture speed on more mature fault segments; instead, our observations suggest that fault orientation with respect to the regional stress can exert a more important control than fault maturity on coseismic rupture behavior when both factors are at play.

We study layered solutions in a one-dimensional version of the scalar Ginzburg-Landau equation that involves a mixture of a second spatial derivative and a fractional half-derivative, together with a periodically modulated nonlinearity. This equation appears as the Euler-Lagrange equation of a suitably renormalized fractional Ginzburg-Landau energy with a double-well potential that is multiplied by a 1-periodically varying nonnegative factor $ g(x) $ with $ \int_0^1 \frac{1}{g(x)} dx < \infty. $ A priori this energy is not bounded below due to the presence of a nonlocal term in the energy. Nevertheless, through a careful analysis of a minimizing sequence we prove existence of global energy minimizers that connect the two wells at infinity. These minimizers are shown to be the classical solutions of the associated nonlocal Ginzburg-Landau type equation.

Abstract Nanoparticles, films, and patterns are three critical piezoelectric elements with widespread applications in sensing, actuations, catalysis and energy harvesting. High productivity and large-area fabrication of these functional elements is still a significant challenge, let alone the control of their structures and feature sizes on various substrates. Here, we report a fast and versatile electrostatic disc microprinting, enabled by triggering the instability of liquid-air interface of inks. The printing process allows for fabricating lead zirconate titanate free-standing nanoparticles, films, and micro-patterns. The as-fabricated lead zirconate titanate films exhibit a high piezoelectric strain constant of 560 pm V−1, one to two times higher than the state-of-the-art. The multiplexed tip jetting mode and the large layer-by-layer depositing area can translate into depositing speeds up to 109 μm3 s−1, one order of magnitude faster than current techniques. Printing diversified functional materials, ranging from suspensions of dielectric ceramic and metal nanoparticles, to insulating polymers, to solutions of biological molecules, demonstrates the great potential of the electrostatic disc microprinting in electronics, biotechnology and beyond.

Abstract Piezoelectric biomaterials have attracted great attention owing to the recent recognition of the impact of piezoelectricity on biological systems and their potential applications in implantable sensors, actuators, and energy harvesters. However, their practical use is hindered by the weak piezoelectric effect caused by the random polarization of biomaterials and the challenges of large-scale alignment of domains. Here, we present an active self-assembly strategy to tailor piezoelectric biomaterial thin films. The nanoconfinement-induced homogeneous nucleation overcomes the interfacial dependency and allows the electric field applied in-situ to align crystal grains across the entire film. The β-glycine films exhibit an enhanced piezoelectric strain coefficient of 11.2 pm V−1 and an exceptional piezoelectric voltage coefficient of 252 × 10−3 Vm N−1. Of particular significance is that the nanoconfinement effect greatly improves the thermostability before melting (192 °C). This finding offers a generally applicable strategy for constructing high-performance large-sized piezoelectric bio-organic materials for biological and medical microdevices.

Forest ecosystems represent important carbon sinks within terrestrial ecosystems. Simulating carbon budgets in forest ecosystems located within complex terrains forms the foundation for understanding global carbon cycle dynamics. In this study, employing the FORCCHN model and utilizing mountain climate data as forcing parameters, the impact of the terrain factors of the Changbai Mountain Nature Reserve on carbon budget change in 1998–2017 was studied. The dynamics and distribution patterns of carbon fluxes at different slope aspects and elevations were discussed. Findings demonstrated that between 1998 and 2017, the per-unit area gross primary production (GPP), net primary production (NPP), and net ecosystem production (NEP) for the Changbai Mountain Reserve were 839.35, 462.03, and 192.72 gC m−2 a−1, respectively. The carbon fluxes varied significantly with elevation: the GPP of the north, south, and west and the NPP of the east, south, and west decreased, and the NEP of the south and west increased. The total amount in GPP and NPP of the Changbai Mountain Nature Reserve fluctuated slightly year by year, but the carbon sequestration capacity decreased from year to year. The reserve had an average annual total GPP, NPP, and NEP of 1.62, 0.89, and 0.37 TgC a−1, respectively. The north was the strongest carbon sink in the study area, contributing 35.98%, 35.88%, and 36.80% to the total amount of GPP, NPP, and NEP, respectively. This study emphasized the significance of precise mountain meteorological data to accurately quantify the carbon fluxes of mountain forest ecosystems.

Unmanned aerial vehicles (UAVs) have broad applications. However, their use for wildlife surveys in rugged mountains with dense vegetation is uncommon. Therefore, developing appropriately designed methods, selecting suitable facilities, establishing effective monitoring processes, and managing databases that align with a region’s distinctive geographic landscapes, environments, ecology, and habitats are essential. This study focuses on the Giant Panda National Park in China’s densely vegetated Qinling Mountains to carry out surveys using UAVs to assess the Sichuan snub-nosed monkey population size (Rhinopithecus roxellana) over an area of 30,000 ha. The results indicate that eight distinct groups were identified, totaling 648–755 individuals. Thus, this study offers proof-of-principle for using UAVs for surveying wildlife in remote mountainous regions with complex landscapes and dense vegetation and demonstrates how UAVs can be used in animal monitoring and conservation. Furthermore, the study highlights the broader potential application of UAVs in other remote mountainous regions, where animal demographic information is urgently needed to establish database-driven conservation strategies.

