Association between COVID-19 convalescent plasma antibody levels and COVID-19 outcomes stratified by clinical status at presentation.

BACKGROUND: There is a need to understand the relationship between COVID-19 Convalescent Plasma (CCP) anti-SARS-CoV-2 IgG levels and clinical outcomes to optimize CCP use. This study aims to evaluate the relationship between recipient baseline clinical status, clinical outcomes, and CCP antibody levels. METHODS: The study analyzed data from the COMPILE study, a meta-analysis of pooled individual patient data from 8 randomized clinical trials (RCTs) assessing the efficacy of CCP vs. control, in adults hospitalized for COVID-19 who were not receiving mechanical ventilation at randomization. SARS-CoV-2 IgG levels, referred to as 'dose' of CCP treatment, were retrospectively measured in donor sera or the administered CCP, semi-quantitatively using the VITROS Anti-SARS-CoV-2 IgG chemiluminescent immunoassay (Ortho-Clinical Diagnostics) with a signal-to-cutoff ratio (S/Co). The association between CCP dose and outcomes was investigated, treating dose as either continuous or categorized (higher vs. lower vs. control), stratified by recipient oxygen supplementation status at presentation. RESULTS: A total of 1714 participants were included in the study, 1138 control- and 576 CCP-treated patients for whom donor CCP anti-SARS-CoV2 antibody levels were available from the COMPILE study. For participants not receiving oxygen supplementation at baseline, higher-dose CCP (/control) was associated with a reduced risk of ventilation or death at day 14 (OR = 0.19, 95% CrI: [0.02, 1.70], posterior probability Pr(OR < 1) = 0.93) and day 28 mortality (OR = 0.27 [0.02, 2.53], Pr(OR < 1) = 0.87), compared to lower-dose CCP (/control) (ventilation or death at day 14 OR = 0.79 [0.07, 6.87], Pr(OR < 1) = 0.58; and day 28 mortality OR = 1.11 [0.10, 10.49], Pr(OR < 1) = 0.46), exhibiting a consistently positive CCP dose effect on clinical outcomes. For participants receiving oxygen at baseline, the dose-outcome relationship was less clear, although a potential benefit for day 28 mortality was observed with higher-dose CCP (/control) (OR = 0.66 [0.36, 1.13], Pr(OR < 1) = 0.93) compared to lower-dose CCP (/control) (OR = 1.14 [0.73, 1.78], Pr(OR < 1) = 0.28). CONCLUSION: Higher-dose CCP is associated with its effectiveness in patients not initially receiving oxygen supplementation, however, further research is needed to understand the interplay between CCP anti-SARS-CoV-2 IgG levels and clinical outcome in COVID-19 patients initially receiving oxygen supplementation.

Biomechanical analysis of adjacent segments after correction surgery for adult idiopathic scoliosis: a finite element analysis.

The biomechanical aspects of adjacent segment degeneration after Adult Idiopathic Scoliosis (AdIS) corrective surgery involving postoperative changes in motion and stress of adjacent segments have yet to be investigated. The objective of this study was to evaluate the biomechanical effects of corrective surgery on adjacent segments in adult idiopathic scoliosis by finite element analysis. Based on computed tomography data of the consecutive spine from T1-S1 of a 28-year-old male patient with adult idiopathic scoliosis, a three-dimensional finite element model was established to simulate the biomechanics. Two posterior long-segment fixation and fusion operations were designed: Strategy A, pedicle screws implanted in all segments of both sides, and Strategy B, alternate screws instrumentation on both sides. The range of motion (ROM), Maximum von Mises stress value of intervertebral disc (IVD), and Maximum von Mises stress of the facet joint (FJ) at the fixation adjacent segment were calculated and compared with data of the preoperative AdIS model. Corrective surgery decreased the IVD on the adjacent segments, increased the FJ on the adjacent segments, and decreased the ROM of the adjacent segments. A greater decrease of Maximum von Mises stress was observed on the distal adjacent segment compared with the proximal adjacent segment. The decrease of Maximum von Mises stress and increment of Maximum von Mises stress on adjacent FJ in strategy B was greater than that in strategy A. Under the six operation modes, the change of the Maximum von Mises stress on the adjacent IVD and FJ was significant. The decrease in ROM in the proximal adjacent segment was greater than that of the distal adjacent segment, and the decrease of ROM in strategy A was greater than that in strategy B. This study clarified the biomechanical characteristics of adjacent segments after AdIS corrective surgery, and further biomechanical analysis of two different posterior pedicle screw placement schemes by finite element method. Our study provides a theoretical basis for the pathogenesis, prevention, and treatment of adjacent segment degeneration after corrective surgery for AdIS.

