N6-methyldeoxyadenosine modification difference contributes to homocysteine-induced mitochondrial perturbation in rat hippocampal primary neurons and PC12 cells.

Elevated homocysteine (Hcy) levels are detrimental to neuronal cells and contribute to cognitive dysfunction in rats. Mitochondria plays a crucial role in cellular energy metabolism. Interestingly, the damaging effects of Hcy in vivo and in vitro conditions exhibit distinct results. Herein, we aimed to investigate the effects of Hcy on mitochondrial function in primary neurons and PC12 cells and explore the underlying mechanisms involved. The metabolic intermediates of Hcy act as methyl donors and play important epigenetic regulatory roles. N6-methyldeoxyadenosine (6 mA) modification, which is enriched in mitochondrial DNA (mtDNA), can be mediated by methylase METTL4. Our study suggested that mitochondrial perturbation caused by Hcy in primary neurons and PC12 cells may be attributable to mtDNA 6 mA modification difference. Hcy could activate the expression of METTL4 within mitochondria to facilitate mtDNA 6 mA status, and repress mtDNA transcription, then result in mitochondrial dysfunction.

Inulin-gel-based oral immunotherapy remodels the small intestinal microbiome and suppresses food allergy.

Despite the potential of oral immunotherapy against food allergy, adverse reactions and loss of desensitization hinder its clinical uptake. Dysbiosis of the gut microbiota is implicated in the increasing prevalence of food allergy, which will need to be regulated to enable for an effective oral immunotherapy against food allergy. Here we report an inulin gel formulated with an allergen that normalizes the dysregulated ileal microbiota and metabolites in allergic mice, establishes allergen-specific oral tolerance and achieves robust oral immunotherapy efficacy with sustained unresponsiveness in food allergy models. These positive outcomes are associated with enhanced allergen uptake by antigen-sampling dendritic cells in the small intestine, suppressed pathogenic type 2 immune responses, increased interferon-γ+ and interleukin-10+ regulatory T cell populations, and restored ileal abundances of Eggerthellaceae and Enterorhabdus in allergic mice. Overall, our findings underscore the therapeutic potential of the engineered allergen gel as a suitable microbiome-modulating platform for food allergy and other allergic diseases.

Fabrication of chitin-fibrin hydrogels to construct the 3D artificial extracellular matrix scaffold for vascular regeneration and cardiac tissue engineering.

As the cornerstone of tissue engineering and regeneration medicine research, developing a cost-effective and bionic extracellular matrix (ECM) that can precisely modulate cellular behavior and form functional tissue remains challenging. An artificial ECM combining polysaccharides and fibrillar proteins to mimic the structure and composition of natural ECM provides a promising solution for cardiac tissue regeneration. In this study, we developed a bionic hydrogel scaffold by combining a quaternized ß-chitin derivative (QC) and fibrin-matrigel (FM) in different ratios to mimic a natural ECM. We evaluated the stiffness of those composite hydrogels with different mixing ratios and their effects on the growth of human umbilical vein endothelial cells (HUVECs). The optimal hydrogels, QCFM1 hydrogels were further applied to load HUVECs into nude mice for in vivo angiogenesis. Besides, we encapsulated human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) into QCFM hydrogels and employed 3D bioprinting to achieve batch fabrication of human-engineered heart tissue (hEHT). Finally, the myocardial structure and electrophysiological function of hEHT were evaluated by immunofluorescence and optical mapping. Designed artificial ECM has a tunable modulus (220-1380 Pa), which determines the different cellular behavior of HUVECs when encapsulated in these. QCFM1 composite hydrogels with optimal stiffness (800 Pa) and porous architecture were finally identified, which could adapt for in vitro cell spreading and in vivo angiogenesis of HUVECs. Moreover, QCFM1 hydrogels were applied in 3D bioprinting successfully to achieve batch fabrication of both ring-shaped and patch-shaped hEHT. These QCFM1 hydrogels-based hEHTs possess organized sarcomeres and advanced function characteristics comparable to reported hEHTs. The chitin-derived hydrogels are first used for cardiac tissue engineering and achieve the batch fabrication of functionalized artificial myocardium. Specifically, these novel QCFM1 hydrogels provided a reliable and economical choice serving as ideal ECM for application in tissue engineering and regeneration medicine.

