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High-efficacy therapies in multiple sclerosis are traditionally used after unsuccessful treatment with first-line disease modifying therapies. We hypothesised that early commencement of high-efficacy therapy would be associated with reduced long-term disability. We therefore aimed to compare long-term disability outcomes between patients who started high-efficacy therapies within 2 years of disease onset with those who started 4–6 years after disease onset. In this retrospective international observational study, we obtained data from the MSBase registry and the Swedish MS registry, which prospectively collect patient data that are specific to multiple sclerosis as part of routine clinical care. We identified adult patients (aged ≥18 years) with relapsing-remitting multiple sclerosis, with at least 6 years of follow-up since disease onset, and who started the high-efficacy therapy (rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab) either 0–2 years (early) or 4–6 years (late) after clinical disease onset. We matched patients in the early and late groups using propensity scores calculated on the basis of their baseline clinical and demographic data. The primary outcome was disability, measured with the Expanded Disability Status Score (EDSS; an ordinal scale of 0–10, with higher scores indicating increased disability), at 6–10 years after disease onset, assessed with a linear mixed-effects model. We identified 6149 patients in the MSBase registry who had been given high-efficacy therapy, with data collected between Jan 1, 1975, and April 13, 2017, and 2626 patients in the Swedish MS Registry, with data collected between Dec 10, 1997, and Sept 16, 2019. Of whom, 308 in the MSBase registry and 236 in the Swedish MS registry were eligible for inclusion. 277 (51%) of 544 patients commenced therapy early and 267 (49%) commenced therapy late. For the primary analysis, we matched 213 patients in the early treatment group with 253 in the late treatment group. At baseline, the mean EDSS score was 2·2 (SD 1·2) in the early group and 2·1 (SD 1·2) in the late group. Median follow-up time for matched patients was 7·8 years (IQR 6·7–8·9). In the sixth year after disease onset, the mean EDSS score was 2·2 (SD 1·6) in the early group compared with 2·9 (SD 1·8) in the late group (p<0·0001). This difference persisted throughout each year of follow-up until the tenth year after disease onset (mean EDSS score 2·3 [SD 1·8] vs 3·5 [SD 2·1]; p<0·0001), with a difference between groups of −0·98 (95% CI −1·51 to −0·45; p<0·0001, adjusted for proportion of time on any disease-modifying therapy) across the 6–10 year follow-up period. High-efficacy therapy commenced within 2 years of disease onset is associated with less disability after 6–10 years than when commenced later in the disease course. This finding can inform decisions regarding optimal sequence and timing of multiple sclerosis therapy. National Health and Medical Research Council Australia and MS Society UK.

Unconscious neural activity has been repeatedly shown to precede and potentially even influence subsequent free decisions. However, to date, such findings have been mostly restricted to simple motor choices, and despite considerable debate, there is no evidence that the outcome of more complex free decisions can be predicted from prior brain signals. Here, we show that the outcome of a free decision to either add or subtract numbers can already be decoded from neural activity in medial prefrontal and parietal cortex 4 s before the participant reports they are consciously making their choice. These choice-predictive signals co-occurred with the so-called default mode brain activity pattern that was still dominant at the time when the choice-predictive signals occurred. Our results suggest that unconscious preparation of free choices is not restricted to motor preparation. Instead, decisions at multiple scales of abstraction evolve from the dynamics of preceding brain activity.

Recently, we demonstrated using functional magnetic resonance imaging (fMRI) that the outcome of free decisions can be decoded from brain activity several seconds before reaching conscious awareness. Activity patterns in anterior frontopolar cortex (BA 10) were temporally the first to carry intention-related information and thus a candidate region for the unconscious generation of free decisions. In the present study, the original paradigm was replicated and multivariate pattern classification was applied to functional images of frontopolar cortex, acquired using ultra-high field fMRI at 7 Tesla. Here, we show that predictive activity patterns recorded before a decision was made became increasingly stable with increasing temporal proximity to the time point of the conscious decision. Furthermore, detailed questionnaires exploring subjects' thoughts before and during the decision confirmed that decisions were made spontaneously and subjects were unaware of the evolution of their decision outcomes. These results give further evidence that FPC stands at the top of the prefrontal executive hierarchy in the unconscious generation of free decisions.