Abstract Vegetation phenology can profoundly modulate the climate-biosphere interactions and thus plays a crucial role in regulating the terrestrial carbon cycle and the climate. However, most previous phenology studies rely on traditional vegetation indices, which are inadequate to characterize the seasonal activity of photosynthesis. Here, we generated an annual vegetation photosynthetic phenology dataset with a spatial resolution of 0.05 degrees from 2001 to 2020, using the latest gross primary productivity product based on solar-induced chlorophyll fluorescence (GOSIF-GPP). We combined smoothing splines with multiple change-point detection to retrieve the phenology metrics: start of the growing season (SOS), end of the growing season (EOS), and length of growing season (LOS) for terrestrial ecosystems above 30° N latitude (Northern Biomes). Our phenology product can be used to validate and develop phenology or carbon cycle models and monitor the climate change impacts on terrestrial ecosystems.

Abstract ABCB10, a member of ABC transporter superfamily that locates in the inner membrane of mitochondria, plays crucial roles in hemoglobin synthesis, antioxidative stress and stabilization of the iron transporter mitoferrin-1. Recently, it was found that ABCB10 is a mitochondrial biliverdin exporter. However, the molecular mechanism of biliverdin export by ABCB10 remains elusive. Here we report the cryo-EM structures of ABCB10 in apo (ABCB10-apo) and biliverdin-bound form (ABCB10-BV) at 3.67 Å and 2.85 Å resolution, respectively. ABCB10-apo adopts a wide-open conformation and may thus represent the apo form structure. ABCB10-BV forms a closed conformation and biliverdin situates in a hydrophobic pocket in one protomer and bridges the interaction through hydrogen bonds with the opposing one. We also identify cholesterols sandwiched by BVs and discuss the export dynamics based on these structural and biochemical observations.

While a gambler may occasionally win, continuous gambling inevitably results in a net loss to the casino. This study experimentally demonstrates the profitability of a particularly deceptive casino game: a two-armed antique Mills Futurity slot machine. The main findings clearly show that both non-random and random two-arm strategies, predetermined by the player and repeated without interruption, are always profitable for the casino, despite two coins being refunded for every two consecutive losses by the gambler. We theoretically explore the cyclical nature of slot machine strategies and speculate on the impact of the frequency of switching strategies on casino returns. Our results not only assist casino owners in developing and improving casino designs, but also guide gamblers to participate more cautiously in gambling.

This paper proposes a dynamic encircling cooperative guidance (DECG) law to enable multiple interceptors to cooperatively intercept a superior target, considering low velocity, limited overload, impact angle and simultaneous arrival constraints. First, the feasible escaping area of the target is analyzed and a dynamic encircling strategy for the target is established. This strategy efficiently provides virtual escaping points, allowing interceptors to dynamically encircle the target without excessive energy consumption, ultimately leading to a successful interception. Second, to enhance the physical feasibility of the kinematic equations governing the interaction between interceptors and target at the virtual escaping points, the independent variable is substituted and the kinematic equations are remodeled. Convex optimization is employed to address the multi-constraint optimal guidance problem for each interceptor, thereby facilitating simultaneous interception. Compared with the existing guidance laws, DECG has a more practical and feasible cooperative strategy, is able to handle more constraints including the interceptor’s own constraints and cooperative constraints, and does not rely on the precise calculation of explicit remaining flight time in the guidance law implementation. Lastly, the effectiveness, superiority and robustness of the DECG law are evaluated through a series of numerical simulations, and its performance is compared with that of the cooperative proportional navigation guidance law (CPNG).

In unsupervised learning, clustering is a common starting point for data processing. The convex or concave fusion clustering method is a novel approach that is more stable and accurate than traditional methods such as k-means and hierarchical clustering. However, the optimization algorithm used with this method can be slowed down significantly by the complexity of the fusion penalty, which increases the computational burden. This paper introduces a random projection ADMM algorithm based on the Bernoulli distribution and develops a double random projection ADMM method for high-dimensional fusion clustering. These new approaches significantly outperform the classical ADMM algorithm due to their ability to significantly increase computational speed by reducing complexity and improving clustering accuracy by using multiple random projections under a new evaluation criterion. We also demonstrate the convergence of our new algorithm and test its performance on both simulated and real data examples.

Based on daily gauge station datum， monthly reanalysis datasets from NCEP/NCAR and monthly SST data from Hadley Center in UK （HadISST）， The climatic characteristics of freezing days and their causes have been studied on.It is found that there are 69 stations （85.2%） of longest persistent days in the single freezing processes and 63 stations （77.8%） of total winter freezing days occurred in 1976， 1983 and 2007， Weining's 66 d （1976） and 39 d （2007） being the longest events respectively.The main mode of winter freezing days in Guizhou which the center is in central showed a consistent distribution in the whole region with a variance of 65.04%.When the winter freezing days in Guizhou were abnormally large， the abnormally active Ural Mountain blocking high pressure and the abnormally strong East Asian Trough were conducive to the formation of stable meridional circulation in East Asia.while the low value system in Central Asia guided the cold air in front of the blocking high and the Mongolian cold high southward， formed a shallow abnormal cold pad in the lower troposphere of Guizhou and its north.At the same time， the warm and humid air flow in the middle and lower troposphere from the Bay of Bengal and the South China Sea crawled and uplifted along the edge of the cold air pile near the Yunnan-Guizhou Quasi-Stationary Front under the action of the abnormal circulation circle， and formed an unstable vertical stratification anomaly of warm up and cold down in the middle and lower troposphere over Guizhou， resulting in the formation of winter freezing in Guizhou.In addition， the wave disturbance energy propagation from North Atlantic and low latitude tropical played an important role in the formation and maintenance of the blocking situation in the middle and high latitudes and the anomaly of the low trough system in Eurasia.When the freezing days were abnormal less， the situation is opposite.Finally， there is a closely relationship between the winter freezing days anomaly in Guizhou with the La Niña event in the equatorial Middle East Pacific and the SST anomaly in the North Pacific， Indian Ocean， and South China Sea.

