A mark-specific quantile regression model.

Quantile regression has become a widely used tool for analysing competing risk data. However, quantile regression for competing risk data with a continuous mark is still scarce. The mark variable is an extension of cause of failure in a classical competing risk model where cause of failure is replaced by a continuous mark only observed at uncensored failure times. An example of the continuous mark variable is the genetic distance that measures dissimilarity between the infecting virus and the virus contained in the vaccine construct. In this article, we propose a novel mark-specific quantile regression model. The proposed estimation method borrows strength from data in a neighbourhood of a mark and is based on an induced smoothed estimation equation, which is very different from the existing methods for competing risk data with discrete causes. The asymptotic properties of the resulting estimators are established across mark and quantile continuums. In addition, a mark-specific quantile-type vaccine efficacy is proposed and its statistical inference procedures are developed. Simulation studies are conducted to evaluate the finite sample performances of the proposed estimation and hypothesis testing procedures. An application to the first HIV vaccine efficacy trial is provided.

Rational Design of a Yeast-derived 3',5'-bisphosphate Nucleotidase with Improved Substrate Specificity.

In recent years, a convenient phosphatase-coupled sulfotransferase assay method has been proven to be applicable to most sulfotransferases. The central principle of the method is that phosphatase specifically degrades 3'-phosphoadenosine-5'-phosphate (PAP) and leaves 3'-phosphoadenosine-5'-phosphosulfate (PAPS). Our group previously acquired a yeast 3',5'-bisphosphate nucleotidase (YND), which showed a higher catalytic activity for PAP than PAPS and could be a potential phosphatase for the sulfotransferase assay. Here, we obtained a beneficial mutant of YND with markedly improved substrate specificity towards PAP via rational design. Of 9 chosen mutation sites in the active site pocket, the mutation G236D showed the best specificity for PAP. After optimization of the reaction conditions, the mutant YNDG236D displayed a 4.8-fold increase in the catalytic ratio PAP/PAPS compared to the wild-type. We subsequently applied YNDG236D to the assay of human SULT1A1 and SULT1A3 with their known substrate 1-naphthol, indicating that the mutant could be used to evaluate sulfotransferase activity by colorimetry. Analysis of the MD simulation results revealed that the improved substrate specificity of the mutant towards PAP may stem from a more stable protein conformation and the changed flexibility of key residues in the entrance of the substrate tunnel. This research will provide a valuable reference for the development of efficient sulfotransferase activity assays.

The value of cholinesterase inhibitors for improving neuropsychiatric and functional assessment scores in patients with Alzheimer disease: a systematic review and meta-analysis of on placebo-controlled RCTs.

