Longitudinal varying coefficient single-index model with censored covariates.

It is of interest to health policy research to estimate the population-averaged longitudinal medical cost trajectory from initial cancer diagnosis to death, and understand how the trajectory curve is affected by patient characteristics. This research question leads to a number of statistical challenges because the longitudinal cost data are often non-normally distributed with skewness, zero-inflation, and heteroscedasticity. The trajectory is nonlinear, and its length and shape depend on survival, which are subject to censoring. Modeling the association between multiple patient characteristics and nonlinear cost trajectory curves of varying lengths should take into consideration parsimony, flexibility, and interpretation. We propose a novel longitudinal varying coefficient single-index model. Multiple patient characteristics are summarized in a single-index, representing a patient's overall propensity for healthcare use. The effects of this index on various segments of the cost trajectory depend on both time and survival, which is flexibly modeled by a bivariate varying coefficient function. The model is estimated by generalized estimating equations with an extended marginal mean structure to accommodate censored survival time as a covariate. We established the pointwise confidence interval of the varying coefficient and a test for the covariate effect. The numerical performance was extensively studied in simulations. We applied the proposed methodology to medical cost data of prostate cancer patients from the Surveillance, Epidemiology, and End Results-Medicare-Linked Database.

Preclinical assessment of IL-1ß primed human umbilical cord mesenchymal stem cells for tendon functional repair through TGF-ß/IL-10 signaling.

Background: Inadequate repair capacity and disturbed immune compartments are the main pathological causes of tendinopathy. Transplantation of mesenchymal stem cells (MSCs) become an effective clinic option to alleviate tendinopathy. Interleukin-1ß (IL-1ß) could confer on MSCs enhanced immunoregulatory capability to remodel the repair microenvironment favoring tissue repair. Therefore, IL-1ß activated UC-MSCs (1ßUC-MSCs) may exert favorable efficacy in promoting tendon repair in a preclinical tendinopathy rat model. Methods: Tendon-derived stem cells (TDSCs) were isolated and characterized. In vitro, the levels of immunoregulatory-related cytokines such as IL-1ß, IL-6, IL-10, and TGF-ß secreted by 1ßUC-MSCs and unprimed UC-MSCs was measured. And tendon-specific markers expressed by TDSCs cultured with primed cultured medium (CM) or unprimed CM were detected. In vivo, Achilles tendinopathy was induced by 30 µL collagenase I injection in Sprague Dawley rats. One week later, the rats were randomly injected with UC-MSCs primed with IL-1ß (106 cells per tendon), UC-MSCs, or PBS. After rats were sacrificed, histological evaluation, electron microscopy, biomechanical tests, gait performance were conducted to evaluate the structural and functional recovery of Achilles tendons. The inflammation and metabolic state of the extracellular matrix, and the potential mechanism were assessed by immunohistochemical staining and Western blot. Results: UC-MSCs were activated by IL-1ß to secrete higher levels of IL-10 and TGF-ß while the secretion levels of IL-6 and IL-1ß were not changed significantly, promoting a higher expression level of COL I and TNMD in TDSCs under proinflammatory environment. In vivo, the transplanted 1ßUC-MSCs could survive up to 5 weeks after injection with tenogenic differentiation and improved tendon healing histologically semi-quantified by modified Bonar scores. This structural regeneration was further confirmed by observation of ultrastructural morphology, and led to good functional recovery including improved biomechanical properties and gait performance. During this process, the inflammatory response and metabolism of the extracellular matrix was improved through TGF-ß/IL-10 pathway. Conclusion: This study demonstrated that the transplantation of UC-MSCs activated by IL-1ß exhibited satisfactory ability for promoting tendon functional repair in a tendinopathy rat model. During this process, the balance of inflammatory response and extracellular matrix metabolism was remodeled, and the TGF-ß/Smad2/3 and IL-10 signaling pathways were activated simultaneously. We cautiously conclude that the IL-1ß primed UC-MSCs could be a promising strategy for enhancing the ability of MSCs to treat tendinopathy.

Concrete Cover Cracking and Reinforcement Corrosion Behavior in Concrete with New-to-Old Concrete Interfaces.