Abstract Background Propensity score analysis is increasingly used to control for confounding factors in observational studies. Unfortunately, unavoidable missing values make estimating propensity scores extremely challenging. We propose a new method for estimating propensity scores in data with missing values. Materials and methods Both simulated and real-world datasets are used in our experiments. The simulated datasets were constructed under 2 scenarios, the presence (T = 1) and the absence (T = 0) of the true effect. The real-world dataset comes from LaLonde’s employment training program. We construct missing data with varying degrees of missing rates under three missing mechanisms: MAR, MCAR, and MNAR. Then we compare MTNN with 2 other traditional methods in different scenarios. The experiments in each scenario were repeated 20,000 times. Our code is publicly available at https://github.com/ljwa2323/MTNN . Results Under the three missing mechanisms of MAR, MCAR and MNAR, the RMSE between the effect and the true effect estimated by our proposed method is the smallest in simulations and in real-world data. Furthermore, the standard deviation of the effect estimated by our method is the smallest. In situations where the missing rate is low, the estimation of our method is more accurate. Conclusions MTNN can perform propensity score estimation and missing value filling at the same time through shared hidden layers and joint learning, which solves the dilemma of traditional methods and is very suitable for estimating true effects in samples with missing values. The method is expected to be broadly generalized and applied to real-world observational studies.

With the Guiyang ground-based microwave radiometer, radiosonde and ground observation data at 08:00 and 20:00 from January 2017 to May 2019, this paper evaluates the seasonal variation and the standard deviation of bias of temperature profile retrieved from the microwave radiometer in clear sky. The results show that: (1) the average relative biases of the vertical profiles of temperature from spring to winter are as follows: -1.71-1.35℃, -1.69-0.78℃, -2.24-1.29℃ and -4.98-1.49℃, and the standard deviations of biases are as follows: 1.13-2.93℃, 0.43-1.86℃, 0.76-1.92℃, 0.62-3.48℃. The vertical changes and standard deviations of biases from spring to autumn are the same, while the changes and standard deviations of error in winter are larger than those in other seasons. (2) The samples of inversion and biases have the best correlation. Among the three expressions of inversion, the inversion thickness and the bias have an best correlation when the inversion thickness is 490-740 m. The largest correlation coefficient appears when the inversion thickness is 650 m. The inversion magnitude and the error have the best correlation when the inversion thickness is less than 490 m or more than 740 m and inversion threshold is taken as 1.2℃. (3) The correlation between the average height of inversion and bias is analyzed. It is found that the correlation between the two is poor. The height of bias can not be reflected by the height of inversion.

This study presenting the cryo-EM structure of human SNAPc in complex with U6-1 PSE, significantly enforces our understanding of the mechanism of the SNAPc assembly, the PSE-specific recognition by SNAPc and the PIC assembly on U6 snRNA promoter.

Adenocarcinoma is the most prevalent histological subtype of colorectal cancer (CRC), with mucinous colorectal adenocarcinoma (MCA) being a unique form. Although the mucinous subtype is known to elicit a worse response to chemotherapy and immunotherapy than the nonmucinous subtype, its pathogenesis remains poorly understood. Neurogenic locus notch homolog protein 3 (NOTCH3), a member of the NOTCH subfamilies, is highly expressed in CRC. In the past three decades, many studies have been performed evaluating the biological role of NOTCH3 in CRC. However, the precise activities of NOTCH3 in MCA, as well as the mechanisms involved in its transcriptional control, are yet to be elucidated. Our finding showed that the critical transcriptional regulatory factor transcription activator BRG1 (SMARCA4) directly binds to the intracellular domain of NOTCH3 to control transcriptional regulation. Moreover, RNA‐sequencing results indicated a common targeting effect on the transcriptional activity of mucin‐5AC (MUC5AC) and mucin‐2 (MUC2) in CRC cells by NOTCH3 and SMARCA4. Furthermore, NOTCH3 was found to control the expressions of MUC5AC and MUC2 in a SMARCA4‐dependent manner. MUC5AC and MUC2, which encode two secreted mucins, are located on chromosome 11p15.5, and are linked to the development of MCA. This finding suggests that the interaction between NOTCH3 and SMARCA4 may be involved in MCA differentiation by jointly targeting MUC5AC and MUC2. Patients with MCA are often treated in accordance with CRC guidelines. Determining the relationship between NOTCH3 and SMARCA4 by demonstrating their interactions in the pathophysiology of MCA could provide novel therapeutic targets and help identify potential prognostic markers for MCA.