Development of deaminase-free T-to-S base editor and C-to-G base editor by engineered human uracil DNA glycosylase.

DNA base editors enable direct editing of adenine (A), cytosine (C), or guanine (G), but there is no base editor for direct thymine (T) editing currently. Here we develop two deaminase-free glycosylase-based base editors for direct T editing (gTBE) and C editing (gCBE) by fusing Cas9 nickase (nCas9) with engineered human uracil DNA glycosylase (UNG) variants. By several rounds of structure-informed rational mutagenesis on UNG in cultured human cells, we obtain gTBE and gCBE with high activity of T-to-S (i.e., T-to-C or T-to-G) and C-to-G conversions, respectively. Furthermore, we conduct parallel comparison of gTBE/gCBE with those recently developed using other protein engineering strategies, and find gTBE/gCBE show the outperformance. Thus, we provide several base editors, gTBEs and gCBEs, with corresponding engineered UNG variants, broadening the targeting scope of base editors.

Elevated CO2 exacerbates the risk of methylmercury exposure in consuming aquatic products: Evidence from a complex paddy wetland ecosystem.

Elevated CO2 levels and methylmercury (MeHg) pollution are important environmental issues faced across the globe. However, the impact of elevated CO2 on MeHg production and its biological utilization remains to be fully understood, particularly in realistic complex systems with biotic interactions. Here, a complete paddy wetland microcosm, namely, the rice-fish-snail co-culture system, was constructed to investigate the impacts of elevated CO2 (600 ppm) on MeHg formation, bioaccumulation, and possible health risks, in multiple environmental and biological media. The results revealed that elevated CO2 significantly increased MeHg concentrations in the overlying water, periphyton, snails and fish, by 135.5%, 66.9%, 45.5%, and 52.1%, respectively. A high MeHg concentration in periphyton, the main diet of snails and fish, was the key factor influencing the enhanced MeHg in aquatic products. Furthermore, elevated CO2 alleviated the carbon limitation in the overlying water and proliferated green algae, with subsequent changes in physico-chemical properties and nutrient concentrations in the overlying water. More algal-derived organic matter promoted an enriched abundance of Archaea-hgcA and Deltaproteobacteria-hgcA genes. This consequently increased the MeHg in the overlying water and food chain. However, MeHg concentrations in rice and soil did not increase under elevated CO2, nor did hgcA gene abundance in soil. The results reveal that elevated CO2 exacerbated the risk of MeHg intake from aquatic products in paddy wetland, indicating an intensified MeHg threat under future elevated CO2 levels.

Effects of nonsynonymous single nucleotide polymorphisms of the KIAA1217, SNTA1 and LTBP1 genes on the growth traits of Ujumqin sheep.

Sheep body size can directly reflect the growth rates and fattening rates of sheep and is also an important index for measuring the growth performance of meat sheep. In this study, high-resolution resequencing data from four sheep breeds (Dorper sheep, Suffolk sheep, Ouessant sheep, and Shetland sheep) were analyzed. The nonsynonymous single nucleotide polymorphisms of three candidate genes (KIAA1217, SNTA1, and LTBP1) were also genotyped in 642 healthy Ujumqin sheep using MALDI-TOFMS and the genotyping results were associated with growth traits. The results showed that different genotypes of the KIAA1217 g.24429511T>C locus had significant effects on the chest circumferences of Ujumqin sheep. The SNTA1 g.62222626C>A locus had different effects on the chest depths, shoulder widths and rump widths of Ujumqin sheep. This study showed that these two sites can be used for marker-assisted selection, which will be beneficial for future precision molecular breeding.

V6 vein-preserving superior segmentectomy: A potentially preferable option.