INTRODUCTION: At present, increasing reports from different aspects indicated that cholinesterase inhibitors (ChEIs) may be effective on improving neuropsychiatric and functional assessment scores in patients with Alzheimer disease (AD). However, no studies comprehensively and detailedly evaluated the effect of ChEIs on AD. The present analysis was designed to comprehensively evaluate the efficacy and safety of ChEIs for AD. METHODS: Two independent researchers systematically reviewed 1096 searching records in PubMed, Embase, Cochrane Library, and Web of Science from inception to 10 May 2023, and finally identified 12 randomized, double-blind, placebo-controlled trials with 6908 participants according to predetermined inclusion and exclusion criteria. The effects were assessed with standardized mean difference (SMD) or odds ratio (OR). The primary outcomes were the mean change and least squares (LS) mean change from baseline to endpoint of neuropsychiatric and functional assessment scores. The secondary outcome was adverse events of ChEIs when compared to placebo for patients with AD. All statistical analyses were performed using the standard statistical procedures provided in Review Manager 5.2 and and Stata 12.0. RESULTS: Pooled analysis indicated that ChEIs significantly improved the assessment scores of the AD Assessment Scale (ADAS) (SMD -1.57; 95% CI: -2.64 to -0.51), Clinician's Interview-Based Impression of Change-Plus caregiver input (CIBIC-Plus) (SMD -0.28; 95% CI: -0.41 to -0.15), the Neuropsychiatric Inventory (NPI) (both SMD -1.67; 95% CI: -2.88 to -0.47 for 10-tiem total score and SMD -1.83; 95% CI: -3.25 to -0.42 for 12-tiem total score), and the AD Cooperative Study-Activities of Daily Living (ADCS-ADL) total score (SMD 2.44; 95% CI: 1.29-3.59), evaluated with mean change from baseline to endpoint. In addition, when evaluated with the LS mean change from baseline to endpoint, ChEIs significantly improved Mini-Mental State Examination (MMSE) total score, the Clinician Interview-Based Impression of Severity, CIBIC-Plus, ADCS-ADL total score, NPI, ADAS. Regarding to adverse events (AEs) of patients with AD, it indicated that compared to placebo, ChEIs did not increase the frequency of severe and serious AEs (fatal or nonfatal) as well as the incidence of death. CONCLUSIONS: Our analysis indicated that ChEIs treatment generally improved neuropsychiatric and functional assessment scores in patients with AD though opposite result was observed in Wechsler Memory Scale. ChEIs had an acceptable safety profile in patients with AD without increasing of any crucial adverse or outcomes.

Quantifying how single dose Ad26.COV2.S vaccine efficacy depends on Spike sequence features.

In the ENSEMBLE randomized, placebo-controlled phase 3 trial (NCT04505722), estimated single-dose Ad26.COV2.S vaccine efficacy (VE) was 56% against moderate to severe-critical COVID-19. SARS-CoV-2 Spike sequences were determined from 484 vaccine and 1,067 placebo recipients who acquired COVID-19. In this set of prespecified analyses, we show that in Latin America, VE was significantly lower against Lambda vs. Reference and against Lambda vs. non-Lambda [family-wise error rate (FWER) p < 0.05]. VE differed by residue match vs. mismatch to the vaccine-insert at 16 amino acid positions (4 FWER p < 0.05; 12 q-value ≤ 0.20); significantly decreased with physicochemical-weighted Hamming distance to the vaccine-strain sequence for Spike, receptor-binding domain, N-terminal domain, and S1 (FWER p < 0.001); differed (FWER ≤ 0.05) by distance to the vaccine strain measured by 9 antibody-epitope escape scores and 4 NTD neutralization-impacting features; and decreased (p = 0.011) with neutralization resistance level to vaccinee sera. VE against severe-critical COVID-19 was stable across most sequence features but lower against the most distant viruses.

Near-Infrared Light-Excited Quinolinium-Carbazole Small Molecule as Two-Photon Fluorescence Nucleic Acid Probe.

This article reports three new two-photon absorption (TPA) materials that are quinolinium-carbazole derivates. They are 3-(N-methyl-4-ethylquinolinium iodide)-9-ethylcarbazole (M4), 3-(N-methyl-4-ethylquinolinium iodide)-9-ethylcarbazole (H2), and 3-(N-methyl-4-ethylquinolinium iodide)-9-ethylcarbazole (H4). Their TPA cross-sections are 491, 515, and 512 GM, respectively. Under the excitation of near-infrared light, their fluorescence emission is about 650 nm. The compounds can stain nucleic acid DNA with the same level of nuclear localization as Hoechst 33342. Under continuous irradiation with a near-infrared laser, the three new compounds showed less fluorescence decay than DAPI, and the average fluorescence decay rates were 0.016%/s, 0.020%/s, and 0.023%/s. They are expected to become new two-photon fluorescent probes of nucleic acid DNA because of their excellent performance.

Technology-enabled great leap in deciphering plant genomes.