Immune cell infiltration occurs in the tumor microenvironment (TME) and influences cancer progression through interaction with tumor cells. Runt-related transcription factors (RUNXs), RUNX1-3, are the master regulators of development and differentiation and are all important to the development of immune cells. However, the role of RUNXs in the immune cells of TME remains unclear. In this study, we first used online related databases and related LGG data from TCGA and CGGA to conduct bioinformatics analysis, which confirmed that RUNXs were significantly and positively correlated with immune infiltration in multiple tumors, especially in low-grade glioma (LGG) and there was the highest correlation between RUNXs and the progress and prognosis of LGG. Furthermore, the functional enrichment analysis revealed that RUNXs might be involved in the inflammatory and immune responses of the biological processes, and RUNXs were tightly associated with the multiple immune checkpoint molecules. Subsequent results confirmed that RUNX1, as an independent prognostic factor for LGG, may target interferon-gamma receptor 2 (IFNGR2) to regulate glioma cell proliferation, invasion, and migration. Besides, we also found that the expression levels of RUNX1 and IFNGR2 were significantly reduced, and their correlation was enhanced in the IDH-mutant subtype. Patients with a high expression of RUNX1 and/or IFNGR2 (HH/H) in the IDH-mutant subtype showed poorer prognosis and significantly increased infiltration of M2 macrophages. This finding implied the possible key role of RUNX1 in the differentiation of IDH mutant subtypes as well as in the formation of tumor microenvironment (TME) infiltration signatures by monitoring IFNGR2.

Here, Xiao et al. isolate a large panel of antibodies against human metapneumovirus fusion protein from human B cells, and characterize their epitopes, neutralization activities, and antigen binding specificity, providing a useful framework for understanding the immune response against hMPV.

The drug AT-527 targets the SARS-CoV-2 replication machinery. Here the authors use Cryo-EM to show how AT-527 inhibits SARS-CoV-2 polymerase by acting as an immediate RNA chain terminator and stably binding in a NiRAN active-site pocket; impeding an essential nucleotide-transfer activity.

The operation process of free-piston engine generator (FPEG) can be divided into starting process and power generation process, and each of them faces severe challenges especially for the opposed-piston FPEG. As the first part of the investigation, this paper focuses the starting process of opposed piston FPEG. Two novel general methods to start the opposed-piston FPEG are investigated by the linear electric machine operating as linear motor. Both simulation and test results are presented, and the numerical model is successfully validated. The test results show that the maximum in-cylinder pressure of the engine cylinder is 11.85bar, indicating that the engine is ready for ignition, and the synchronization error of opposed-piston fluctuates within ± 2 mm with the limitation of the synchronization mechanism Further investigations on the opposed-piston scheme performance with the displacement master–slave control strategy and current master–slave control strategy are carried out. The results demonstrate that both control strategies are feasible to start the opposed-piston FPEG. More importantly, the current master–slave control strategy has faster response to external interference and therefore the piston synchronization error is smaller. And the smaller motor force of the current master–slave control strategy makes the peak in-cylinder pressure reach the target value. Further research shows that the mass of moving parts, constant motor force and the synchronization mechanism are crucial factors for such schematic prototype during starting process.

Boltzmann Machines offer the potential of more efficient solutions to combinatorial problems compared to von Neumann computing architectures. Here, Yan et al introduce a stochastic memristor with dynamically tunable properties, a vital feature for the efficient implementation of a Boltzmann Machine.

Purpose: To evaluate the effects of physical exercise on neck and shoulder muscle strength and pain in military pilots.Method: Embase, PubMed, and Cochrane Library databases were searched studies published up to April 1, 2022. Studies that met the screening criteria were included in the final meta-analysis. We calculated neck and shoulder maximal voluntary isometric contractions (MVICs), prevalence of pain, and pain intensity. Heterogeneity was explored by subgroup and sensitivity analyses.Result: A total of 15 studies with 907 participants were included. In the exercise group, muscle strength was significantly increased in four directions of neck motion: flexion (standardized mean difference (SMD) = 0.45; 95% CI, 0.08–0.82), extension (SMD = 0.63; 95% CI, 0.27–1.00), right lateral flexion (Rtflx) (SMD = 0.53; 95% CI, 0.12–0.94), and left lateral flexion (Ltflx) (SMD = 0.50; 95% CI, 0.09–0.91). Subgroup analysis showed that fighter pilots, strength plus endurance training, and a follow-up period

Nature-based Solutions (NbS) can undoubtedly play a significant role in carbon neutrality strategy. Forests are a major part of the carbon budget in terrestrial ecosystems. The possible response of the carbon balance of southwestern forests to different climate change scenarios was investigated through a series of simulations using the forest ecosystem carbon budget model for China (FORCCHN), which clearly represents the influence of climate factors on forest carbon sequestration. Driven by downscaled global climate model (GCM) data, the FORCCHN evaluates the carbon sink potential of southwestern forest ecosystems under different shared socioeconomic pathways (SSPs). The results indicate that, first, gross primary productivity (GPP), ecosystem respiration (ER) and net primary productivity (NPP) of forest ecosystems are expected to increase from 2020 to 2060. Forest ecosystems will maintain a carbon sink, but net ecosystem productivity (NEP) will peak and begin to decline in the 2030s. Second, not only is the NEP in the SSP1-2.6 scenario higher than in the other climate change scenarios for 2025–2035 and 2043–2058, but the coefficient of variation of the NEP is also narrower than in the other scenarios. Third, in terms of spatial distribution, the carbon sequestration potential of northwest and central Yunnan is significantly higher than that of other regions, with a slight upward trend in NEP in the future. Finally, GPP and ER are significantly positively correlated with temperature and insignificantly correlated with precipitation, and the increasing temperature will have a negative and unstable impact on forest carbon sinks. This study provides a scientific reference for implementing forest management strategies and achieving sustainable development.