In reinforced concrete (RC) structures, new-to-old concrete interfaces are widely present due to precast splices, repairs, and construction joints. In this paper, both monolithic and segmental specimens were fabricated with five kinds of water-cement ratios, including ordinary and high-strength concrete. The impressed current-accelerated corrosion test was used, and the degree of reinforcement corrosion was controlled by Faraday's Law. In the accelerated corrosion process, the concrete surface cracking, steel corrosion, and mechanical properties of the corroded steels in the segmental specimens were investigated and compared with monolithic specimens considering the pouring method, concrete strength, and the strength difference between new and old concrete. The prediction of concrete cracking time was also discussed. The results indicated that, for the monolithic specimens, longitudinal cracks could be observed on the ordinary concrete surface, while no cracks were produced on a high-strength concrete surface; only the rust leaked out at the ends. For the segmental specimens, both longitudinal and transverse cracks were produced on an ordinary concrete surface, while only transverse cracks were produced at the high-strength new-to-old concrete interfaces. The steel embedded in the segmental specimens suffered more sectional loss at the new-to-old concrete interfaces. An influence coefficient based on the section loss of the rebar was proposed to evaluate the influence of interfaces on the rust uniformity of rebars. When there were differences in strength between new and old concrete, the influence of the interface on the uniformity of steel bar cross-section loss slightly increased. Based on available theoretical analysis for uniform corrosion, the concrete cracking time of the monolithic specimens was predicted, which was basically consistent with experimental phenomena. However, further research is needed to predict the service life of segmental specimens with new-to-old concrete interfaces.

Trifluoroethanol and the behavior of a tardigrade desiccation-tolerance protein.

The cosolvent 2,2,2-trifluoroethanol (TFE) is often used to mimic protein desiccation. We assessed the effects of TFE on cytosolic abundant heat soluble protein D (CAHS D) from tardigrades. CAHS D is a member of a unique protein class that is necessary and sufficient for tardigrades to survive desiccation. We find that the response of CAHS D to TFE depends on the concentration of both species. Dilute CAHS D remains soluble and, like most proteins exposed to TFE, gains α-helix. More concentrated solutions of CAHS D in TFE accumulate ß-sheet, driving both gel formation and aggregation. At even higher TFE and CAHS D concentrations, samples phase separate without aggregation or increases in helix. Our observations show the importance of considering protein concentration when using TFE.

Glycolipotoxicity conferred tendinopathy through ferroptosis dictation of tendon-derived stem cells by YAP activation.

Tendinopathy is a condition characterized by chronic, complex, and multidimensional pathological changes in the tendons. The etiology of tendinopathy is the combination of several factors, and diabetes mellitus (DM) is a risk factor. Increasing evidence has shown that the diabetic microenvironment plays an important role in tendinopathy. However, the mechanism causing tendinopathy in patients with DM remains unclear. Our study found that ferroptosis played an important role in tendinopathy in patients with DM. In vitro, high glucose and high fat treatment was used to simulate the DM microenvironment. Results showed that such a mechanism significantly increased ferroptosis, which was characterized by mass cell death, lipid peroxide accumulation, mitochondrial morphological changes, mitochondrial membrane potential decline, iron overload, and the activation of ferroptosis-related genes, in tendon-derived stem cells cultured in vitro. In the animal studies, db/db mice were used in the DM model, and the db mice had severe tendon injury and high ACSL4 and TfR1 expressions. These phenomena could be alleviated by the ferroptosis inhibitor ferrostatin-1. In conclusion, ferroptosis is associated with tendinopathy in patients with DM, and ferroptosis targeting may be a novel approach for treating diabetic tendinopathy. Our results can provide a new strategy for managing tendinopathy clinically in patients with DM.

Prostate cancer in New York City: impact of neighborhood level social determinants of care.

Social determinants of health may impact prostate cancer presentation. Since neighborhoods may influence adjacent neighborhoods across often porous and arbitrary borders, we performed generalized spatial two stage least squares cross sections regression to assess direct and indirect (via adjacent neighborhoods) impact of neighborhood level independent variables. Using the New York State Public Access Cancer Epidemiology Data and the NYC Open neighborhood-level dataset, we discovered a direct association between Race and poverty with the likelihood of presenting with advanced prostate cancer. There were no indirect impacts of neighborhood variables, indicating the need to directly target neighborhoods to improve outcomes.

