Volume 138 · Issue 18 · 2025

Brain science is the frontier of modern science, and new advances have been made in brain-like designs and brain-computer interfaces to simulate or develop brain functions. However, given that the brain is hermetically sealed within the skull, exploration and deciphering of the brain structure and functions are limited. Growing evidence suggests that the gut is not just a digestive organ. It not only provides essential nutrients and electrolytes for brain neurodevelopment and the maintenance of brain function, but it also transmits external environmental and intestinal wall signals from the intestinal lumen to the central nervous system through multiple pathways to regulate brain activity, function, and structure. A variety of gut-brain interaction pathways have been identified, including neural pathways, neuroimmune signaling, endocrine pathways, and biochemical messengers produced by gut microbes. Gut microbes interact with food and the gut to modulate gut-brain communication. The gut’s important role and potential in neurodevelopment, maintenance of normal function, and disease development make it an increasingly important area of research in brain science and neuropsychiatric disorders. The gut’s unique role in brain functions and its accessibility for research (compared to direct brain studies) establish it as a critical gate to understanding the mysteries of brain science. Crucially, intestinal nutrients and microbes provide two unique keys to unlock this gate—enabling neural regulation and novel treatments for neuropsychiatric diseases.

Transposable elements (TEs), once considered genomic "junk" , are now recognized as critical regulators of genome function and human disease. These mobile genetic elements—including retrotransposons (long interspersed nuclear elements [LINE-1], Alu, short interspersed nuclear element-variable numbers of tandem repeats-Alu [SVA], and human endogenous retrovirus [HERV]) and DNA transposons—are tightly regulated by multilayered mechanisms that operate from transcription through to genomic integration. Although typically silenced in somatic cells, TEs are transiently activated during key developmental stages—such as zygotic genome activation and cell fate determination—where they influence chromatin architecture, transcriptional networks, RNA processing, and innate immune responses. Dysregulation of TEs, however, can lead to genomic instability, chronic inflammation, and various pathologies, including cancer, neurodegeneration, and aging. Paradoxically, their reactivation also presents new opportunities for clinical applications, particularly as diagnostic biomarkers and therapeutic targets. Understanding the dual role of TEs—and balancing their contributions to normal development and disease—is essential for advancing novel therapies and precision medicine.

Cellular senescence, stable cell cycle arrest that can be triggered in normal cells in response to various intrinsic and extrinsic stressors, has been highlighted as one of the most important mechanisms involved in kidney diseases. It not only serves as a fundamental biological process promoting normal organogenesis and successful wound repair but also contributes to organ dysfunction, tissue fibrosis, and the generalized aging phenotype. Moreover, senescent cells exhibit reduced regenerative capacity, which impairs renal function recovery from injuries. Importantly, senescent cells are involved in immune regulation via secreting a diverse array of proinflammatory and profibrotic factors known as senescence-associated secretory phenotype (SASP) with autocrine, paracrine, and endocrine activities. Thus, eliminating detrimental senescent cells or inhibiting SASP production holds great promise for developing innovative therapeutic strategies for kidney diseases. In this review, we summarize the current knowledge of the intricate mechanisms and hallmarks of cellular senescence in kidney diseases and emphasize novel therapeutic targets, including epigenetic regulators, G protein-coupled receptors, and lysosome-related proteins. Particularly, we highlight the recently identified senotherapeutics, which provide new therapeutic strategies for treating kidney diseases.

The Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation is one of the most prevalent activating alterations in cancer. It indicates a poor overall prognosis due to its highly invasive nature. Although several KRAS inhibitors have been developed in recent years, a significant clinical challenge has emerged as a substantial proportion of patients eventually develop resistance to these therapies. Therefore, identifying determinants of drug resistance is critical for guiding treatment strategies. This review provides a comprehensive overview of the mutation landscape and molecular mechanisms of KRAS activity in various cancers. Meanwhile, it summaries the progress and prospects of small molecule KRAS inhibitors undergoing clinical trials. Furthemore, this review explores potential strategies to overcome drug resistance, with the ultimate goal of steering toward patient-centric precision oncology in the foreseeable future.