Genome-wide association study and genomic selection of flax powdery mildew in Xinjiang Province.

Flax powdery mildew (PM), caused by Oidium lini, is a globally distributed fungal disease of flax, and seriously impairs its yield and quality. To data, only three resistance genes and a few putative quantitative trait loci (QTL) have been reported for flax PM resistance. To dissect the resistance mechanism against PM and identify resistant genetic regions, based on four years of phenotypic datasets (2017, 2019 to 2021), a genome-wide association study (GWAS) was performed on 200 flax core accessions using 674,074 SNPs and 7 models. A total of 434 unique quantitative trait nucleotides (QTNs) associated with 331 QTL were detected. Sixty-four loci shared in at least two datasets were found to be significant in haplotype analyses, and 20 of these sites were shared by multiple models. Simultaneously, a large-effect locus (qDI 11.2) was detected repeatedly, which was present in the mapping study of flax pasmo resistance loci. Oil flax had more QTL with positive-effect or favorable alleles (PQTL) and showed higher PM resistance than fiber flax, indicating that effects of these QTL were mainly additive. Furthermore, an excellent resistant variety C120 was identified and can be used to promote planting. Based on 331 QTLs identified through GWAS and the statistical model GBLUP, a genomic selection (GS) model related to flax PM resistance was constructed, and the prediction accuracy rate was 0.96. Our results provide valuable insights into the genetic basis of resistance and contribute to the advancement of breeding programs.

Enantio- and Diastereoselective Copper-Catalyzed Borylative Coupling of Styrenes and Azadienes.

Here we disclose a CuB-catalyzed reaction between aurone-derived α,ß-unsaturated imines and styrenes to produce 2-substituted benzofuran derivatives bearing both the γ-boryl functionality and α,ß-unsymmetric stereogenic centers. The reaction represents the first transition-metal-catalyzed unsymmetric 1,4-Michael additions of azadienes, which would enrich the arsenal of CuB catalysis in organic synthesis. In addition, the synthetically versatile boron-alkylated products can be elaborated by chemical transformations to useful optically active benzofuran heterocycles.

How social support and resilience impact mental health: The moderating role of time in isolation during the COVID-19 pandemic.

During the COVID-19 pandemic, quarantines effectively prevented the spread of COVID-19 but also caused people to develop mental health problems. We thus aimed to verify the impact of social support and resilience on mental health and to uncover the moderating role played by time in isolation during the post-pandemic era. We administered a cross-sectional survey to 510 college students. The results found that social support directly and negatively predicted mental health problems, and this relationship was mediated by resilience. Through multigroup analysis, resilience partially mediated the relationship between social support and mental health during period of isolation 1 (PI1) and fully mediated this relationship during period of isolation 2 (PI2) and period of isolation 3 (PI3). Moreover, the path coefficient of resilience to mental health at T3 was significantly higher than that at T2. Thus, the effect of resilience on mental health increases with the duration of time in isolation.

Assessment of PD-L1 Expression in Non-Small Cell Lung Cancers Using [68Ga]Ga-DOTA-WL12 PET/CT.