Comparisons of Medical Cost Trajectories Between Non-Hispanic Black and Non-Hispanic White Patients With Newly Diagnosed Localized Prostate Cancer.

OBJECTIVES: This study applied a recently developed statistical method to compare the mean cost trajectories between non-Hispanic White (NHW) and non-Hispanic Black (NHB) patients with localized prostate cancer conditioning on patients' survival. METHODS: In this observational study, we modeled cost trajectories of NHW and NHB patients with localized prostate cancer for 3 survival durations: 24, 48, and 72 months. We also compared the cost trajectories between NHW and NHB, stratified by comorbidities scores. RESULTS: We find that the mean cost trajectories of NHB were significantly higher than the trajectories of NHW in the last 12 months before death, regardless of the survival duration and patients' baseline comorbidity scores. For patients with comorbidity score ≥2, mean cost trajectories within the first year of diagnosis for NHB were significantly higher than those for NHW, except for the subgroup of patients with comorbidity 2-3 and whose survival length was 72 months. CONCLUSIONS: Our results suggested that a higher proportion of NHB patients with high comorbidity scores are likely contribute to their higher end-of-life costs than those for NHW patients. To narrow the gap in healthcare-related financial burden between NHB and NHW patients with localized prostate cancer, policy makers need to explore different strategies to better manage comorbidities.

[Lamin B1 regulates the growth of hepatocellular carcinoma cells by influencing telomerase activity].

Lamin B1 (LMNB1) is highly expressed in liver cancer tissues, and its influence and mechanism on the proliferation of hepatocellular carcinoma cells were explored by knocking down the expression of the protein. In liver cancer cells, siRNAs were used to knock down LMNB1. Knockdown effects were detected by Western blotting. Changes in telomerase activity were detected by telomeric repeat amplification protocol assay (TRAP) experiments. Telomere length changes were detected by quantitative real-time polymerase chain reaction (qPCR). CCK8, cloning formation, transwell and wound healing were performed to detect changes in its growth, invasion and migration capabilities. The lentiviral system was used to construct HepG2 cells that steadily knocked down LMNB1. Then the changes of telomere length and telomerase activity were detected, and the cell aging status was detected by SA-ß-gal senescence staining. The effects of tumorigenesis were detected by nude mouse subcutaneous tumorigenesis experiments, subsequent histification staining of tumors, SA-ß-gal senescence staining, fluorescence in situ hybridization (FISH) for telomere analysis and other experiments. Finally, the method of biogenesis analysis was used to find the expression of LMNB1 in clinical liver cancer tissues, and its relationship with clinical stages and patient survival. Knockdown of LMNB1 in HepG2 and Hep3B cells significantly reduced telomerase activity, cell proliferation, migration and invasion abilities. Experiments in cells and tumor formation in nude mice had demonstrated that stable knockdown of LMNB1 reduced telomerase activity, shortened telomere length, senesced cells, reduced cell tumorigenicity and KI-67 expression. Bioinformatics analysis showed that LMNB1 was highly expressed in liver cancer tissues and correlated with tumor stage and patient survival. In conclusion, LMNB1 is overexpressed in liver cancer cells, and it is expected to become an indicator for evaluating the clinical prognosis of liver cancer patients and a target for precise treatment.

Insulin-like growth factor binding protein 4 loaded electrospun membrane ameliorating tendon injury by promoting retention of IGF-1.