Abstract Background Cancer stem cells (CSCs) play an important role in tumor invasion and metastasis. CD44 is the most commonly used marker of CSCs, with the potential to act as a determinant against the invasion and migration of CSCs and as the key factor in epithelial–mesenchymal transition (EMT)-like changes that occur in colorectal cancer (CRC). Runt-related transcription factor-2 (RUNX2) is a mesenchymal stem marker for cancer that is involved in stem cell biology and tumorigenesis. However, whether RUNX2 is involved in CSC and in inducing EMT-like changes in CRC remains uncertain, warranting further investigation. Methods We evaluated the role of RUNX2 in the invasion and migration of CRC cells as a promoter of CD44-induced stem cell- and EMT-like modifications. For this purpose, western blotting was employed to analyze the expression of differential proteins in CRC cells. We conducted sphere formation, wound healing, and transwell assays to investigate the biological functions of RUNX2 in CRC cells. Cellular immunofluorescence and coimmunoprecipitation (co-IP) assays were performed to study the relationship between RUNX2 and BRG1. Real-time quantitative PCR (RT-qPCR) and immunohistochemistry (IHC) were performed to analyze the expressions of RUNX2, BRG1, and CD44 in the CRC tissues. Results We found that RUNX2 could markedly induce the CRC cell sphere-forming ability and EMT. Interestingly, the RUNX2-mediated EMT in CRC cell may be associated with the activation of CD44. Furthermore, RUNX2 was found to interact with BRG1 to promote the recruitment of RUNX2 to the CD44 promoter. Conclusions Our cumulative findings suggest that RUNX2 and BRG1 can form a compact complex to regulate the transcription and expression of CD44, which has possible involvement in the invasion and migration of CRC cells.

Periodontitis is an inflammatory disease accompanied by alveolar bone loss. Moreover, M1 macrophages play a critical role in the development of periodontal disease. Uncoupling protein-2 (UCP2) is a mitochondrial transporter protein that controls M1 macrophage activation by modulating reactive oxygen species (ROS) production. We investigated the role of UCP2 in M1 macrophage infiltration in gingival tissues with periodontitis. We found that the expression of UCP2 was upregulated in M1 macrophages infiltrating human periodontal tissues with periodontitis. Macrophage-specific knockout of UCP2 could increase the infiltration of macrophage and exacerbate inflammatory response in a mouse gingiva affected with periodontitis, induced by Porphyromonas gingivalis-LPS (Pg-LPS) injection. The loss of UCP2 may contribute to the enhanced abilities of proliferation, migration, pro-inflammatory cytokine secretion, and ROS production in Pg-LPS-treated macrophages. Our results indicate that UCP2 has an important role in M1 macrophage polarization in the periodontal tissue with periodontitis. It might be helpful to provide theoretical basis for design of new therapeutic strategies for periodontitis.

Abstract Background Gap models are individual-based models for forests. They simulate dynamic multispecies assemblages over multiple tree-generations and predict forest responses to altered environmental conditions. Their development emphases designation of the significant biological and ecological processes at appropriate time/space scales. Conceptually, they are with consistent with A.G. Tansley’s original definition of “the ecosystem”. Results An example microscale application inspects feedbacks among terrestrial vegetation change, air-quality changes from the vegetation’s release of volatile organic compounds (VOC), and climate change effects on ecosystem production of VOC’s. Gap models can allocate canopy photosynthate to the individual trees whose leaves form the vertical leaf-area profiles. VOC release depends strongly on leaf physiology by species of these trees. Leaf-level VOC emissions increase with climate-warming. Species composition change lowers the abundance of VOC-emitting taxa. In interactions among ecosystem functions and biosphere/atmosphere exchanges, community composition responses can outweigh physiological responses. This contradicts previous studies that emphasize the warming-induced impacts on leaf function. As a mesoscale example, the changes in climate (warming) on forests including pest-insect dynamics demonstrates changes on the both the tree and the insect populations. This is but one of many cases that involve using a gap model to simulate changes in spatial units typical of sampling plots and scaling these to landscape and regional levels. As this is the typical application scale for gap models, other examples are identified. The insect/climate-change can be scaled to regional consequences by simulating survey plots across a continental or subcontinental zone. Forest inventories at these scales are often conducted using independent survey plots distributed across a region. Model construction that mimics this sample design avoids the difficulties in modelling spatial interactions, but we also discuss simulation at these scales with contagion effects. Conclusions At the global-scale, successful simulations to date have used functional types of plants, rather than tree species. In a final application, the fine-scale predictions of a gap model are compared with data from micrometeorological eddy-covariance towers and then scaled-up to produce maps of global patterns of evapotranspiration, net primary production, gross primary production and respiration. New active-remote-sensing instruments provide opportunities to test these global predictions.

Abstract A breakthrough in advancing power density and stability of carbon-based supercapacitors is trapped by inefficient pore structures of electrode materials. Herein, an ultra-microporous carbon with ultrahigh integrated capacitance fabricated via one-step carbonization/activation of dense bacterial cellulose (BC) precursor followed by nitrogen/sulfur dual doping is reported. The microporous carbon possesses highly concentrated micropores (~ 2 nm) and a considerable amount of sub-micropores (

This work, for the first time, experimentally demonstrates a TCAD-Machine Learning (TCAD-ML) framework to assist the analysis of device-to-device variation and operating (ambient) temperature without the need of physical quantities extraction. The ML algorithm used in this work is the Principal Component Analysis (PCA) followed by third order polynomial regression. After calibrated to limited ‘expensive’ experimental data, ‘low cost’ TCAD simulation is used to generate a large amount of device data to train the ML model. The ML was then used to identify the root cause of device variation and operating temperature from any given experimental current-voltage (I-V) characteristics. We applied this framework to study the ultra-wide-bandgap gallium oxide (Ga2O3) Schottky barrier diode (SBD), an emerging device technology that holds great promise for temperature sensing, RF, and power applications in harsh environments. After calibration, over 150,000 electrothermal TCAD simulations are performed with random variation of physical parameters (anode effective work function, drift layer doping, and drift layer thickness) and operating temperature. An ML model is trained using these TCAD data and we found 1,000–10,000 TCAD data can train an accurate machine. We show that without physical quantities extraction, performing PCA is essential for the TCAD trained ML model to be applicable to analyze experimental characteristics. The physical parameters and temperatures predicted by the ML model show good agreement with experimental analysis. Our TCAD-ML framework shows great promise to accelerate the development of new device technologies with a significantly more efficient process of material and device experimentation.