Adverse events (AEs) associated with COVID-19 vaccines remain a critical aspect of safety surveillance. In 2022, we reported the first systematic profiling of COVID-19 vaccine AEs using the Vaccine Adverse Event Reporting System (VAERS). Since then, vaccines have evolved with the introduction of bivalent formulations. This study provides an updated analysis to capture evolving safety trends. Building upon our previous analysis, we systematically analyzed AE profiles for the Pfizer-BioNTech, Moderna, and Janssen vaccines, along with the newer bivalent Pfizer-BioNTech and Moderna vaccines and the protein subunit Novavax vaccine, using VAERS data through 28 June 2024. We obtained processed VAERS data via Cov19VaxKB. Significance of each AE was determined using Pearson's Chi-square test, proportional reporting ratios, and case report frequencies with established thresholds. Overlap and age- or sex-stratified analyses were conducted to characterize shared and unique AE patterns across vaccine types. AE classification using the Ontology of Adverse Events was performed to categorize and interpret significant AEs within a structured hierarchy. We observed a marked decrease in unique AEs reported for the Pfizer-BioNTech and Moderna monovalent mRNA vaccines and the recombinant vector vaccine Janssen. The bivalent versions of Pfizer-BioNTech and Moderna exhibited distinct overlapping AE profiles compared to their monovalent counterparts, and bivalent vaccines were generally associated with fewer AEs than the classical monovalent vaccines. Significant differences were observed in thrombosis, myocarditis, and Guillain-Barré syndrome (GBS) across vaccines. Age-specific analyses revealed a bimodal pattern with higher AE reporting in children aged 0-9 and adults aged 50-69, and clear sex differences. Females reported more common AEs, while males were more often linked to serious AEs (thrombosis, myocarditis, and GBS). Death-related AEs were uncommon but more frequent among older males and primarily associated with monovalent formulations. Ontology-based classification revealed that females were more likely to experience sensory-related AEs, whereas males were more prone to cardiovascular-related AEs. The adverse event profiles of COVID-19 vaccines during 2020-2024 largely overlapped those identified during 2020-2021, while also revealing new overall and age- and sex-specific AE patterns. Ontology-guided classification enhanced the interpretation of large-scale vaccine safety data, supporting more precise risk assessment across groups.

Functional surfaces with broadband ultralow optical reflectance have many potential applications in the fields of enhancing solar energy utilization, stray light shielding, infrared stealth, and so on. To fabricate broadband anti-reflection surfaces with low cost, high quality, and more controllability, a strategy of preparing multi-scale structures by thermal-assisted nanosecond laser was proposed. This strategy combines laser ablation with Marangoni flow of molten materials and in situ deposition of nanoparticles. The thermal-assisted strategy increases the depth to width ratio of the anti-reflection structures. The average reflectance of laser-textured TC4 (Ti-6Al-4V) surface is as low as 1.71% in the wavelength range of 200–2250 nm and 7.8% in the 2500–25,000 nm. The ultra-low reflectance surface has a significantly enhanced photothermal conversion performance. Meanwhile, the anti-reflection effect can be extended to the mid-infrared band, which has potential stealth application prospect. This synergetic manufacturing strategy has wide adaptability of materials, which provides new paths for the preparation of broadband ultralow reflectance surface. Moreover, this thermal-assisted laser fabrication strategy is prospective in the preparation of other functional micro-nano structures.

The germination rate of pepper (Capsicum annuum L.) seeds is a key indicator of their vitality, which is complexly regulated by genetic and environmental factors. This study aims to elucidate the physiological and molecular mechanisms underlying the differences in germination rates among different pepper germplasm resources and identify the key genes regulating this trait. Three representative pepper materials (‘22HL6’, ‘22HL14’, ‘22HL2’) with significantly different germination rates were selected for this study. Key physiological and biochemical parameters during their germination process were systematically evaluated, including germination rate, vigor index, water absorption characteristics, amylase activity, antioxidant enzyme activity, and soluble sugar and protein content. Based on this, candidate genes related to germination rate were screened through transcriptome sequencing, and core candidate genes were preliminarily functionally validated using the Arabidopsis thaliana heterologous overexpression system. Materials with fast germination rates (‘22HL6’, ‘22HL14’) exhibited higher water absorption efficiency, amylase activity, antioxidant protection (such as lower MDA content and higher POD activity), and more active material metabolism (soluble sugar and protein) during the critical 72-h period. Transcriptome analysis successfully identified seven candidate genes closely related to germination rate. Among them, gene Capann_59V1aChr03g048850 had extremely high expression levels in fast-germinating materials but was almost not expressed in slow-germinating materials, and was identified as a core candidate gene. Heterologous overexpression of Capann_59V1aChr03g048850 in A. thaliana significantly promoted seed germination, with transgenic lines exhibiting earlier germination initiation, more developed taproot and lateral root systems, larger rosette diameter, and earlier bolting and flowering compared to wild-type plants. This study reveals the basis for the differences in germination rates of pepper seeds from the physiological and biochemical to molecular mechanism levels, and for the first time links the function of Capann_59V1aChr03g048850 gene to promoting seed germination and early seedling development. This gene provides valuable genetic resources for improving the germination uniformity and seedling vitality of pepper and even other crops through molecular breeding in the future.