The Baveno Cooperation is a consortium of internationally renowned experts committed to setting standards for the clinical management of patients with advanced chronic liver disease, with a particular emphasis on complications related to portal hypertension. Updated every five years and endorsed by major scientific societies, the Baveno recommendations have significantly influenced clinical practice and improved patient outcomes worldwide. The latest Baveno consensus, Baveno VII, provided a series of recommendations that have shifted our understanding of chronic liver disease and portal hypertension and profoundly shaped clinical practice. However, many areas of research remain to be explored in the short to intermediate term to enable a more personalized medicine approach. This review highlights some of the most relevant advancements introduced in Baveno VII and discusses future challenges.

The achievement of an optimal return to sport (RTS) has remained a key goal after sports-related injuries, with the ongoing debate on the effectiveness of different surgical approaches for anterior cruciate ligament (ACL) rupture. This study aims to assess clinical outcomes and RTS across various surgical methods, such as anatomical single-bundle reconstruction (ASBR), central-axial single-bundle reconstruction (CASBR), and double-bundle reconstruction (DBR).

A randomized clinical trial was conducted, comprising 191 patients who underwent ACL rupture. These patients were divided into three groups based on the ACL reconstruction techniques they received (ASBR, CASBR, DBR). Over the 2-year follow-up period, the study assessed RTS through four single-hop tests, isokinetic extension tests, and limb asymmetry indices. Postoperative graft status was determined using the signal-to-noise quotient (SNQ), while knee function was evaluated using the International Knee Documentation Committee 2000 (IKDC-2000) score, Lysholm score, Tegner score, and degree of knee laxity. A binary logistic regression model was developed to forecast the factors influencing ideal RTS.

DBR (67.63%) and CASBR (58.00%) exhibited higher RTS passing rates compared to ASBR (30.39%; χ² = 19.57, P <0.05). Quadriceps strength symmetry in the lower limbs was identified as the key determinant of RTS (χ² = 17.08, P <0.05). The RTS rate was influenced by SNQs of the graft’s tibial site (odds ratio: 0.544) and quadriceps strength of the reconstructed knee joint at 60°/s (odds ratio: 6.346). Notably, the DBR group showed enhanced knee stability, evidenced by superior results in the Lachman test (χ² = 13.49, P <0.01), objective IKDC-2000 (χ² = 27.02, P = 0.002), and anterior instability test (χ² = 9.46, P <0.01). Furthermore, DBR demonstrated superior clinical outcomes based on the Lysholm score (DBR: 89.57 ± 7.72, CASBR: 83.00 ± 12.71, ASBR: 83.21 ± 11.95; F = 10.452, P <0.01) and IKDC-2000 score (DBR: 90.95 ± 7.00, CASBR: 84.64 ± 12.68, ASBR: 83.63 ± 11.41; F = 11.78, P <0.01).

For patients with ACL rupture, more ideal RTS rate and clinical outcomes were shown in the DBR group than in the ASBR and CASBR groups. Autograft status and quadriceps strength are postively related to RTS.

The primary limitation to kidney transplantation is organ shortage. Recent progress in gene editing and immunosuppressive regimens has made xenotransplantation with porcine organs a possibility. However, evidence in pig-to-human xenotransplantation remains scarce, and antibody-mediated rejection (AMR) is a major obstacle to clinical applications of xenotransplantation.

We conducted a kidney xenotransplantation in a brain-dead human recipient using a porcine kidney with five gene edits (5GE) on March 25, 2024 at Xijing Hospital, China. Clinical-grade immunosuppressive regimens were employed, and the observation period lasted 22 days. We collected and analyzed the xenograft function, ultrasound findings, sequential protocol biopsies, and immune surveillance of the recipient during the observation.