The Three Rivers Source Region (TRSR) is a natural habitat for rare animals and a genetic treasure trove of plateau organisms. It is an important eco-safety barrier in China and even Asia, and a priority of China’s to promote ecological advancement. Precisely assessing the dynamics and mechanisms of alpine grassland ecosystem carbon budgets is beneficial for quantifying the response to climate change on a regional scale. The spatial distribution and dynamic changes in carbon fluxes in the TRSR from 1985 to 2018 were analyzed by the Theil–Sen + Mann–Kendall and ensemble empirical mode decomposition (EEMD) methods, and multiple linear regression was used to quantify the contribution of meteorological elements to the carbon flux trends. The results indicated that (1) the alpine grassland ecosystem was a weak carbon sink. The multiyear mean gross primary production (GPP) and net ecosystem production (NEP) in the TRSR were 147.86 and 11.27 g C/m2/yr, respectively. The distribution of carbon fluxes progressively decreased from east to west. (2) The carbon fluxes of the alpine grassland ecosystem were dominated by a monotonically increasing trend, with increasing rates of GPP and NEP of 1.31 and 0.40 g C/m2/yr, respectively. A total of 48.60% of the alpine grassland showed a significant increase in NEP, whereas only 0.21% showed a significant decrease during the research term. (3) The alpine meadow sequestered carbon better than the alpine steppe did and accounted for more than 60% of the regional carbon sink. (4) In a correlation analysis between NEP and temperature, precipitation and solar radiation, the positive correlation accounted for 89.67%, 90.51%, and 21.16% of the TRSR, respectively. Rising temperatures and increased precipitation were the main drivers contributing to the increase in NEP. Research on carbon budget variability and mechanisms can help guide preservation zoning initiatives in national parks.

More than 18 human papillomaviruses (HPV) are associated with cervical cancer, and ideally vaccines should protect from all of them. Here, the authors engineer a triple-type, chimeric HPV vaccine, using loop swapping, that elicits robust neutralizing antibody titers in mice and non-human primates.

Background: The symptoms of sciatic herpes zoster are sometimes difficult to distinguish from sciatica caused by lumbar disc herniation. We describe a case of suspected lumbar disc herniation with sciatic herpes zoster to reduce the rate of misdiagnosis.Case Report: A 55-year old man, male, developed low back pain after carrying heavy items 20 years ago. Characteristics of symptoms: 1. Symptoms were aggravated in the upright lumbar forward flexion position; 2. The VAS (leg) score was 8–9 points and the VSA (lumbar) score was 0 point; 3. It can be relieved when rested in the supine position; 4. It came on intermittently with radiation pain in the right lower limb. There were several attacks every year. One month ago, there was radiating pain in the right lower limb. The pain was from the back of the right hip, behind the thigh, in lateral crural region, to the back of the foot. And Symptoms worsened for 10 days. The VAS score was 8 points. Pain could not be relieved by rest or changing posture. There was no back pain, no lower limbs, weak walking, no claudication and other symptoms. Analgesics and neurotrophic drugs are ineffective. After the application of antiviral drugs, the radiation pain in the right lower extremity was significantly relieved.Conclusion: We describe this case in detail and discuss how to make an authentic diagnosis, with a concomitant literature review.

Objective Long noncoding (lnc)RNAs regulate multiple biological processes including cancer. Oral squamous cell carcinoma (OSCC) is a common malignancy with poor prognosis. We aimed to identify the function of lncRNA HOXA10 antisense RNA (HOXA10-AS) and its clinical significance. Methods We used differential expression analysis to identify aberrantly expressed lncRNAs associated with OSCC. We identified key genes related to HOXA10-AS and their biological functions using bioinformatics tools and functional enrichment analyses. We predicted the function of HOXA10-AS using gene set enrichment and variation analyses and analyzed proliferation markers at the mRNA and protein levels. Finally, we silenced HOXA10-AS using antisense oligonucleotide and assessed proliferation ability using a cell counting kit (CCK8) and clone formation assays. Results In total, 506 aberrantly expressed lncRNAs were identified. HOXA10-AS was identified as a risk factor for OSCC and its expression was positively associated with tumor grade. We identified hub genes involved in regulating proliferation and predicted that HOXA10-AS is associated with an active cell cycle and increased proliferation. Silencing HOXA10-AS decreased proliferation in OSCC cell lines. Conclusions HOXA10-AS is involved in cell proliferation and silencing it decreases proliferation. Thus, HOXA10-AS could serve as prognostic biomarker and therapeutic target for OSCC.