Assessing programmed death ligand-1 (PD-L1) expression in non-small cell lung cancer (NSCLC), particularly in metastatic cases, remains challenging. In this study, surface plasmon resonance (SPR) analysis and [68Ga]Ga-DOTA-WL12 micro-PET/CT imaging are performed. [68Ga]Ga-DOTA-WL12 PET/CT and [18F]FDG PET/CT are performed on a cohort of 20 patients with NSCLC. Semi-quantitative assessments include SUVmax, metabolic tumor volume (MTV), total lesion glycolysis (TLG), and target-to-background ratio (TBR). DOTA-WL12 exhibits robust PD-L1 binding with a KD value of 0.2 nM. Subsequent human studies reveal significant correlations between PD-L1 expression and the [68Ga]Ga-DOTA-WL12 SUVmax in primary and metastatic lesions, surpassing the [18F]FDG results (r = 0.8889, p <0.0001 vs r = 0.0469, p = 0.8127). Notably, [68Ga]Ga-DOTA-WL12 imaging discerned SUVmax and TBR differences between PD-L1 TPS ≤1% and PD-L1 TPS > 1% groups (p all <0.001). In an NSCLC patient with brain metastases, [68Ga]Ga-DOTA-WL12 shows a SUVmean of 0.04 in the brain background, with TBR values of 17 and 23, underscoring its potential for detecting brain metastases. The study provides initial evidence for the clinical utility of [68Ga]Ga-DOTA-WL12 PET/CT for lesion detection, immunotherapy selection, and therapeutic efficacy evaluation in PD-L1-expressing NSCLC, demonstrating its potential as a valuable tool in NSCLC research and management.

Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Emergent flat band and topological Kondo semimetal driven by orbital-selective correlations.

Flat electronic bands are expected to show proportionally enhanced electron correlations, which may generate a plethora of novel quantum phases and unusual low-energy excitations. They are increasingly being pursued in d-electron-based systems with crystalline lattices that feature destructive electronic interference, where they are often topological. Such flat bands, though, are generically located far away from the Fermi energy, which limits their capacity to partake in the low-energy physics. Here we show that electron correlations produce emergent flat bands that are pinned to the Fermi energy. We demonstrate this effect within a Hubbard model, in the regime described by Wannier orbitals where an effective Kondo description arises through orbital-selective Mott correlations. Moreover, the correlation effect cooperates with symmetry constraints to produce a topological Kondo semimetal. Our results motivate a novel design principle for Weyl Kondo semimetals in a new setting, viz. d-electron-based materials on suitable crystal lattices, and uncover interconnections among seemingly disparate systems that may inspire fresh understandings and realizations of correlated topological effects in quantum materials and beyond.

In vivo reactive astrocyte imaging using [18F]SMBT-1 in tauopathy and familial Alzheimer's disease mouse models: A multi-tracer study.

BACKGROUND: Reactive astrocytes play an important role in the development of Alzheimer's disease and primary tauopathies. Here, we aimed to investigate the relationships between reactive astrocytes. Microgliosis and glucose metabolism with Tau and amyloid beta pathology by using multi-tracer imaging in widely used tauopathy and familial Alzheimer's disease mouse models. RESULTS: Positron emission tomography imaging using [18F]PM-PBB3 (tau), [18F]florbetapir (amyloid-beta), [18F]SMBT-1 (monoamine oxidase-B), [18F]DPA-714 (translocator protein) and [18F]fluorodeoxyglucose was carried out in 3- and 7-month-old rTg4510 tau mice, 5 × FAD familial Alzheimer's disease mice and wild-type mice. Immunofluorescence staining was performed to validate the pathological distribution in the mouse brain after in vivo imaging. We found increased regional levels of [18F]PM-PBB3, [18F]SMBT-1, and [18F]DPA-714 and hypoglucose metabolism in the brains of 7-month-old rTg4510 mice compared to age-matched wild-type mice. Increased [18F]SMBT-1 uptake was observed in the brains of 3, 7-month-old 5 × FAD mice, with elevated regional [18F]florbetapir and [18F]DPA-714 uptakes in the brains of 7-month-old 5 × FAD mice, compared to age-matched wild-type mice. Positive correlations were shown between [18F]SMBT-1 and [18F]PM-PBB3, [18F]DPA-714 and [18F]PM-PBB3 in rTg4510 mice, and between [18F]florbetapir and [18F]DPA-714 SUVRs in 5 × FAD mice. CONCLUSION: In summary, these findings provide in vivo evidence that reactive astrocytes, microglial activation, and cerebral hypoglucose metabolism are associated with tau and amyloid pathology development in animal models of tauopathy and familial Alzheimer's disease.