The combination of 5GE in the porcine kidney and clinical-grade immunosuppressive regimens prevented hyperacute rejection. The xenograft kidney underwent delayed graft function in the first week, but urine output increased later and the single xenograft kidney maintained electrolyte and pH homeostasis from postoperative day (POD) 12 to 19. We observed AMR at 24 h post-transplantation, due to the presence of pre-existing anti-porcine antibodies and cytotoxicity before transplantation; this AMR persisted throughout the observation period. Plasma exchange and intravenous immunoglobulin treatment mitigated the AMR. We observed activation of latent porcine cytomegalovirus toward the end of the study, which might have contributed to coagulation disorder in the recipient.

5GE and clinical-grade immunosuppressive regimens were sufficient to prevent hyperacute rejection during pig-to-human kidney xenotransplantation. Pre-existing anti-porcine antibodies predisposed the xenograft to AMR. Plasma exchange and intravenous immunoglobulin were safe and effective in the treatment of AMR after kidney xenotransplantation.

The profile and clinical significance of the oral microbiome in patients with non-obstructive hypertrophic cardiomyopathy (noHCM) and obstructive hypertrophic cardiomyopathy (oHCM) remain unexplored. The objective of this study was to evaluate the difference of oral microbiome between noHCM and oHCM patients.

This cross-sectional study enrolled 18 noHCM patients and 26 oHCM patients from Fuwai Hospital, Chinese Academy of Medical Sciences between 2020 and 2021. Clinical and periodontal evaluations were conducted, and subgingival plaque samples were collected. Metagenomic sequencing and subsequent microbial composition and functional analyses were performed.

Compared to oHCM patients, those with noHCM had higher systolic blood pressure (138.1 ± 18.8 mmHg vs. 124.2 ± 13.8 mmHg, P = 0.007), a larger body circumference (neck circumference: 39.2 ± 4.0 cm vs. 35.1 ± 3.7 cm, P = 0.001; waist circumference: 99.7 ± 10.5 cm vs. 92.2 ± 10.8 cm, P = 0.027; hip circumference: 102.5 ± 5.6 cm vs. 97.5 ± 9.1 cm, P = 0.030), a greater left ventricular end-diastolic diameter (46.6 ± 4.9 mm vs. 43.1 ± 4.9 mm, P = 0.026), and a lower left ventricular ejection fraction (64.1 ± 5.7 % vs. 68.5 ± 7.8%, P = 0.048). While overall biodiversity and general microbial composition were similar between the noHCM and oHCM groups, ten taxa displayed significant differences at the genus and species levels, with Porphyromonas gingivalis showing the highest abundance and greater enrichment in noHCM (relative abundance: 7.79535 vs. 4.87697, P = 0.043). Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis identified ten distinct pathways, with pathways related to energy and amino acid metabolism being enriched in oHCM patients, and those associated with genetic information processing less abundant in the oHCM group. Metabolic potential analysis revealed ten significantly altered metabolites primarily associated with amino sugar and nucleotide sugar metabolism, porphyrin metabolism, pentose and glucuronate interconversion, and lysine degradation.

The higher abundance of Porphyromonas gingivalis, which is known to impact cardiovascular health, in noHCM patients may partially account for clinical differences between the groups. Pathway enrichment and metabolic potential analyses suggest microbial functional shifts between noHCM and oHCM patients, potentially reflecting inherent metabolic changes in HCM.

There is little literature describing the artificial intelligence (AI)-aided diagnosis of severe pneumonia (SP) subphenotypes and the association of the subphenotypes with the ventilatory treatment efficacy. The aim of our study is to illustrate whether clinical and biological heterogeneity, such as ventilation and gas-exchange, exists among patients with SP using chest computed tomography (CT)-based AI-aided latent class analysis (LCA).

This retrospective study included 413 patients hospitalized at Xinhua Hospital diagnosed with SP from June 1, 2015 to May 30, 2020. AI quantification results of chest CT and their combination with additional clinical variables were used to develop LCA models in an SP population. The optimal subphenotypes were determined though evaluating statistical indicators of all the LCA models, and clinical implications of them such as guiding ventilation strategies were further explored by statistical methods.