Abstract Background Methylation is a common modification of DNA. It has been a very important and hot topic to study the correlation between methylation and diseases in medical science. Because of the special process with bisulfite treatment, traditional mapping tools do not work well with such methylation experimental reads. Traditional aligners are not designed for mapping bisulfite-treated reads, where the un-methylated ‘C’s are converted to ‘T’s. Results In this paper, we develop a reliable and visual tool, named VAliBS, for mapping bisulfate sequences to a genome reference. VAliBS works well even on large scale data or high noise data. By comparing with other state-of-the-art tools (BisMark, BSMAP, BS-Seeker2), VAliBS can improve the accuracy of bisulfite mapping. Moreover, VAliBS is a visual tool which makes its operations more easily and the alignment results are shown with colored marks which makes it easier to be read. VAliBS provides fast and accurate mapping of bisulfite-converted reads, and a friendly window system to visualize the detail of mapping of each read. Conclusions VAliBS works well on both simulated data and real data. It can be useful in DNA methylation research. VALiBS implements an X-Window user interface where the methylation positions are visual and the operations are friendly.

Coxsackievirus A6 (CVA6) causes hand, foot and mouth disease in children. Here the authors present the CVA6 procapsid and A-particle cryo-EM structures and identify an immune-dominant neutralizing epitope, which can be exploited for vaccine development.

Environmental and human health concerns about lead toxicity have prompted the development of lead-free piezoceramics. Among them, (Ba0.85Ca0.15)(Zr0.1Ti0.9)O3 (BCTZ) with excellent piezoelectric properties has the most potential and attracts extensive attention. However, lack of concern toward electrical resistivity and mechanical properties has greatly hindered its practical application. Here, we report the achievement of enhanced insulation characteristics (grain electrical resistivity increased by one order of magnitude) and superior mechanical properties (Vickers hardness value increased by 40%) in Al2O3-added BCTZ composite ceramics. Such improvement can be attributed to specific composite microstructure, where the nonferroelectric second phase dispersed in the grain interior and grain boundary of BCTZ matrix results in blocking effect on the electric current paths as well as propagation of microcracks. These findings will pave a new way for the practical application of BCTZ ceramics.

The question as to which piezoelectric composition is favorable for energy harvesting has been addressed in the past few years. However, discussion on this topic continues. In this work, an answer is provided through a feasible method which can be used in selecting piezoelectric material. The energy harvesting behavior of hard (P4 and P8) and soft (P5 and P5H) lead zirconate titanate (PZT) ceramics was investigated. The results show that the maximum piezoelectric voltage coefficient g33 and transduction coefficient d33 × g33 were obtained in P5 ceramic. Meanwhile, the power generation characteristics at low frequencies were compared by the vibration energy harvester with a cantilever beam structure. The results indicate that the energy harvester fabricated by the P5 ceramic with the maximum d33 × g33 values also demonstrated the best power generation characteristics. The results unambiguously demonstrate that the power density and energy conversion efficiency of the energy harvesting devices are dominated by the d33 × g33 value of the piezoelectric materials.

A series of LiNbO3 crystals doped with various MgO concentrations (0, 3%, and 5 mol%) was simultaneously grown in one furnace by the modified vertical Bridgman method. The wet chemistry method was used to prepare the polycrystalline powders, and the growth conditions were optimized. The full width at half maximum of high-resolution X-ray rocking curves for (001) reflection of 5 mol% Mg doped lithium niobate (LN) crystal was about 8″, which meant it possessed high crystalline quality. The OH− absorption spectra shifted to 3534.7 cm−1, and the UV absorption edge violet shift indicated that 5 mol% MgO successfully doped in LN and exceeded the threshold. The extraordinary refractive index gradient of 5 mol% Mg doped LN crystal was as small as 2.5 × 10−5/cm, which exhibited high optical homogeneity.

Spinal cord injury (SCI) affects more than 2.5 million people worldwide. Spinal cord edema plays critical roles in the pathological progression of SCI. This study aimed to delineate the roles of aquaporin 4 (AQP4) and Na+-K+-Cl− cotransporter 1 (NKCC1) in acute phase edema and tissue destruction after SCI and to explore whether inhibiting both AQP4 and NKCC1 could improve SCI-induced spinal edema and damage. Rat SCI model was established by modified Allen's method. Spinal cord water content, cerebrospinal fluid lactose dehydrogenase (LDH) activity, AQP4 and NKCC1 expression, and spinal cord pathology from 30 min to 7 days after SCI were monitored. Additionally, aforementioned parameters in rats treated with AQP4 and/or NKCC1 inhibitors were assessed 2 days after SCI. Spinal cord water content was significantly increased 1 h after SCI while AQP4 and NKCC1 expression and spinal fluid LDH activity elevated 6 h after SCI. Spinal cord edema and spinal cord destruction peaked around 24 h after SCI and maintained at high levels thereafter. Treating rats with AQP4 inhibitor TGN-020 and NKCC1 antagonist bumetanide significantly reduced spinal cord edema, tissue destruction, and AQP4 and NKCC1 expression after SCI in an additive manner. These results demonstrated the benefits of simultaneously inhibiting both AQP4 and NKCC1 after SCI.

The concept and simulated device characteristics of tunneling field-effect transistors (TFETs) based on III-nitride heterojunctions are presented for the first time. Through polarization engineering, interband tunneling can become significant in III-nitride heterojunctions, leading to the potential for a viable TFET technology. Two prototype device designs, inline and sidewall-gated TFETs, are discussed. Polarization-assisted p-type doping is used in the source region to mitigate the effect of the deep Mg acceptor level in p-type GaN. Simulations indicate that TFETs based on III-nitride heterojunctions can be expected to achieve ON/OFF ratios of 106 or more, with switching slopes well below 60 mV/decade, ON-current densities approaching 100 μA/μm, and energy delay products as low as 67 aJ-ps/μm.