Parafoveal Processing of Orthography, Phonology, and Semantics during Chinese Reading: Effects of Foveal Load.

The foveal load hypothesis assumes that the ease (or difficulty) of processing the currently fixated word in a sentence can influence processing of the upcoming word(s), such that parafoveal preview is reduced when foveal load is high. Recent investigations using pseudo-character previews reported an absence of foveal load effects in Chinese reading. Substantial Chinese studies to date provide some evidence to show that parafoveal words may be processed orthographically, phonologically, or semantically. However, it has not yet been established whether parafoveal processing is equivalent in terms of the type of parafoveal information extracted (orthographic, phonological, semantic) under different foveal load conditions. Accordingly, the present study investigated this issue with two experiments. Participants' eye movements were recorded as they read sentences in which foveal load was manipulated by placing a low- or high-frequency word N preceding a critical word. The preview validity of the upcoming word N + 1 was manipulated in Experiment 1, and word N + 2 in Experiment 2. The parafoveal preview was either identical to word N + 1(or word N + 2); orthographically related; phonologically related; semantically related; or an unrelated pseudo-character. The results showed robust main effects of frequency and preview type on both N + 1 and N + 2. Crucially, however, interactions between foveal load and preview type were absent, indicating that foveal load does not modulate the types of parafoveal information processed during Chinese reading.

Characterization of Thermotoga maritima Esterase Capable of Hydrolyzing Bis(2-hydroxyethyl) Terephthalate.

The gene-encoding carboxylesterase (TM1022) from the hyperthermophilic bacterium Thermotoga maritima (T. maritima) was cloned and expressed in Escherichia coli Top10 and BL21 (DE3). Recombinant TM1022 showed the best activity at pH 8.0 and 85 °C and retained 57% activity after 8 h cultivation at 90 °C. TM1022 exhibited good stability at pH 6.0-9.0, maintaining 53% activity after incubation at pH 10.0 and 37 °C for 6 h. The esterase TM1022 exhibited the optimum thermo-alkali stability and kcat/Km (598.57 ± 19.97 s-1mM-1) for pN-C4. TM1022 hydrolyzed poly(ethylene terephthalate) (PET) degradation intermediates, such as bis(2-hydroxyethyl) terephthalate (BHET) and mono(2-hydroxyethyl) terephthalate (MHET). The Km, kcat, and kcat/Km values for BHET were 0.82 ± 0.01 mM, 2.20 ± 0.02 s-1, and 2.67 ± 0.02 mM-1 s-1, respectively; those for MHET were 2.43 ± 0.07 mM, 0.04 ± 0.001 s-1, and 0.02 ± 0.001 mM-1 s-1, respectively. When purified TM1022 was added to the cutinase BhrPETase, hydrolysis of PET from drinking water bottle tops produced pure terephthalic acids (TPA) with 166% higher yield than those obtained after 72 h of incubation with BhrPETase alone as control. The above findings demonstrate that the esterase TM1022 from T. maritima has substantial potential for depolymerizing PET into monomers for reuse.

Metabolic phenotyping reveals an emerging role of ammonia abnormality in Alzheimer's disease.

The metabolic implications in Alzheimer's disease (AD) remain poorly understood. Here, we conducted a metabolomics study on a moderately aging Chinese Han cohort (n = 1397; mean age 66 years). Conjugated bile acids, branch-chain amino acids (BCAAs), and glutamate-related features exhibited strong correlations with cognitive impairment, clinical stage, and brain amyloid-ß deposition (n = 421). These features demonstrated synergistic performances across clinical stages and subpopulations and enhanced the differentiation of AD stages beyond demographics and Apolipoprotein E ε4 allele (APOE-ε4). We validated their performances in eight data sets (total n = 7685) obtained from Alzheimer's Disease Neuroimaging Initiative (ADNI) and Religious Orders Study and Memory and Aging Project (ROSMAP). Importantly, identified features are linked to blood ammonia homeostasis. We further confirmed the elevated ammonia level through AD development (n = 1060). Our findings highlight AD as a metabolic disease and emphasize the metabolite-mediated ammonia disturbance in AD and its potential as a signature and therapeutic target for AD.