Tendon injury is one of the most common musculoskeletal disorders that impair joint mobility and lower quality of life. The limited regenerative capacity of tendon remains a clinical challenge. Local delivery of bioactive protein is a viable therapeutic approach for tendon healing. Insulin-like growth factor binding protein 4 (IGFBP-4) is a secreted protein capable of binding and stabilizing insulin-like growth factor 1 (IGF-1). Here, we applied an aqueous-aqueous freezing-induced phase separation technology to obtain the IGFBP4-encapsulated dextran particles. Then, we added the particles into poly (L-lactic acid) (PLLA) solution to fabricate IGFBP4-PLLA electrospun membrane for efficient IGFBP-4 delivery. The scaffold showed excellent cytocompatibility and a sustained release of IGFBP-4 for nearly 30 days. In cellular experiments, IGFBP-4 promoted tendon-related and proliferative markers expression. In a rat Achilles tendon injury model, immunohistochemistry and quantitative real-time polymerase chain reaction confirmed better outcomes by using the IGFBP4-PLLA electrospun membrane at the molecular level. Furthermore, the scaffold effectively promoted tendon healing in functional performance, ultrastructure and biomechanical properties. We found addition of IGFBP-4 promoted IGF-1 retention in tendon postoperatively and then facilitated protein synthesis via IGF-1/AKT signaling pathway. Overall, our IGFBP4-PLLA electrospun membrane provides a promising therapeutic strategy for tendon injury.

Enabling Specific Photocatalytic Methane Oxidation by Controlling Free Radical Type.

Selective CH4 oxidation to CH3OH or HCHO with O2 in H2O under mild conditions provides a desired sustainable pathway for synthesis of commodity chemicals. However, manipulating reaction selectivity while maintaining high productivity remains a huge challenge due to the difficulty in the kinetic control of the formation of a desired oxygenate against its overoxidation. Here, we propose a highly efficient strategy, based on the precise control of the type of as-formed radicals by rational design on photocatalysts, to achieve both high selectivity and high productivity of CH3OH and HCHO in CH4 photooxidation for the first time. Through tuning the band structure and the size of active sites (i.e., single atoms or nanoparticles) in our Au/In2O3 catalyst, we show alternative formation of two important radicals, •OOH and •OH, which leads to distinctly different reaction paths to the formation of CH3OH and HCHO, respectively. This approach gives rise to a remarkable HCHO selectivity and yield of 97.62% and 6.09 mmol g-1 on In2O3-supported Au single atoms (Au1/In2O3) and an exceptional CH3OH selectivity and yield of 89.42% and 5.95 mmol g-1 on In2O3-supported Au nanoparticles (AuNPs/In2O3), respectively, upon photocatalytic CH4 oxidation for 3 h at room temperature. This work opens a new avenue toward efficient and selective CH4 oxidation by delicate design of composite photocatalysts.

Risk Factors for Bronchiolitis Obliterans Syndrome after Initial Detection of Pulmonary Impairment after Hematopoietic Cell Transplantation.

Pulmonary chronic graft-versus-host-disease (cGVHD), or bronchiolitis obliterans syndrome (BOS), is a highly morbid complication of hematopoietic cell transplantation (HCT). The clinical significance of a single instance of pulmonary decline not meeting the criteria for BOS is unclear. We conducted a retrospective analysis in a cohort of patients who had an initial post-HCT decline in the absolute value of forced expiratory volume in 1 second (FEV1) of ≥10% or mid-expiratory flow rate of ≥25% but not meeting the criteria for BOS (pre-BOS). We examined the impact of clinical variables in patients with pre-BOS on the risk for subsequent BOS. Pre-BOS developed in 1325 of 3170 patients (42%), of whom 72 (5%) later developed BOS. Eighty-four patients developed BOS without detection of pre-BOS by routine screening. Among patients with pre-BOS, after adjusting for other significant variables, airflow obstruction (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.1 to 3.7; P = .02), percent-predicted FEV1 on decline (HR, .98; 95% CI, .97 to 1.0; P = .02), active cGVHD (HR, 7.7; 95% CI, 3.1 to 19.3; P < .001), peripheral blood stem cell source (HR, 3.8; 95% CI, 1.7 to 8.6; P = .001), and myeloablative conditioning (HR, 2.0; 95% CI, 1.1 to 3.5; P = .02) were associated with subsequent BOS. The absence of airflow obstruction and cGVHD had a negative predictive value of 100% at 6 months for subsequent BOS, but the positive predictive value of both factors was low (cGVHD, 3%; any obstruction, 4%; combined, 6%). Several clinical factors at the time of pre-BOS, particularly active cGVHD and airflow obstruction, increase the risk for subsequent BOS. These factors merit consideration to be included in screening practices to improve the detection of BOS, with the caveat that the predictive utility of these factors is limited by the overall low incidence of BOS among patients with pre-BOS.

Secondary structure and stability of a gel-forming tardigrade desiccation-tolerance protein.