ABSTRACT Persistent, high-risk human papillomavirus (HPV) infection is the primary cause of cervical cancer. Neutralizing antibodies elicited by L1-only virus-like particles (VLPs) can block HPV infection; however, the lack of high-resolution structures has limited our understanding of the mode of virus infection and the requirement for type specificity at the molecular level. Here, we describe two antibodies, A12A3 and 28F10, that specifically bind to and neutralize HPV58 and HPV59, respectively, through two distinct binding stoichiometries. We show that the epitopes of A12A3 are clustered in the DE loops of two adjacent HPV58 L1 monomers, whereas 28F10 recognizes the HPV59 FG loop of a single monomer. Via structure-based mutagenesis and analysis of antibody binding, we further identified the residues HPV58 D154, S168, and N170 and HPV59 M267, Q270, E273, Y276, K278, and R283, which play critical roles in virus infection. By substituting these strategic epitope residues into other HPV genotypes, we could then redirect the type-specific binding of the antibodies to these genotypes, thus highlighting the importance of these specific residues, HPV58 R161, S168, and N308 and HPV59 Q270, E273, and D281. Overall, our findings provide molecular insights into potential structural determinants of HPV required for infectivity and type specificity. IMPORTANCE High-risk human papillomaviruses (HPVs) are considered the major causative pathogens of cancers that affect epithelial mucosa, such as cervical cancer. However, because of the lack of high-resolution structural information on the sites of neutralization, we have yet to determine the precise mode of HPV infection and how different types of HPV cause infection. Our crystal structures in this study have uncovered discrete binding stoichiometries for two different antibodies. We show that one A12A3 Fab binds to the center of one HPV58 pentamer, whereas five 28F10 Fabs bind along the top fringe of one HPV59 pentamer. Furthermore, through targeted epitope analysis, we show that 6 to 7 discontinuous residues of the L1 major capsid protein of HPV are determinants, at least in part, for virus infection and type specificity. This knowledge will help us to unravel the process of HPV infection and can potentially be used to drive the development of therapeutics that target neutralization-sensitive sites.

Titanium dioxide (TiO2) nanomaterials are widely considered to be state-of-the-art photocatalysts for environmental protection and energy conversion. However, the low photocatalytic efficiency caused by large bandgap and rapid recombination of photo-excited electrons and holes is a challenging issue that needs to be settled for their practical applications. Structure engineering has been demonstrated to be a highly promising approach to engineer the optical and electronic properties of the existing materials or even endow them with unexpected properties. Surface structure engineering has witnessed the breakthrough in increasing the photocatalytic efficiency of TiO2 nanomaterials by creating a defect-rich or amorphous surface layer with black color and extension of optical absorption to the whole visible spectrum, along with markedly enhanced photocatalytic activities. In this review, the recent progress in the development of black TiO2 nanomaterials is reviewed to gain a better understanding of the structure-property relationship with the consideration of preparation methods and to project new insights into the future development of black TiO2 nanomaterials in photocatalytic applications.

A novel method based on the ensemble empirical mode decomposition (EEMD) method was developed to improve model performance. This method was evaluated by applying it to global surface air temperatures, which were simulated by eight general circulation models from the Coupled Model Intercomparison Project Phase 5 (CMIP5). The temperature simulations of the eight models were separated into their different components by EEMD. The model's performance improved after the first high-frequency component was removed from the original simulations by EEMD for each model, on both the global and continental scale. Moreover, EEMD was more effective in improving the model's performance compared to the wavelet transform method. The multi-model ensembles (MMEs) were calculated based on the EEMD-improved model simulations using the Average Ensemble Mean, Multiple Linear Regression, Singular Value Decomposition and Bayesian Model Averaging methods. The results showed that the MME forecasts performed better when the calculations were based on the EEMD-improved simulations as opposed to the original simulations on both the global and continental scale. Therefore, the results of the MME were further improved by using the EEMD-improved model simulations. This new method provides a simple way to improve model performance and can be easily applied to further improve MME simulations.

Electrical stimulation (ES)-triggered up-regulation of brain-derived neurotrophic factor (BDNF) and neurite outgrowth in cultured rat postnatal dorsal root ganglion neurons (DRGNs) is calcium (Ca2+)-dependent. The effects of increased Ca2+ on BDNF up-regulation and neurite outgrowth remain unclear. We showed here that ES increased phosphorylation of the cAMP-response element binding protein (CREB). Blockade of Ca2+ suppressed CREB phosphorylation and neurite outgrowth. Down-regulation of phosphorylated (p)-CREB reduced BDNF transcription and neurite outgrowth triggered by ES. Furthermore, blockade of calmodulin-dependent protein kinase II (CaMKII) using the inhibitors KN93 or KN62 reduced p-CREB, and specific knockdown of the CaMKIIα or CaMKIIβ subunit was sufficient to suppress p-CREB. Recombinant BDNF or hyperforin reversed the effects of Ca2+ blockade and CaMKII knockdown. Taken together, these data establish a potential signaling pathway of Ca2+-CaMKII-CREB in neuronal activation. To our knowledge, this is the first report of the mechanisms of Ca2+-dependent BDNF transcription and neurite outgrowth triggered by ES. These findings might help further investigation of complex molecular signaling networks in ES-triggered nerve regeneration in vivo.