The two-class LCA model based on AI quantification results of chest CT can describe the biological characteristics of the SP population well and hence yielded the two clinical subphenotypes. Patients with subphenotype-1 had milder infections (P <0.001) than patients with subphenotype-2 and had lower 30-day (P <0.001) and 90-day (P <0.001) mortality, and lower in-hospital (P = 0.001) and 2-year (P <0.001) mortality. Patients with subphenotype-1 showed a better match between the percentage of non-infected lung volume (used to quantify ventilation) and oxygen saturation (used to reflect gas exchange), compared with patients with subphenotype-2. There were significant differences in the matching degree of lung ventilation and gas exchange between the two subphenotypes (P <0.001). Compared with patients with subphenotype-2, those with subphenotype-1 showed a relatively better match between CT-based AI metrics of the non-infected region and oxygenation, and their clinical outcomes were effectively improved after receiving invasive ventilation treatment.

A two-class LCA model based on AI quantification results of chest CT in the SP population particularly revealed clinical heterogeneity of lung function. Identifying the degree of match between ventilation and gas-exchange may help guide decisions about assisted ventilation.

Bile acids (BAs) facilitate the progression of gastric intestinal metaplasia (GIM). Long non-coding RNAs (lncRNAs) dysregulation was observed along with the initiation of gastric cancer. However, how lncRNAs function in GIM remains unclear. This study aimed to explore the role and mechanism of lncRNA PVT1 in GIM, and provide a potential therapeutic target for GIM treatment.

We employed RNA sequencing (RNA-seq) to screen dysregulated lncRNAs in gastric epithelial cells after BA treatment. Bioinformatics analysis was conducted to reveal the regulatory mechanism. PVT1 expression was detected in 21 paired biopsies obtained under endoscopy. Overexpressed and knockdown cell models were established to explore gene functions in GIM. Molecular interactions were validated by dual-luciferase reporter assay, RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (Ch-IP). The levels of relative molecular expression were detected in GIM tissues.

We confirmed that lncRNA PVT1 was upregulated in BA-induced GIM model. PVT1 promoted the expression of intestinal markers such as CDX2, KLF4, and HNF4α. Bioinformatics analysis revealed that miR-34b-5p was a putative target of PVT1. miR-34b-5p mimics increased CDX2, KLF4, and HNF4α levels. Restoration of miR-34b-5p decreased the pro-metaplastic effect of PVT1. The interactions between PVT1, miR-34b-5p, and the downstream target HNF4α were validated. Moreover, HNF4α could transcriptionally activated PVT1, sustaining the GIM phenotype. Finally, the activation of the PVT1/miR-34b-5p/HNF4α loop was detected in GIM tissues.

BAs facilitate GIM partially via a PVT1/miR-34b-5p/HNF4α positive feedback loop. PVT1 may become a novel target for blocking the continuous development of GIM and preventing the initiation of gastric cancer in patients with bile reflux.

The protective effect of mesenchymal stem cells (MSCs) on cardiac ischemia-reperfusion (I/R) injury has been widely reported. Dental pulp-derived mesenchymal stem cells (DP-MSCs) have therapeutic effects on various diseases, including diabetes and cirrhosis. This study aimed to determine the therapeutic effects of DP-MSCs on I/R injury and elucidate the underlying mechanism.

Myocardial I/R injury model mice were treated with DP-MSCs or a miR-19a-3p mimic. The infarct volume, fibrotic area, pyroptosis, inflammation level, and cardiac function were measured. Cardiomyocytes exposed to hypoxia-reoxygenation were transfected with the miR-19a-3p mimic, miR-19a-3p inhibitor, or negative control. Pyroptosis and protein expression in the interferon regulatory factor 8/mitogen-activated protein kinase (IRF-8/MAPK) pathway were measured.