Objective: The increasing identification of pulmonary nodules has led to a growing emphasis on segmentectomy. Nevertheless, the surgical process for segmentectomy is complex and optimizing segmentectomy is a critical clinical concern. This study aimed to evaluate the safety and short- and long-term efficacy of V6-preserving superior segmentectomy. Methods: We performed a retrospective analysis of patients who underwent thoracoscopic superior segmentectomy at our hospital between January 2019 and June 2020. Eligible patients were categorized into an V6 vein-preserving segmentectomy (VVPS) group and a Non V6 vein-preserving segmentectomy (NVVPS) group depending on the preservation of V6. Primary outcome measures encompassed the evaluation of surgical safety (surgical margins, 3-year overall survival, and disease-free survival), whereas secondary measures included postoperative complication rates, operative time, estimated intraoperative blood loss, length of hospital stay, and associated costs. Results: The analysis included a final cohort of 78 patients. In the NVVPS group (n = 43), 95.3 % of patients exceeded the tumor diameter, and no positive surgical margins were observed. The 3-year overall survival (OS) and disease-free survival (DFS) rates for the NVVPS group were 95.3 %, with no significant differences in OS (p = 0.572) and DFS (P = 0.800) compared with the VVPS group. Additionally, the median total hospitalization cost for the NVVPS group was 41,400 RMB (IQR, 38,800-43,400), which was significantly lower than that of the VVPS group, showing statistical significance (P < 0.05). No statistically significant differences were observed in the incidence of postoperative complications and length of stay between the two groups (P > 0.05). Conclusion: V6-preserving superior segmentectomy is a secure and optimized surgical alternative. Its streamlined procedure facilitates easier adoption in primary healthcare facilities, rendering it a superior choice for superior segmentectomy.

Effects of added trunk load on the in vivo kinematics of talocrural and subtalar joints during landing.

BACKGROUND: Landing from heights is a common movement for active-duty military personnel during training. And the additional load they carry while performing these tasks can affect the kinetics and ankle kinematic of the landing. Traditional motion capture techniques are limited in accurately capturing the in vivo kinematics of the talus. This study aims to investigate the effect of additional trunk load on the kinematics of the talocrural and subtalar joints during landing, using a dual fluoroscopic imaging system (DFIS). METHODS: Fourteen healthy male participants were recruited. Magnetic resonance imaging was performed on the right ankle of each participant to create three-dimensional (3D) models of the talus, tibia, and calcaneus. High-speed DFIS was used to capture the images of participants performing single-leg landing jumps from a height of 40 cm. A weighted vest was used to apply additional load, with a weight of 16 kg. Fluoroscopic images were acquired with or without additional loading condition. Kinematic data were obtained by importing the DFIS data and the 3D models in virtual environment software for 2D-3D registration. The kinematics and kinetics were compared between with or without additional loading conditions. RESULTS: During added trunk loading condition, the medial-lateral translation range of motion (ROM) at the talocrural joint significantly increased (p < 0.05). The subtalar joint showed more extension at 44-56 ms (p < 0.05) after contact. The subtalar joint was more eversion at 40-48 ms (p < 0.05) after contact under the added trunk load condition. The peak vertical ground reaction force (vGRF) significantly increased (p < 0.05). CONCLUSIONS: With the added trunk load, there is a significant increase in peak vGRF during landing. The medial-lateral translation ROM of the talocrural joint increases. And the kinematics of the subtalar joint are affected. The observed biomechanical changes may be associated with the high incidence of stress fractures in training with added load.

Molecular mechanisms and emerging therapies in wild-type transthyretin amyloid cardiomyopathy.

Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is an underrecognized cause of heart failure due to misfolded wild-type transthyretin (TTRwt) myocardial deposition. The development of wild-type TTR amyloid fibrils is a complex pathological process linked to the deterioration of homeostatic mechanisms owing to aging, plausibly implicating multiple molecular mechanisms. The components of amyloid transthyretin often include serum amyloid P, proteoglycans, and clusterin, which may play essential roles in the localization and elimination of amyloid fibrils. Oxidative stress, impaired mitochondrial function, and perturbation of intracellular calcium dynamics induced by TTR contribute to cardiac impairment. Recently, tafamidis has been the only drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of ATTRwt-CM. In addition, small interfering RNAs and antisense oligonucleotides for ATTR-CM are promising therapeutic approaches and are currently in phase III clinical trials. Newly emerging therapies, such as antibodies targeting amyloid, inhibitors of seed formation, and CRISPR‒Cas9 technology, are currently in the early stages of research. The development of novel therapies is based on progress in comprehending the molecular events behind amyloid cardiomyopathy. There is still a need to further advance innovative treatments, providing patients with access to alternative and effective therapies, especially for patients diagnosed at a late stage.