LncRNA IRAIN overcomes imatinib resistance in chronic myeloid leukemia via NF-κB/CD44 pathway inhibition.

The development of tyrosine kinase inhibitors (TKIs) has revolutionarily increased the overall survival of patients with chronic myeloid leukemia (CML). However, drug resistance remains a major obstacle. Here, we demonstrated that a BCR-ABL1-independent long non-coding RNA, IRAIN, is constitutively expressed at low levels in CML, resulting in imatinib resistance. IRAIN knockdown decreased the sensitivity of CD34+ CML blasts and cell lines to imatinib, whereas IRAIN overexpression significantly increased sensitivity. Mechanistically, IRAIN downregulates CD44, a membrane receptor favorably affecting TKI resistance, by binding to the nuclear factor kappa B subunit p65 to reduce the expression of p65 and phosphorylated p65. Therefore, the demethylating drug decitabine, which upregulates IRAIN, combined with imatinib, formed a dual therapy strategy which can be applied to CML with resistance to TKIs.

The associations between nutritional status and physical frailty and Alzheimer's disease plasma biomarkers in older cognitively unimpaired adults with positive of amyloid-ß PET.

BACKGROUND & AIMS: It has been revealed good nutritional status and no physical frailty, which are modifiable lifestyle factors, are linked to less cognitive decline and a lower risk of Alzheimer's disease (AD). We aimed to investigate the associations between nutritional status and physical frailty and plasma AD biomarkers, especially the Tau-associated biomarkers in older cognitively unimpaired (CU) adults with higher ß-amyloid (Aß) burden. METHODS: The nutritional status and physical frailty were assessed via Mini-Nutritional Assessment Short-Form (MNA-SF) and Fried frailty index. The participants underwent the examination of plasma AD biomarkers and 18F-florbetapir PET scan as well as 18F-MK6240 PET in the validation cohort. Correlation and multiple linear regression analyses were used to investigate the associations between nutritional status and frailty and AD biomarkers. RESULTS: Two cohorts were included in our study. A total of 129 participants with Aß-PET positive were enrolled in the development cohort. Multiple linear regression analysis showed MNA-SF scores, normal nutritional status, Fried frailty index scores, frailty and some domains of frailty including weight loss, maximal grip strength and exhaustion were associated with plasma p-Tau-181. Furthermore, weight loss, Fried frailty index scores and frailty were associated with higher Aß-PET standard uptake value ratio. We further performed subgroup analyses stratified by age, sex and apolipoprotein E ε4 genotype to investigate the beneficial characteristics of nutrition and frailty in the special subgroups. Validation cohort contained 38 Aß-PET positive participants. MNA-SF scores, normal nutritional status, Fried frailty index scores and frailty were associated with Tau burden evaluated by 18F-MK6240 PET Braak-like stages. CONCLUSIONS: Our data indicates that normal nutritional status and no physical frailty may be associated with expected trend of plasma AD biomarkers, especially less Tau pathology in older CU adults with Aß deposition. Adjusting to these characteristics of nutrition and physical frailty may help reduce the risk of AD development.

Increased Cerebral Level of P2X7R in a Tauopathy Mouse Model by PET Using [18F]GSK1482160.