Plant genomes provide essential and vital basic resources for studying many aspects of plant biology and applications (for example, breeding). From 2000 to 2020, 1,144 genomes of 782 plant species were sequenced. In the past three years (2021-2023), 2,373 genomes of 1,031 plant species, including 793 newly sequenced species, have been assembled, representing a great leap. The 2,373 newly assembled genomes, of which 63 are telomere-to-telomere assemblies and 921 have been generated in pan-genome projects, cover the major phylogenetic clades. Substantial advances in read length, throughput, accuracy and cost-effectiveness have notably simplified the achievement of high-quality assemblies. Moreover, the development of multiple software tools using different algorithms offers the opportunity to generate more complete and complex assemblies. A database named N3: plants, genomes, technologies has been developed to accommodate the metadata associated with the 3,517 genomes that have been sequenced from 1,575 plant species since 2000. We also provide an outlook for emerging opportunities in plant genome sequencing.

Investigating the levels, spatial distribution, and trophic transfer patterns of short-chain chlorinated paraffins in the Southern Bohai Sea, China.

The marine environment of the southern Bohai Sea is severely polluted by short-chain chlorinated paraffins (SCCPs). To improve understanding of how SCCPs occur and of how they migrate, are transformed, and transferred in this area, we collected seawater, sediment, and organism samples, and determined the SCCP contents using a new approach based on high-resolution mass spectrometry. The ΣSCCP concentrations in the seawater, sediment, and organism samples ranged from 57.5 to 1150.4 ng/L, 167.7-1105.9 ng/g (dry weight), and 11.4-583.0 ng/g (wet weight), respectively. Simulation of the spatial distribution of SCCPs using Kriging interpolation showed that SCCPs were markedly influenced by land-based pollution. Substantial quantities of SCCPs were transported to the marine environment via surface runoff from rivers that passed through areas of major SCCP production. Once discharged from such rivers into the Bohai Sea, these SCCPs were further dispersed under the influence of ocean currents. Furthermore, the logarithmic bioaccumulation factor that varied from 2.12 to 3.20 and the trophic magnification factor that reached 5.60 (r2 = 0.750, p < 0.01) suggest that organisms have the ability to accumulate and biomagnify SCCPs through the food chain, which could potentially present risks to both marine ecosystems and human health.

Engineered Macrophage Membrane-Coated Nanoparticles with Enhanced CCR2 Expression Promote Spinal Cord Injury Repair by Suppressing Neuroinflammation and Neuronal death.

Spinal cord injury (SCI) is a severe neurological disorder characterized by significant disability and limited treatment options. Mitigating the secondary inflammatory response following the initial injury is the primary focus of current research in the treatment of SCI. CCL2 (C─C motif chemokine ligand 2) serves as the primary regulator responsible for inflammatory chemotaxis of the majority of peripheral immune cells, blocking the CCL2-CCR2 (C─C chemokine receptor type 2) axis has shown considerable therapeutic potential for inflammatory diseases, including SCI. In this study, it presents a multifunctional biomimetic nanoplatform (CCR2-MM@PLGA/Cur) specifically designed to target the CCL2-CCR2 axis, which consisted of an engineered macrophage membrane (MM) coating with enhanced CCR2 expression and a PLGA (poly (lactic-co-glycolic acid)) nanoparticle that encapsulated therapeutic drugs. CCR2 overexpression on MM not only enhanced drug-targeted delivery to the injury site, but also attenuated macrophage infiltration, microglia pro-inflammatory polarization, and neuronal apoptosis by trapping CCL2. Consequently, it facilitated neural regeneration and motor function recovery in SCI mice, enabling a comprehensive treatment approach for SCI. The feasibility and efficacy of this platform are confirmed through a series of in vitro and in vivo assays, offering new insights and potential avenues for further exploration in the treatment of SCI.

Poaceae Chloroplast Genome Sequencing: Great Leap Forward in Recent Ten Years.