BackgroundChimeric antigen receptor macrophage (CAR-Mφ) therapy has promising therapeutic potential in solid tumors, yet challenges remain in target compatibility and systemic toxicity.MethodsIn this study, we screened the CD47-scFv sequence of CAR-Mφ as the extracellular structure. We then constructed a classical CD47 CAR-Mφ incorporated the costimulatory domain of the α1β1 integrin-mediated Fc-gamma receptor I (FcγRI) signaling component. Subsequently, we developed a tumor microenvironment (TME)-responsive CAR macrophage platform by the arginase 1 (Arg1) promoter to target CD47, a highly expressed but clinically challenging immune checkpoint in solid tumors.ResultsWe found that anti-CD47-scFv-mediated macrophages can effectively kill tumor cells both in vivo and in vitro. Furthermore, by integrating an α1β1 integrin-mediated FcγRI signaling domain, CD47 CAR-Mφ exhibited superior antitumor activity in hCD47+4T1 and SGC-7901 cells in vitro, which demonstrated that the CD47 CAR-Mφ was effective against solid tumors. Subsequently, Arg1-mediated activated pArg1 CD47 CAR-Mφ exhibited strong cytotoxicity against target cancer cells. We further demonstrated TME-controllable CAR gene expression in situ and induced a significant regression of established tumors in vivo. Besides, TME-dependent activation of CD47 CAR Mφ reduced the cytotoxic killing effect on erythrocytes.ConclusionsOur findings confirmed that the TME-specific activation mechanism of pArg1 CD47 CAR-Mφ based on intrinsic Arg1 promoter reprogramming endowed CAR-Mφ to effectively mitigate erythrocyte toxicity while enabling safe multidose administration regimens. This Trojan horse-like CAR-Mφ system achieves tumor-specific activation while minimizing systemic toxicity, offering a novel strategy to expand CAR-Mφ applications for solid tumors.

Houttuynia cordata Thunb. is an important traditional medical herb in China and other Asian countries, with high medicinal and economic value. However, a lack of available genomic information has become a limitation for research on this species. Thus, we carried out high-throughput transcriptomic sequencing of H. cordata to generate an enormous transcriptome sequence dataset for gene discovery and molecular marker development. Illumina paired-end sequencing technology produced over 56 million sequencing reads from H. cordata mRNA. Subsequent de novo assembly yielded 63,954 unigenes, 39,982 (62.52%) and 26,122 (40.84%) of which had significant similarity to proteins in the NCBI nonredundant protein and Swiss-Prot databases (E-value <10(-5)), respectively. Of these annotated unigenes, 30,131 and 15,363 unigenes were assigned to gene ontology categories and clusters of orthologous groups, respectively. In addition, 24,434 (38.21%) unigenes were mapped onto 128 pathways using the KEGG pathway database and 17,964 (44.93%) unigenes showed homology to Vitis vinifera (Vitaceae) genes in BLASTx analysis. Furthermore, 4,800 cDNA SSRs were identified as potential molecular markers. Fifty primer pairs were randomly selected to detect polymorphism among 30 samples of H. cordata; 43 (86%) produced fragments of expected size, suggesting that the unigenes were suitable for specific primer design and of high quality, and the SSR marker could be widely used in marker-assisted selection and molecular breeding of H. cordata in the future. This is the first application of Illumina paired-end sequencing technology to investigate the whole transcriptome of H. cordata and to assemble RNA-seq reads without a reference genome. These data should help researchers investigating the evolution and biological processes of this species. The SSR markers developed can be used for construction of high-resolution genetic linkage maps and for gene-based association analyses in H. cordata. This work will enable future functional genomic research and research into the distinctive active constituents of this genus.

Background Cognitive composite scores are used as the primary outcome measures for Alzheimer’s disease (AD) prevention trials; however, the extent to which these composite measures correlate with AD pathology has not been fully investigated. Since many on-going AD prevention studies are testing therapies that target either amyloid or tau, we sought to establish an association between a cognitive composite score and the underlying pathology of AD. Methods Data from 192 older deceased and autopsied persons from the Rush Religious Order Study were used in this study. All participants were classified at their initial evaluations with a clinical diagnosis of no cognitive impairment (NCI). Of these individuals, 105 remained NCI at the time of their death while the remaining 87 progressed to mild cognitive impairment (MCI) or AD. A cognitive composite score composed of eight cognitive tests was used as the outcome measure. Individuals were classified into groups based on Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropathological diagnosis and Braak stage. Results The rate of annualized composite score decline was significantly greater for the high CERAD ( p  < 0.001, d  = 0.56) and Braak ( p  < 0.001, d  = 0.55) groups compared with the low CERAD and Braak groups, respectively. Mixed-model repeated measure (MMRM) analyses revealed a significantly greater difference in composite score change from baseline for the high CERAD group relative to the low CERAD group after 5 years (Δ = −2.74, 95% confidence interval (CI) −5.01 to −0.47; p  = 0.02). A similar analysis between low and high Braak stage groups found no significant difference in change from baseline (Δ = −0.69, 95% CI −3.03 to 1.66; p  = 0.56). Conclusions These data provide evidence that decreased cognitive composite scores were significantly associated with increased AD pathology and provide support for the use of cognitive composite scores in AD prevention trials.