Protein-based pharmaceuticals are increasingly important, but their inherent instability necessitates a "cold chain" requiring costly refrigeration during production, shipment, and storage. Drying can overcome this problem, but most proteins need the addition of stabilizers, and some cannot be successfully formulated. Thus, there is a need for new, more effective protective molecules. Cytosolically, abundant heat-soluble proteins from tardigrades are both fundamentally interesting and a promising source of inspiration; these disordered, monodisperse polymers form hydrogels whose structure may protect client proteins during drying. We used attenuated total reflectance Fourier transform infrared spectroscopy, differential scanning calorimetry, and small-amplitude oscillatory shear rheometry to characterize gelation. A 5% (wt/vol) gel has a strength comparable with human skin, and melts cooperatively and reversibly near body temperature with an enthalpy comparable with globular proteins. We suggest that the dilute protein forms α-helical coiled coils and increasing their concentration drives gelation via intermolecular ß-sheet formation.

Elevating Photooxidation of Methane to Formaldehyde via TiO2 Crystal Phase Engineering.

Photocatalytic conversion of methane to value-added products under mild conditions, which represents a long sought-after goal for industrial sustainable production, remains extremely challenging to afford high production and selectivity using cheap catalysts. Herein, we present the crystal phase engineering of commercially available anatase TiO2 via simple thermal annealing to optimize the structure-property correlation. A biphase catalyst with anatase (90%) and rutile (10%) TiO2 with the optimal phase interface concentration exhibits exceptional performance in the oxidation of methane to formaldehyde under the reaction conditions of water solvent, oxygen atmosphere, and full-spectrum light irradiation. An unprecedented production of 24.27 mmol gcat-1 with an excellent selectivity of 97.4% toward formaldehyde is acquired at room temperature after a 3 h reaction. Both experimental results and theoretical calculations disclose that the crystal phase engineering of TiO2 lengthens the lifetime of photogenerated carriers and favors the formation of intermediate methanol species, thus maximizing the efficiency and selectivity in the aerobic oxidation of methane to formaldehyde. More importantly, the feasibility of the scale-up production of formaldehyde is demonstrated by inventing a "pause-flow" reactor. This work opens the avenue toward industrial methane transformation in a sustainable and economical way.

Energy-Supporting Enzyme-Mimic Nanoscaffold Facilitates Tendon Regeneration Based on a Mitochondrial Protection and Microenvironment Remodeling Strategy.

Tendon injury is a tricky and prevalent motor system disease, leading to compromised daily activity and disability. Insufficient regenerative capability and dysregulation of immune microenvironment are the leading causes of functional loss. First, this work identifies persistent oxidative stress and mitochondrial impairment in the regional tendon tissues postinjury. Therefore, a smart scaffold incorporating the enzyme mimicry nanoparticle-ceria nanozyme (CeNPs) into the nanofiber bundle scaffold (NBS@CeO) with porous, anisotropic, and enhanced mechanical properties is designed to innovatively explore a targeted energy-supporting repair strategy by rescuing mitochondrial function and remodeling the microenvironment favoring endogenous regeneration. The integrated CeNPs scavenge excessive reactive oxygen species (ROS), stabilize the mitochondria membrane potential (ΔΨm), and ATP synthesis of tendon-derived stem cells (TDSCs) under oxidative stress. In a rat Achilles tendon defect model, NBS@CeO reduces oxidative damage and accelerates structural regeneration of collagen fibers, manifesting as recovering mechanical properties and motor function. Furthermore, NBS@CeO mediates the rebalance of endogenous regenerative signaling and dysregulated immune microenvironment by alleviating senescence and apoptosis of TDSCs, downregulating the secretion of senescence-associated secretory phenotype (SASP), and inducing macrophage M2 polarization. This innovative strategy highlights the role of NBS@CeO in tendon repair and thus provides a potential therapeutic approach for promoting tendon regeneration.

Neural Peptide α-CGRP Coregulated Angiogenesis and Osteogenesis via Promoting the Cross-Talk between Mesenchymal Stem Cells and Endothelial Cells.