A Large Field-of-view, Single-cell-resolution Two- and Three-Photon Microscope for Deep Imaging.

In vivo imaging of large-scale neuron activity plays a pivotal role in unraveling the function of the brain's network. Multiphoton microscopy, a powerful tool for deep-tissue imaging, has received sustained interest in advancing its speed, field of view and imaging depth. However, to avoid thermal damage in scattering biological tissue, field of view decreases exponentially as imaging depth increases. We present a suite of innovations to overcome constraints on the field of view in three-photon microscopy and to perform deep imaging that is inaccessible to two-photon microscopy. These innovations enable us to image neuronal activities in a ~3.5-mm diameter field-of-view at 4 Hz with single-cell resolution and in the deepest cortical layer of mouse brains. We further demonstrate simultaneous large field-of-view two-photon and three-photon imaging, subcortical imaging in the mouse brain, and whole-brain imaging in adult zebrafish. The demonstrated techniques can be integrated into any multiphoton microscope for large-field-of-view imaging for system-level neural circuit research.

Improving Individualized Treatment Decisions: A Bayesian Multivariate Hierarchical Model for Developing a Treatment Benefit Index using Mixed Types of Outcomes.

Background: Precision medicine has led to the development of targeted treatment strategies tailored to individual patients based on their characteristics and disease manifestations. Although precision medicine often focuses on a single health outcome for individualized treatment decision rules (ITRs), relying only on a single outcome rather than all available outcomes information leads to suboptimal data usage when developing optimal ITRs. Methods: To address this limitation, we propose a Bayesian multivariate hierarchical model that leverages the wealth of correlated health outcomes collected in clinical trials. The approach jointly models mixed types of correlated outcomes, facilitating the "borrowing of information" across the multivariate outcomes, and results in a more accurate estimation of heterogeneous treatment effects compared to using single regression models for each outcome. We develop a treatment benefit index, which quantifies the relative treatment benefit of the experimental treatment over the control treatment, based on the proposed multivariate outcome model. Results: We demonstrate the strengths of the proposed approach through extensive simulations and an application to an international Coronavirus Disease 2019 (COVID-19) treatment trial. Simulation results indicate that the proposed method reduces the occurrence of erroneous treatment decisions compared to a single regression model for a single health outcome. Additionally, the sensitivity analysis demonstrates the robustness of the model across various study scenarios. Application of the method to the COVID-19 trial exhibits improvements in estimating the individual-level treatment efficacy (indicated by narrower credible intervals for odds ratios) and optimal ITRs. Conclusion: The study jointly models mixed types of outcomes in the context of developing ITRs. By considering multiple health outcomes, the proposed approach can advance the development of more effective and reliable personalized treatment.

Persistence and potential risks of tetracyclines and their transformation products in two typical different animal manure composting treatments.

Abundant residues of tetracyclines in animal manures and manure-derived organic fertilizers can pose a substantial risk to environments. However, our knowledge on the residual levels and potential risk of tetracyclines and their transformation products (TPs) in manure and manure-derived organic fertilizers produced by different composting treatments is still limited. Herein, the occurrence and distribution of four veterinary tetracyclines (tetracycline, oxytetracycline, chlortetracycline, and doxycycline) and ten of their TPs were investigated in paired samples of fresh manure and manure-derived organic fertilizers. Tetracyclines and TPs were frequently detected in manure and manure-derived organic fertilizer samples in ranging from 130 to 118,137 µg·kg-1 and 54.6 to 104,891 µg·kg-1, respectively. Notably, the TPs concentrations of tetracycline and chlortetracycline were comparable to those of the parent compounds, with 4-epimers being always dominant and retained antibacterial potency. Based on paired-sampling strategy, the removal efficiency of tetracyclines and TPs in thermophilic composting was higher than that in manure storage. Toxicological data in the soil environment and the data derived from equilibrium partitioning method, indicated that tetracyclines and some TPs like 4-epitetracycline, 4-epichlortetracycline and isochlortetracycline could pose median to high ecological risk to terrestrial organisms. Total concentrations of TPs in manure-derived organic fertilizers were significantly correlated with the absolute abundance of tet(X) family genes, which provide evidence to evaluate the effects of TPs on the levels of antibiotic resistance in the environment. Among them, the 4-epitetracycline could pose ecological risk and retain antibacterial potency. Our findings emphasize the importance of monitoring and controlling the prevalence of tetracyclines and their TPs in livestock-related environments.