Neuroinflammation plays an important role in Alzheimer's disease and primary tauopathies. The aim of the current study was to map [18F]GSK1482160 for imaging of purinergic P2X7R in Alzheimer's disease and primary tauopathy mouse models. Small animal PET was performed using [18F]GSK1482160 in widely used mouse models of Alzheimer's disease (APP/PS1, 5×FAD, and 3×Tg), 4-repeat tauopathy (rTg4510) mice, and age-matched wild-type mice. Increased uptake of [18F]GSK1482160 was observed in the brains of 7-month-old rTg4510 mice compared to wild-type mice and compared to 3-month-old rTg4510 mice. A positive correlation between hippocampal tau [18F]APN-1607 and [18F]GSK1482160 uptake was found in rTg4510 mice. No significant differences in the uptake of [18F]GSK1482160 was observed for APP/PS1 mice, 5×FAD mice, or 3×Tg mice. Immunofluorescence staining further indicated the distribution of P2X7Rs in the brains of 7-month-old rTg4510 mice with accumulation of tau inclusion. These findings provide in vivo imaging evidence for an increased level of P2X7R in the brains of tauopathy mice.

GmNLP1 and GmNLP4 activate nitrate-induced CLE peptides NIC1a/b to mediate nitrate-regulated root nodulation.

Symbiotic nitrogen fixation is an energy-intensive process, to maintain the balance between growth and nitrogen fixation, high concentrations of nitrate inhibit root nodulation. However, the precise mechanism underlying the nitrate inhibition of nodulation in soybean remains elusive. In this study, CRISPR-Cas9-mediated knockout of GmNLP1 and GmNLP4 unveiled a notable nitrate-tolerant nodulation phenotype. GmNLP1b and GmNLP4a play a significant role in the nitrate-triggered inhibition of nodulation, as the expression of nitrate-responsive genes was largely suppressed in Gmnlp1b and Gmnlp4a mutants. Furthermore, we demonstrated that GmNLP1b and GmNLP4a can bind to the promoters of GmNIC1a and GmNIC1b and activate their expression. Manipulations targeting GmNIC1a and GmNIC1b through knockdown or overexpression strategies resulted in either increased or decreased nodule number in response to nitrate. Additionally, transgenic roots that constitutively express GmNIC1a or GmNIC1b rely on both NARK and hydroxyproline O-arabinosyltransferase RDN1 to prevent the inhibitory effects imposed by nitrate on nodulation. In conclusion, this study highlights the crucial role of the GmNLP1/4-GmNIC1a/b module in mediating high nitrate-induced inhibition of nodulation.

Pathway to Approval of Innovative Radiopharmaceuticals in China.

Since the late 1950s, radiopharmaceuticals have been used for diagnosis and treatment in clinical nuclear medicine in China. Over the decades, China has successfully established a relatively sophisticated system for radiopharmaceutical production and management, supported by state-of-the-art facilities. With the rapid growth of the national economy, the radiopharmaceutical market in China is expanding at a remarkable pace. This burgeoning market has led to an escalating demand for clinical-stage radiopharmaceuticals, either produced domestically or imported. Despite this positive trajectory, the development and application of radiopharmaceuticals in China have been hindered by several challenges that persist, such as inadequate research, insufficient investment, limited availability of radionuclides, shortage of trained personnel in related fields, and imperfections in policies and regulations. In an exciting development, the regulation reforms implemented since 2015 have positively affected China's drug regulatory system. The introduction of the "Mid- and Long-Term Development Plan (2021-2035) for Medical Isotopes" created concurrently an opportune environment for the advancement of innovative radiopharmaceuticals. In this review, we aim to provide an overview of the approval process for novel radiopharmaceuticals by the National Medical Products Administration and the status of radiopharmaceuticals in research and development in China. Preclinical development and clinical translation of radiopharmaceuticals are undergoing rapid evolution in China. As practitioners in the field in China, we provide several practical suggestions to stimulate open discussions and thoughtful consideration.

Development and validation of machine learning models to predict frailty risk for elderly.