The first complete chloroplast genome of rice (Oryza sativa) was published in 1989, ushering in a new era of studies of chloroplast genomics in Poaceae. Progresses in Next-Generation Sequencing (NGS) and Third-Generation Sequencing (TGS) technologiesand in the development of genome assembly software, have significantly advanced chloroplast genomics research. Poaceae is one of the most targeted families in chloroplast genome research because of its agricultural, ecological, and economic importance. Over the last 30 years, 2,050 complete chloroplast genome sequences from 40 tribes and 282 genera have been generated, most (97%) of them in the recent ten years. The wealth of data provides the groundwork for studies on species evolution, phylogeny, genetic transformation, and other aspects of Poaceae chloroplast genomes. As a result, we have gained a deeper understanding of the properties of Poaceae chloroplast genomes. Here, we summarize the achievements of the studies of the Poaceae chloroplast genomes and envision the challenges for moving the area ahead.

A syntelog-based pan-genome provides insights into rice domestication and de-domestication.

BACKGROUND: Asian rice is one of the world's most widely cultivated crops. Large-scale resequencing analyses have been undertaken to explore the domestication and de-domestication genomic history of Asian rice, but the evolution of rice is still under debate. RESULTS: Here, we construct a syntelog-based rice pan-genome by integrating and merging 74 high-accuracy genomes based on long-read sequencing, encompassing all ecotypes and taxa of Oryza sativa and Oryza rufipogon. Analyses of syntelog groups illustrate subspecies divergence in gene presence-and-absence and haplotype composition and identify massive genomic regions putatively introgressed from ancient Geng/japonica to ancient Xian/indica or its wild ancestor, including almost all well-known domestication genes and a 4.5-Mbp centromere-spanning block, supporting a single domestication event in main rice subspecies. Genomic comparisons between weedy and cultivated rice highlight the contribution from wild introgression to the emergence of de-domestication syndromes in weedy rice. CONCLUSIONS: This work highlights the significance of inter-taxa introgression in shaping diversification and divergence in rice evolution and provides an exploratory attempt by utilizing the advantages of pan-genomes in evolutionary studies.

Quantifying how single dose Ad26.COV2.S vaccine efficacy depends on Spike sequence features.

It is of interest to pinpoint SARS-CoV-2 sequence features defining vaccine resistance. In the ENSEMBLE randomized, placebo-controlled phase 3 trial, estimated single-dose Ad26.COV2.S vaccine efficacy (VE) was 56% against moderate to severe-critical COVID-19. SARS-CoV-2 Spike sequences were measured from 484 vaccine and 1,067 placebo recipients who acquired COVID-19 during the trial. In Latin America, where Spike diversity was greatest, VE was significantly lower against Lambda than against Reference and against all non-Lambda variants [family-wise error rate (FWER) p < 0.05]. VE also differed by residue match vs. mismatch to the vaccine-strain residue at 16 amino acid positions (4 FWER p < 0.05; 12 q-value ≤ 0.20). VE significantly decreased with physicochemical-weighted Hamming distance to the vaccine-strain sequence for Spike, receptor-binding domain, N-terminal domain, and S1 (FWER p < 0.001); differed (FWER ≤ 0.05) by distance to the vaccine strain measured by 9 different antibody-epitope escape scores and by 4 NTD neutralization-impacting features; and decreased (p = 0.011) with neutralization resistance level to vaccine recipient sera. VE against severe-critical COVID-19 was stable across most sequence features but lower against viruses with greatest distances. These results help map antigenic specificity of in vivo vaccine protection.

A semiparametric Cox-Aalen transformation model with censored data.