ARID1A loss induces P4HB to activate fibroblasts to support lung cancer cell growth, invasion, and chemoresistance.

Loss of AT-interacting domain-rich protein 1A (ARID1A) frequently occurs in human malignancies including lung cancer. The biological consequence of ARID1A mutation in lung cancer is not fully understood. This study was designed to determine the effect of ARID1A-depleted lung cancer cells on fibroblast activation. Conditioned media was collected from ARID1A-depleted lung cancer cells and employed to treat lung fibroblasts. The proliferation and migration of lung fibroblasts were investigated. The secretory genes were profiled in lung cancer cells upon ARID1A knockdown. Antibody-based neutralization was utilized to confirm their role in mediating the cross-talk between lung cancer cells and fibroblasts. NOD-SCID-IL2RgammaC-null (NSG) mice received tumor tissues from patients with ARID1A-mutated lung cancer to establish patient-derived xenograft (PDX) models. Notably, ARID1A-depleted lung cancer cells promoted the proliferation and migration of lung fibroblasts. Mechanistically, ARID1A depletion augmented the expression and secretion of prolyl 4-hydroxylase beta (P4HB) in lung cancer cells, which induced the activation of lung fibroblasts through the ß-catenin signaling pathway. P4HB-activated lung fibroblasts promoted the proliferation, invasion, and chemoresistance in lung cancer cells. Neutralizing P4HB hampered the tumor growth and increased cisplatin cytotoxic efficacy in two PDX models. Serum P4HB levels were higher in ARID1A-mutated lung cancer patients than in healthy controls. Moreover, increased serum levels of P4HB were significantly associated with lung cancer metastasis. Together, our work indicates a pivotal role for P4HB in orchestrating the cross-talk between ARID1A-mutated cancer cells and cancer-associated fibroblasts during lung cancer progression. P4HB may represent a promising target for improving lung cancer treatment.

Spatial and temporal regeneration patterns within gaps in the primary forests vs. secondary forests of Northeast China.

Forest gaps play an important role during forest succession in temperate forest ecosystems. However, the differences in spatial distribution and replacement patterns of woody plants (trees and shrubs) between primary and secondary forests remain unclear during the gap-filling processes, especially for temperate forests in Northeast China. We recorded 45,619 regenerated trees and shrubs in young gaps (<10 years), old gaps (10~20 years), and closed forest stands (i.e., filled gaps) in the primary broadleaved Korean pine (Pinus koraiensis Sieb. Rt Zucc.) forests vs. secondary forests (degraded from primary forests). The gap-filling processes along horizontal (Cartesian coordinate system) and vertical (lower layer: 0~5 m, medium layer: 5~10 m, and upper layer: >10 m) dimensions were quantified by shade tolerance groups of trees and shrubs. We found that gap age, competition between species, and pre-existing regeneration status resulted in different species replacement patterns within gaps in primary vs. secondary forests. Gap formation in both primary and secondary forests increased species richness, with 33, 38, 39, and 41 in the primary closed stands, primary forest gaps, secondary closed stands, and secondary forest gaps, respectively. However, only 35.9% of species in primary forest gaps and 34.1% in secondary forest gaps successfully reached the upper layer. Based on the importance values (IVs) of tree species across different canopy heights, light-demanding trees in the upper layer of the secondary forests were gradually replaced by intermediate and shade-tolerant trees. In the primary forests, Korean pine exhibited intermittent growth patterns at different canopy heights, while it had continuous regeneration along vertical height gradients in the secondary forests. The differences in Korean pine regeneration between the primary and secondary forests existed before gap formation and continued during the gap-filling processes. The interspecific competition among different tree species gradually decreased with increasing vertical height, and compared to the primary forests, the secondary forests showed an earlier occurrence of competition exclusion within gaps. Our findings revealed the species replacement patterns within gaps and provided a further understanding of the competition dynamics among tree species during the gap-filling processes.