AIMS: Early identification and intervention of the frailty of the elderly will help lighten the burden of social medical care and improve the quality of life of the elderly. Therefore, we used machine learning (ML) algorithm to develop models to predict frailty risk in the elderly. DESIGN: A prospective cohort study. METHODS: We collected data on 6997 elderly people from Chinese Longitudinal Healthy Longevity Study wave 6-7 surveys (2011-2012, 2014). After the baseline survey in 1998 (wave 1), the project conducted follow-up surveys (wave 2-8) in 2000-2018. The osteoporotic fractures index was used to assess frailty. Four ML algorithms (random forest [RF], support vector machine, XGBoost and logistic regression [LR]) were used to develop models to identify the risk factors of frailty and predict the risk of frailty. Different ML models were used for the prediction of frailty risk in the elderly and frailty risk was trained on a cohort of 4385 elderly people with frailty (split into a training cohort [75%] and internal validation cohort [25%]). The best-performing model for each study outcome was tested in an external validation cohort of 6997 elderly people with frailty pooled from the surveys (wave 6-7). Model performance was assessed by receiver operating curve and F2-score. RESULTS: Among the four ML models, the F2-score values were similar (0.91 vs. 0.91 vs. 0.88 vs. 0.90), and the area under the curve (AUC) values of RF model was the highest (0.75), followed by LR model (0.74). In the final two models, the AUC values of RF and LR model were similar (0.77 vs. 0.76) and their accuracy was identical (87.4% vs. 87.4%). CONCLUSION: Our study developed a preliminary prediction model based on two different ML approaches to help predict frailty risk in the elderly. IMPACT: The presented models from this study can be used to inform healthcare providers to predict the frailty probability among older adults and maybe help guide the development of effective frailty risk management interventions. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: Detecting frailty at an early stage and implementing timely targeted interventions may help to improve the allocation of health care resources and to reduce frailty-related burden. Identifying risk factors for frailty could be beneficial to provide tailored and personalized care intervention for older adults to more accurately prevent or improve their frail conditions so as to improve their quality of life. REPORTING METHOD: The study has adhered to STROBE guidelines. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Tau pathology is associated with synaptic density and longitudinal synaptic loss in Alzheimer's disease.

The associations of synaptic loss with amyloid-ß (Aß) and tau pathology measured by positron emission tomography (PET) and plasma analysis in Alzheimer's disease (AD) patients are unknown. Seventy-five participants, including 26 AD patients, 19 mild cognitive impairment (MCI) patients, and 30 normal controls (NCs), underwent [18F]SynVesT-1 PET/MR scans to assess synaptic density and [18F]florbetapir and [18F]MK6240 PET/CT scans to evaluate Aß plaques and tau tangles. Among them, 19 AD patients, 12 MCI patients, and 29 NCs had plasma Aß42/40 and p-tau181 levels measured by the Simoa platform. Twenty-three individuals, 6 AD patients, 4 MCI patients, and 13 NCs, underwent [18F]SynVesT-1 PET/MRI and [18F]MK6240 PET/CT scans during a one-year follow-up assessment. The associations of Aß and tau pathology with cross-sectional and longitudinal synaptic loss were investigated using Pearson correlation analyses, generalized linear models and mediation analyses. AD patients exhibited lower synaptic density than NCs and MCI patients. In the whole cohort, global Aß deposition was associated with synaptic loss in the medial (r = -0.431, p < 0.001) and lateral (r = -0.406, p < 0.001) temporal lobes. Synaptic density in almost all regions was related to the corresponding regional tau tangles independent of global Aß deposition in the whole cohort and stratified groups. Synaptic density in the medial and lateral temporal lobes was correlated with plasma Aß42/40 (r = 0.300, p = 0.020/r = 0.289, p = 0.025) and plasma p-tau 181 (r = -0.412, p = 0.001/r = -0.529, p < 0.001) levels in the whole cohort. Mediation analyses revealed that tau tangles mediated the relationship between Aß plaques and synaptic density in the whole cohort. Baseline tau pathology was positively associated with longitudinal synaptic loss. This study suggested that tau burden is strongly linked to synaptic density independent of Aß plaques, and also can predict longitudinal synaptic loss.