Background: The coupled vascularization and bone remodeling are key steps during bone healing, during which the cross-talk between mesenchymal stem cells (MSCs) and endothelial cells plays vital roles. Evidence indicates the well-characterized neuropeptide Calcitonin Gene-Related Peptide-α (CGRP) is proven to play an important role during bone regeneration. However, the regulatory effects of αCGRP on angiogenesis and osteogenesis, as well as underlying cellular and molecular mechanisms, remain unclear. Aim: The present study was performed to verify the availability of the CGRP for osteogenic capacity in MSCs and explore its potential underlying molecular mechanism. After that, the promoted angiogenic effect of CGRP as well as its underlying mechanisms was studied. Methods and Results: The results showed that CGRP could significantly increase the cyclic adenosine monophosphate (cAMP) level and promote the osteogenesis ability of MSCs via cAMP/PKA signaling pathway. Direct exposure to CGRP increased nitric oxide synthase expression, the release of NO, tube formation, and wound healing of human umbilical vein endothelial cells (HUVEC). The CGRP-treated MSCs were observed with high expression levels of angiogenic factors, such as bFGF and VEGF-α; the conditioned medium derived from CGRP-treated MSCs was also able to promote tube formation and transmembrane migration of HUVECs. Conclusion: These findings demonstrate the coregulated angiogenesis and osteogenesis effects of CGRP, especially for its regulation effects on the cross-talk between mesenchymal stem cells and endothelial cells.

Biomimetic multilayer polycaprolactone/sodium alginate hydrogel scaffolds loaded with melatonin facilitate tendon regeneration.

Tendon injury is one of the most common musculoskeletal diseases in the world, severely challenging the public health care system. Electrospinning technique using polymer materials (i.e. polycaprolactone (PCL)) and hydrogels (i.e. sodium alginate (ALG)) contribute to the development and application of smart composite scaffolds in the tendon tissue engineering by advantageously integrating mechanical properties and biocompatibility. As a potential natural antioxidant, melatonin (MLT) represents the potential to promote tendon repair. Here, we develop an MLT-loaded PCL/ALG composite scaffold that effectively promotes tendon injury repair in vivo and in vitro via a controlled release of MLT, possibly mechanically relying on an antioxidant stress pathway. This biomimetic composite scaffold will be of great significance in the tendon tissue engineering.

PGC-1α attenuates the oxidative stress-induced impaired osteogenesis and angiogenesis regulation effects of mesenchymal stem cells in the presence of diabetic serum.

Oxidative stress is believed to induce dysfunction of the bone remodeling process and be associated with progressive loss of bone mass. The peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) is a master controller during mitochondrial biogenesis and the antioxidant response. We postulated that PGC-1α could function as a cyto-protective effector in mesenchymal stem cells (MSCs) under oxidative stress conditions. In this study, diabetic serum was firstly used to treat MSCs to induce oxidative damage. The anti-oxidative protective effects of PGC-1α overexpression on MSCs, as well as MSCs' osteogenesis and angiogenic regulation effects were investigated in vitro. Results showed that diabetic conditions induced significantly increase of intracellular oxidative damage and mitochondrial permeability transition pore (mPTP) opening activity, decrease of cellular viability, and osteogenic differentiation and pro-angiogenic regulation effects of MSCs. However, the diabetic conditions induced oxidative impair on MSCs were significantly alleviated via PGC-1α overexpression under diabetic conditions. Taken together, this study indicates the anti-oxidative treatment potential of PGC-1α regulation as a promising strategy to promote coupling pro-osteogenesis and pro-angiogenesis effects of MSCs.

MicroRNA engineered umbilical cord stem cell-derived exosomes direct tendon regeneration by mTOR signaling.