A novel immune-related risk-scoring system associated with the prognosis and response of cervical cancer patients treated with radiation therapy.

Objective: The tumor microenvironment plays a critical role in the radiotherapy and immunotherapy response of cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). Radioresistance is a key factor in treatment failure among patients who receive radical radiotherapy. Thus, new immune-related biomarkers associated with radiotherapy response in CESC are needed. Methods: In this study, the CIBERSORT and ESTIMATE methods were applied to determine the percentage of tumor-infiltrating cells and the number of immune components in 103 CESCs treated with radiotherapy from The Cancer Genome Atlas (TCGA) database. The main dysregulated genes were subjected to multivariate and univariate analyses. The prognostic value of this system was studied via receiver operating characteristic curve and survival analysis. For further confirmation, the biomarkers' expression levels and predictive value were validated by immunohistochemistry (IHC) and qRT-PCR. The CIBERSORT algorithm was used to calculate the compositional patterns of 22 types of immune cells in cervical cancer patients treated with radiation therapy. Results: Data for 17 radioresistant and 86 radiosensitive tumors were obtained from the The Cancer Genome Atlas database. 53 immune-related DEGs were identified. GO and KEGG analyses revealed that the DEGs were enriched in protein kinase B signaling, growth factors in cytokines, the MAPK pathway and the PI3K-Akt pathway. Then, 14 key immune-related genes built a risk scoring model were deemed prognostic in CESC with radiotherapy. The area under the curve (AUC) of the model was 0.723, and the high-risk group presented worse outcomes than the low-risk group. In addition, the high-risk group tended to have persistent tumors (p = 0.001). The high expression of WT1 and SPOUYT4 were associated with relapse, the high expression of Angiotensinogen and MIEN1 were associated with nonrelapse. Analysis of the immune microenvironment indicated that M0 macrophages, M2 macrophages, activated mast cells and resting memory CD4+ T cells were positively correlated with the risk score (p < 0.05). Conclusion: The novel immune-related risk scoring system has some advantages in predicting the prognosis and treatment response of cervical cancer patients treated with radiotherapy. Moreover, it might provide novel clues for providing targeted immune therapy to these patients.

Dental Pulp Stem Cells for Bone Tissue Engineering: A Literature Review.

Bone tissue engineering (BTE) is a promising approach for repairing and regenerating damaged bone tissue, using stem cells and scaffold structures. Among various stem cell sources, dental pulp stem cells (DPSCs) have emerged as a potential candidate due to their multipotential capabilities, ability to undergo osteogenic differentiation, low immunogenicity, and ease of isolation. This article reviews the biological characteristics of DPSCs, their potential for BTE, and the underlying transcription factors and signaling pathways involved in osteogenic differentiation; it also highlights the application of DPSCs in inducing scaffold tissues for bone regeneration and summarizes animal and clinical studies conducted in this field. This review demonstrates the potential of DPSC-based BTE for effective bone repair and regeneration, with implications for clinical translation.

Effect of lace-up ankle brace on the tibiotalar and subtalar joint during the landing.