DP-MSCs protected cardiac function in cardiac I/R-injured mice and inhibited cardiomyocyte pyroptosis. The upregulation of miR-19a-3p protected cardiac function, inhibited cardiomyocyte pyroptosis, and inhibited IRF-8/MAPK signaling in cardiac I/R-injured mice. DP-MSCs inhibited cardiomyocyte pyroptosis and the IRF-8/MAPK signaling by upregulating the miR-19a-3p levels in cardiomyocytes injured by I/R.

DP-MSCs protected cardiac function by inhibiting cardiomyocyte pyroptosis through miR-19a-3p under I/R conditions.

急性慢性肝功能衰竭（ACLF）是一种复杂的临床综合征，其特征是28天和90天死亡率高，范围为13%至93%，由慢性肝病患者肝功能急性恶化引起。不同细胞剂量的脐带来源的间充质干细胞（UC-MSCs）移植已被证明可改善失代偿性肝硬化或ACLF患者的肝功能。^[1,2]值得注意的是，迄今为止大多数临床研究都使用新鲜制备的MSC。本试验旨在评估现成UC-MSC产品在ACLF患者中的耐受性、安全性和有效性。

致编辑：输尿管狭窄可导致上尿路近端和集合系统扩张。长期肾积水对输尿管的拉伸和负荷会引发应力松弛效应，从而降低输尿管的收缩性。^[1]术后即使梗阻解除成功，形态学改变也可能不明显。利尿肾造影通过放射性核素的摄取和排泄判断分裂肾功能和梗阻性质。但受同侧肾脏对利尿剂反应的影响。^[2]目前缺乏同质化的诊疗标准，尤其是评价标准，难以评估手术效果和术后情况。

致编辑：随着全球经济的进步和人类预期寿命的延长，许多国家正在向老龄化社会过渡。中国目前拥有世界上最广泛的老年人口。^[1]因此，老年人的医疗保健在中国变得至关重要。衰老的主要特征是骨骼肌质量下降，导致肌肉力量下降。肌肉力量对于健康衰老过程中的日常活动和独立性至关重要。先前的研究忽略了握力对中国老年住院患者死亡率的影响。本研究试图通过一项详细的队列研究，分析该人群中低握力与2年死亡风险之间的关系，从而填补这一空白。

致编辑：肾脏在维持电解质平衡方面起着关键作用，电解质平衡对于许多代谢和生理过程的正常功能至关重要。电解质失衡（EIs）是肾功能不全的常见表现，可能会导致潜在的危及生命的后果。混合型EIs，定义为单个患者同时存在两种或更多种EIs，在肾病实践中经常观察到。先前的研究通常将不同的EIs视为独立的实体，并探索它们与预后的独立关联。然而，共存EIs的综合预后影响仍不清楚。这一知识差距强调了对混合EIs的更全面了解的必要性，特别是在肾脏疾病（RD）患者中，其中电解质失调既是一个特征，也是一个重要的治疗靶点。

致编辑：乳腺癌是女性常见的癌症，是中国癌症相关死亡的主要原因。齐墩果酸是一种从多种植物中分离出来的五环三萜类化合物，具有抗炎、抗病毒和抗癌等多种生物学特性。我们先前的研究表明，齐墩果酸衍生物N-（（1-（4-氟苯基）-1H-1，2，3-三唑-4-基）甲基）-2-亚甲基-3-氧代-齐墩果-12-烯-28-酰胺（ZQL-4c）抑制乳腺癌细胞，特别是三阴性乳腺癌（TNBC）的增殖。本研究阐明了ZQL-4c在TNBC中的潜在抑制机制。补充图1A，http://links.lww.com/CM9/C427说明了ZQL-4c的合成。

致编辑：血管钙化与死亡率和心血管事件风险升高相关。此外，血管钙化显示与中风、慢性肢体威胁缺血、截肢、痴呆和癌症密切相关。尽管降脂治疗在降低心血管疾病风险方面的疗效得到了广泛认可，但关于其对血管钙化的影响存在相互矛盾的发现。