BACKGROUND: Exosomes are extracellular vesicles of nano-structures and represent an emerging nano-scale acellular therapy in recent years. Tendon regeneration is a sophisticated process in the field of microsurgery due to its poor natural healing ability. To date, no successful long-term solution has been provided for the healing of tendon injuries. Functional recovery requires advanced treatment strategies. Human umbilical cord mesenchymal stem cell-derived exosomes (HUMSC-Exos) are considered as promising cell-free therapeutic agents. However, few studies reported their potential in the tendon repair previously. In this study, we explored the roles and underlying mechanisms of HUMSC-Exos in the tendon regeneration. RESULTS: Expression of tendon-specific markers in, and collagen deposition by, tendon-derived stem cells (TDSCs) treated with HUMSC-Exos increased in vitro. In a rat Achilles tendon injury model, treatment with HUMSC-Exos improved the histological structure, enhanced tendon-specific matrix components, and optimized biomechanical properties of the Achilles tendon. Findings in miRNA sequencing indicated a significant increase in miR-29a-3p in HUMSC-Exo-treated Achilles tendons. Next, luciferase assay in combination with western blot identified phosphatase and tensin homolog (PTEN) as the specific target of miR-29a-3p. Furthermore, we applied a miR-29a-3p-specific agonist to engineer HUMSC-Exos. These HUMSC-Exos overexpressing miR-29a-3p amplified the gain effects of HUMSC-Exos on tendon healing in vivo. To explore the underlying mechanisms, a transforming growth factor-ß1 (TGF-ß1) inhibitor (SB-431542), mTOR inhibitor (rapamycin), and engineered HUMSC-Exos were employed. The results showed that TGF-ß1 and mTOR signaling were involved in the beneficial effects of HUMSC-Exos on tendon regeneration. CONCLUSION: The findings in our study suggest that PTEN/mTOR/TGF-ß1 signaling cascades may be a potential pathway for HUMSC-Exos to deliver miR-29a-3p for tendon healing and implicate a novel therapeutic strategy for tendon regeneration via engineered stem cell-derived exosomes.

Effects of Prey's Diffusion on Predator-Prey Systems with Two Patches.

This paper considers predator-prey systems in which the prey can move between source and sink patches. First, we give a complete analysis on global dynamics of the model. Then, we show that when diffusion from the source to sink is not large, the species would coexist at a steady state; when the diffusion is large, the predator goes to extinction, while the prey persists in both patches at a steady state; when the diffusion is extremely large, both species go to extinction. It is derived that diffusion in the system could lead to results reversing those without diffusion. That is, diffusion could change species' coexistence if non-diffusing, to extinction of the predator, and even to extinction of both species. Furthermore, we show that intermediate diffusion to the sink could make the prey reach total abundance higher than if non-diffusing, larger or smaller diffusion rates are not favorable. The total abundance, as a function of diffusion rates, can be both hump-shaped and bowl-shaped, which extends previous theory. A novel finding of this work is that there exist diffusion scenarios which could drive the predator into extinction and make the prey reach the maximal abundance. Diffusion from the sink to source and asymmetry in diffusion could also lead to results reversing those without diffusion. Meanwhile, diffusion always leads to reduction of the predator's density. The results are biologically important in protection of endangered species.

Interaction analysis under misspecification of main effects: Some common mistakes and simple solutions.

The statistical practice of modeling interaction with two linear main effects and a product term is ubiquitous in the statistical and epidemiological literature. Most data modelers are aware that the misspecification of main effects can potentially cause severe type I error inflation in tests for interactions, leading to spurious detection of interactions. However, modeling practice has not changed. In this article, we focus on the specific situation where the main effects in the model are misspecified as linear terms and characterize its impact on common tests for statistical interaction. We then propose some simple alternatives that fix the issue of potential type I error inflation in testing interaction due to main effect misspecification. We show that when using the sandwich variance estimator for a linear regression model with a quantitative outcome and two independent factors, both the Wald and score tests asymptotically maintain the correct type I error rate. However, if the independence assumption does not hold or the outcome is binary, using the sandwich estimator does not fix the problem. We further demonstrate that flexibly modeling the main effect under a generalized additive model can largely reduce or often remove bias in the estimates and maintain the correct type I error rate for both quantitative and binary outcomes regardless of the independence assumption. We show, under the independence assumption and for a continuous outcome, overfitting and flexibly modeling the main effects does not lead to power loss asymptotically relative to a correctly specified main effect model. Our simulation study further demonstrates the empirical fact that using flexible models for the main effects does not result in a significant loss of power for testing interaction in general. Our results provide an improved understanding of the strengths and limitations for tests of interaction in the presence of main effect misspecification. Using data from a large biobank study "The Michigan Genomics Initiative", we present two examples of interaction analysis in support of our results.