Objective: Ankle braces can affect the kinematics of the ankle joint during landing tasks. Previous studies were primarily relied on traditional marker-based motion capture systems, which pose limitations in non-invasively capturing the motion of the talus bone. The effect of ankle braces on the in vivo kinematics of the tibiotalar and subtalar joints during landing remains unknown. This study used a high-speed dual fluoroscopic imaging system (DFIS) and magnetic resonance imaging (MRI) to investigate effect of ankle braces on the in vivo kinematics of the tibiotalar and subtalar joints during landing. Methods: Fourteen healthy participants were recruited for this study. During the experiment, static three-dimensional MRI data were collected for each participant, and 3D ankle joint models for the calcaneus, talus, and tibia were constructed. The DFIS was used to capture the images of each participant performing a single-leg landing-jump task at a height of 40 cm. The images were captured once with and without a brace in the fatigue condition, which was induced by running. The six-degree-of-freedom (6DOF) kinematic data were obtained by 2D-3D registration. Results: The flexion-extension range of motion (ROM) (42.73 ± 4.76° vs. 38.74 ± 5.43°, p = 0.049) and anterior-posterior translation ROM (16.86 ± 1.74 mm vs. 15.03 ± 1.73 mm, p = 0.009) of the tibiotalar joint were decreased. The maximum inversion angle (-3.71 ± 2.25° vs. 2.11 ± 1.83°, p = 0.047) of the subtalar joint was decreased. Conclusion: The ankle brace limited the flexion-extension ROM of the tibiotalar joints and the inversion angle of the subtalar joint during landing.

MDM2 Antagonist Nutlin-3 Stimulates Global DNA Hydroxymethylation by Enhancing p53-TET1 Signaling Axis.

DNA hydroxymethylation is involved in many biological processes, including nuclear reprogramming, embryonic development, and tumor suppression. In this study, we report that an anticancer agent, nutlin-3, selectively stimulates global DNA hydroxymethylation in TP53 wild-type cancer cells as manifested by the elevation of 5-hydroxymethylcytosine (5hmC) in genomic DNA. In contrast, nutlin 3 fails to enhance DNA hydroxymethylation in TP53-mutated cancer cells. Consistently, nutlin-3 as a MDM2 antagonist only activates wild-type but not mutated TP53. Furthermore, nutlin-3 does not alter the expression of TET1 but slightly reduces the expression of TET2 and TET3 proteins. These TET family proteins are responsible for converting 5-methylcytosine (5mC) to 5hmC. Interestingly, TET1 knockdown could significantly block the nutlin-3-induced DNA hydroxymethylation as well as TP53 and P21 activation. Immunoprecipitation analysis supports that p53 strongly interacts with TET1 proteins. These results suggest that nutlin-3 activates TP53 and promotes p53-TET1 interaction. As positive feedback, the p53-TET1 interaction further enhances p53 activation and promotes apoptosis. Collectively, we demonstrate that nutlin-3 stimulates DNA hydroxymethylation and apoptosis via a positive feedback mechanism.

Programmable deaminase-free base editors for G-to-Y conversion by engineered glycosylase.

Current DNA base editors contain nuclease and DNA deaminase that enables deamination of cytosine (C) or adenine (A), but no method for guanine (G) or thymine (T) editing is available at present. Here we developed a deaminase-free glycosylase-based guanine base editor (gGBE) with G editing ability, by fusing Cas9 nickase with engineered N-methylpurine DNA glycosylase protein (MPG). By several rounds of MPG mutagenesis via unbiased and rational screening using an intron-split EGFP reporter, we demonstrated that gGBE with engineered MPG could increase G editing efficiency by more than 1500 fold. Furthermore, this gGBE exhibited high base editing efficiency (up to 81.2%) and high G-to-T or G-to-C (i.e. G-to-Y) conversion ratio (up to 0.95) in both cultured human cells and mouse embryos. Thus, we have provided a proof-of-concept of a new base editing approach by endowing the engineered DNA glycosylase the capability to selectively excise a new type of substrate.

Bayesian Index Models for Heterogeneous Treatment Effects on a Binary Outcome.

This paper develops a Bayesian model with a flexible link function connecting a binary treatment response to a linear combination of covariates and a treatment indicator and the interaction between the two. Generalized linear models allowing data-driven link functions are often called "single-index models" and are among popular semi-parametric modeling methods. In this paper, we focus on modeling heterogeneous treatment effects, with the goal of developing a treatment benefit index (TBI) incorporating prior information from historical data. The model makes inference on a composite moderator of treatment effects, summarizing the effect of the predictors within a single variable through a linear projection of the predictors. This treatment benefit index can be useful for stratifying patients according to their predicted treatment benefit levels and can be especially useful for precision health applications. The proposed method is applied to a COVID-19 treatment study.