We propose a broad class of so-called Cox-Aalen transformation models that incorporate both multiplicative and additive covariate effects on the baseline hazard function within a transformation. The proposed models provide a highly flexible and versatile class of semiparametric models that include the transformation models and the Cox-Aalen model as special cases. Specifically, it extends the transformation models by allowing potentially time-dependent covariates to work additively on the baseline hazard and extends the Cox-Aalen model through a predetermined transformation function. We propose an estimating equation approach and devise an expectation-solving (ES) algorithm that involves fast and robust calculations. The resulting estimator is shown to be consistent and asymptotically normal via modern empirical process techniques. The ES algorithm yields a computationally simple method for estimating the variance of both parametric and nonparametric estimators. Finally, we demonstrate the performance of our procedures through extensive simulation studies and applications in two randomized, placebo-controlled human immunodeficiency virus (HIV) prevention efficacy trials. The data example shows the utility of the proposed Cox-Aalen transformation models in enhancing statistical power for discovering covariate effects.

[Study on the Mechanism of Multi-Drug Resistance of Agaricus Blazei Extract FA-2-b-ß Mediated Wnt Signaling Pathway to Reverse Acute T Lymphoblastic Leukemia].

OBJECTIVE: To investigate the mechanism of drug reversing resistance of Agaricus blazei extract FA-2-b-ß on T cell acute lymphoblastic leukemia (T-ALL) cell lines. METHODS: Cell proliferation was detected by CCK-8 assay; the apoptosis, cell cycle mitochondrial membrane potential, and intracellular rhodamine accumulation were detected by flow cytometry, and apoptosis-related gene and protein expression were detected by qPCR and Western blot; the membrane surface protein MDR1 was observed by immunofluorescence microscopy. RESULTS: Different concentrations of FA-2-b-ß significantly inhibited proliferation and induced apoptosis of CCRF-CEM and CEM/C1 (P<0.05), and CCRF-CEM cell cycle were arrested at S phase, and CEM/C1 cells were arrested at G0/G1 phase. Western blot and qPCR results show that FA-2-b-ß inhibited ABCB1、ABCG2、CTNNB、MYC and BCL-2 expression, but upregulated Bax expression. In addition, FA-2-b-ß reversed the resistance characteristics of CEM/C1 drug-resistance cells, which decreased mitochondrial membrane potential, and significantly increased the intracellular rhodamine accumulation, and weakening of the expression of the membrane surface protein MDR1. With the Wnt/ß-catenin inhibitor (ICG001), the process was further intensified. CONCLUSION: Agaricus Blazei Extract FA-2-b-ß inhibits cell proliferation, promotes apoptosis, regulates the cell cycle, reduces mitochondrial energy supply, and down-regulate MDR1 expression to reverse the resistance of CEM/C1, which all suggest it is through regulating the Wnt signaling pathway in T-ALL.

Analysis of the Cox Model with Longitudinal Covariates with Measurement Errors and Partly Interval Censored Failure Times, with Application to an AIDS Clinical Trial.

Time-dependent covariates are often measured intermittently and with measurement errors. Motivated by the AIDS Clinical Trials Group (ACTG) 175 trial, this paper develops statistical inferences for the Cox model for partly interval censored failure times and longitudinal covariates with measurement errors. The conditional score methods developed for the Cox model with measurement errors and right censored data are no longer applicable to interval censored data. Assuming an additive measurement error model for a longitudinal covariate, we propose a nonparametric maximum likelihood estimation approach by deriving the measurement error induced hazard model that shows the attenuating effect of using the plug-in estimate for the true underlying longitudinal covariate. An EM algorithm is devised to facilitate maximum likelihood estimation that accounts for the partly interval censored failure times. The proposed methods can accommodate different numbers of replicates for different individuals and at different times. Simulation studies show that the proposed methods perform well with satisfactory finite-sample performances and that the naive methods ignoring measurement error or using the plug-in estimate can yield large biases. A hypothesis testing procedure for the measurement error model is proposed. The proposed methods are applied to the ACTG 175 trial to assess the associations of treatment arm and time-dependent CD4 cell count on the composite clinical endpoint of AIDS or death. Supplementary Information: The online version contains supplementary material available at 10.1007/s12561-023-09372-y.

A Pilot Human Cadaveric Study on Accuracy of the Augmented Reality Surgical Navigation System for Thoracolumbar Pedicle Screw Insertion Using a New Intraoperative Rapid Registration Method.

