National Health and Family Planning Commission

Growing evidence suggests that abnormal lipid metabolism occurs in amyotrophic lateral sclerosis, even in the presymptomatic stage, implying an etiologic link. However, the genetic mechanism underlying altered lipid levels in amyotrophic lateral sclerosis remains elusive. Therefore, in this study, we performed genetic correlation analysis, a cross-trait meta-analysis, tissue-specific enrichment analysis, and bidirectional two-sample Mendelian randomization analysis of European population to explore whether there is a genetic and causal relationship between lipids and amyotrophic lateral sclerosis. The effect of lipid-lowering drugs on amyotrophic lateral sclerosis was also evaluated using a drug target Mendelian randomization approach. The results showed a positive genetic correlation between amyotrophic lateral sclerosis and both high-density lipoprotein cholesterol and apolipoprotein A1 and identified 71 independent shared loci between amyotrophic lateral sclerosis and high-density lipoprotein cholesterol, as well as 55 independent shared loci between amyotrophic lateral sclerosis and apolipoprotein A1. These shared loci were enriched in the lipid metabolic pathway and the alcohol metabolic pathway. Further Mendelian randomization analysis targeting lipid-lowering drugs showed that single nucleotide polymorphisms within the ACLY and PCSK9 genes had a protective effect against amyotrophic lateral sclerosis risk by decreasing low-density lipoprotein cholesterol. The combination of ACLY and PCSK9 inhibitors has a greater protective effect on amyotrophic lateral sclerosis risk than that of PCSK9 inhibitors alone. In summary, there is a common genetic structure between lipids and amyotrophic lateral sclerosis. Mendelian randomization analysis supports an association between elevated blood lipids and the risk of developing amyotrophic lateral sclerosis, and the use of ACLY or PCSK9 inhibitors may improve disease prognosis.

Effective drug accumulation at tumor sites remains a critical challenge in cancer therapy due to poor targeting and off-target effects. This study leverages bioorthogonal chemistry to develop a novel liposome-based drug delivery system designed to enhance tumor-specific accumulation and achieve controlled drug release for improved therapeutic outcomes. DBCO- and azide-modified liposomes were engineered to optimize encapsulation efficiency, stability, and sustained drug release. Their performance was evaluated through in vitro cellular assays to assess uptake and toxicity, alongside in vivo biodistribution and efficacy studies in tumor-bearing models. The bioorthogonal liposomes demonstrated significantly enhanced tumor accumulation compared to free doxorubicin and conventional liposomes, achieving a tumor inhibition rate of 60%. In vitro experiments confirmed improved cellular uptake and retention without additional toxicity, while in vivo results highlighted superior therapeutic efficacy and reduced systemic toxicity, as evidenced by increased tumor apoptosis, suppressed proliferation, and minimal body weight loss. This study underscores the potential of bioorthogonal liposomes as a precise drug delivery platform, offering enhanced tumor targeting, better efficacy, and lower toxicity. These findings pave the way for next-generation targeted cancer therapies, with future efforts aimed at refining liposome design for clinical translation.

Bone mineral density (BMD) is a critical indicator of osteoporosis (OP). Utilizing the latest multi-omics quantitative trait loci (QTLs) data, we aim to identify novel candidates associated with heel BMD (hBMD). We collected QTLs data from the INTERVAL cohort (independent of the UK Biobank (UKB)) that is a randomised trial including approximately 50,000 healthy blood donors enrolled from 25 centres of England's National Health Service Blood and Transplant. We then calculated individual polygenic risk score (PRS) for 13,646 RNAs, 308 proteins (Olink), 2379 proteins (SomaScan), 726 metabolites (Metabolon) and 141 metabolites (Nightingale) in UKB. hBMD was measured by quantitative ultrasound. Generalized linear model was used to evaluate the associations between multi-omics PRS and hBMD in 96,165 subjects. Integrated analysis of multi-omics was performed on the MetaboAnalyst 6.0 platform. Replication analysis was performed using the internal Olink proteomics and Nightingale metabolomics data of UKB. We subsequently explored the causal effects of the targets on hBMD using mendelian randomization (MR) analysis. Significant associations were determined using a false discovery rate (FDR)-adjusted P-value (Padj < 0.05). We identified 195 hBMD-associated genes, such as WNT16 (Padj = 6.417× 10- 14); 180 proteins such as COL1A1 (Padj = 3.132 × 10- 24); 21 metabolites, such as total cholesterol (Padj = 0.008). Those associated proteins/metabolites were replicated in UKB, such as COL1A1 (Padj = 7.480 × 10- 4) and total cholesterol (Padj = 7.773 × 10- 8). The integrated analysis of multi-omics identified several genes/metabolites (DGKZ, PLPP3, GPD1L, CHKB and glycerol 3-phosphate) enriched in the overlapping pathway-glycerophospholipid metabolism. Moreover, MR detected several novel biomarkers among the top/enriched targets, which were causally associated with hBMD, such as NAP1L2 (β= - 0.019, P = 0.003) and PLPP3 (β = - 0.026, P = 0.041). Our study not only identified several novel candidate biomarkers such as PLPP3, RGMB, and RNF128 for hBMD but also provided genetic evidence supporting their potential causal roles in bone mineral regulation. These findings could shed light on the molecular underpinnings of OP.

GABAergic medial septal neurons play a key role in regulating hippocampus-dependent spatial memory, but the underlying mechanisms are not yet fully understood. In male mice, we establish an object-place recognition impairment model using an acute sleep deprivation protocol. Here we show that parvalbumin-positive neurons in the medial septum regulate object-location memory specificity during encoding by modulating hippocampal place cell population activity. Using in vivo electrophysiology combined with optogenetics, we characterize the role of medial septal parvalbumin-positive neurons in object-place recognition during memory encoding. Preference for objects relocated to novel positions parallels directional shifts in place fields of remapping neuronal populations, as well as decreased co-activity among place cells in dorsal CA1 during the encoding phase. Activating medial septal parvalbumin-positive neurons during memory encoding rescues object-place recognition impairments. These findings suggest that parvalbumin-positive neurons in the medial septum play a causal role in object-place recognition memory.

ObjectiveThis study aimed to evaluate treatment preferences for anticancer drugs among patients with non–small cell lung cancer (NSCLC), in order to provide evidence not only for clinical prescribing decisions but also for broader applications such as health insurance reimbursement and policy-making.MethodsA Best–Worst Scaling object‐case (BWS‐1) questionnaire was administered to NSCLC patients. Thirteen choice sets, each containing four attributes, were generated using Balanced Incomplete Block Design. Respondents were asked to identify the most and least important attribute within each set. The attributes include overall survival (OS), disease control rate, progression-free survival (PFS), dyspnea, pain, objective response, hemoptysis, fever, nausea and vomiting, monthly out-of-pocket expenditure, cough, mode of administration, fatigue. Relative attribute importance and preference heterogeneity were estimated using counting analysis and a conditional logit model (CLM).ResultsA total of 102 NSCLC patients were enrolled. High concordance was observed between counting analysis and conditional logit results. In the CLM, OS (β=3.537, P<0.01), disease control rate (β=2.025, P<0.01), and PFS (β=1.574, P<0.01) showed the strongest positive preferences. Fatigue (β=–1.158, P<0.01) and mode of administration (β=–0.600, P<0.01) were associated with lower relative importance. Cough showed a negative coefficient but was not statistically significant (β=–0.185, P=0.11).ConclusionThis study is the first to explore the NSCLC patient medication preference using a BWS-1. The findings suggest OS, disease control rate, and PFS are prioritized by patients when choosing treatment regimens.