To evaluate the feasibility and accuracy of AR-assisted pedicle screw placement using a new intraoperative rapid registration method of combining preoperative CT scanning and intraoperative C-arm 2D fluoroscopy in cadavers. Five cadavers with intact thoracolumbar spines were employed in this study. Intraoperative registration was performed using anteroposterior and lateral views of preoperative CT scanning and intraoperative 2D fluoroscopic images. Patient-specific targeting guides were used for pedicle screw placement from Th1-L5, totaling 166 screws. Instrumentation for each side was randomized (augmented reality surgical navigation (ARSN) vs. C-arm) with an equal distribution of 83 screws in each group. CT was performed to evaluate the accuracy of both techniques by assessing the screw positions and the deviations between the inserted screws and planned trajectories. Postoperative CT showed that 98.80% (82/83) screws in ARSN group and 72.29% (60/83) screws in C-arm group were within the 2-mm safe zone (p < 0.001). The mean time for instrumentation per level in ARSN group was significantly shorter than that in C-arm group (56.17 ± 3.33 s vs. 99.22 ± 9.03 s, p < 0.001). The overall intraoperative registration time was 17.2 ± 3.5 s per segment. AR-based navigation technology can provide surgeons with accurate guidance of pedicle screw insertion and save the operation time by using the intraoperative rapid registration method of combining preoperative CT scanning and intraoperative C-arm 2D fluoroscopy.

Efficient Cr(vi) removal by expanded graphite synergized with oxalic acid under UV irradiation.

Expanded graphite (EG), an easily-obtained carbon material with the potential of transferring electrons, was utilized successfully in the removal of hazardous hexavalent chromium (Cr(vi)) by environment-friendly oxalic acid (Ox) under UV irradiation. EG with a unique worm-like structure was obtained via a facile microwave treatment. The results showed that the EG + Ox + UV system had optimum performance, removing 99.32% of the Cr(vi) (1 mM) within 60 min at pH = 3, and the kinetic rate constant of Cr(vi) elimination was 7.95 mol L-1 min-1. Three components are potentially involved in the Cr(vi) elimination mechanism by the EG + Ox + UV system: (1) the direct electron transfer (DET) pathway of the EG-Ox-Cr(vi) through the acceleration effect of EG caused the majority removal of Cr(vi) under UV; (2) ·CO2 - generated from Ox photolysis was used to reduce some Cr(vi); (3) ·CO2 - created from Cr(vi)-Ox complexes in the solution through the photoinduced electron transfer (PET) pathway also reduced a little Cr(vi). Overall, the efficient removal of Cr(vi) by the EG + Ox + UV system provided new ideas for future research on Cr(vi) treatment.

Engineering of M2 Macrophages-Derived Exosomes via Click Chemistry for Spinal Cord Injury Repair.

Spinal cord injury (SCI) is one of the most common causes of death and disability. The effective modulation of complicated microenvironment, regeneration of injured spinal cord tissue, and the functional recovery after SCI are still clinical challenges. Recently, macrophages-derived exosomes have shown great potential for various diseases due to their inflammation-targeting property. However, further modifications are needed to endow exosomes with the neural regenerative potential for SCI recovery. In the current study, a novel nanoagent (MEXI) is designed for SCI treatment by conjugating bioactive IKVAV peptides to the surface of M2 macrophages-derived exosomes via an easy and rapid click chemistry method. In vitro, MEXI inhibits the inflammation by reprograming macrophages and promotes neuronal differentiation of neural stem cells. In vivo, engineered exosomes target the injured site of the spinal cord after tail vein injection. Furthermore, histological analysis reveals that MEXI improves motor functional recovery of SCI mice by reducing infiltration of macrophages, downregulating pro-inflammatory factors, and improving the regeneration of injured nervous tissues. Taken together, this study provides strong evidence for the significance of MEXI in SCI recovery.