The spatio-temporal heterogeneity of breast cell subsets forms the fundamental biological basis for physiological development and pathological progression, including tumorigenesis; however, its complex regulatory mechanisms are not yet fully elucidated. With its high-resolution capabilities, single-cell RNA sequencing (scRNA-seq) technology offers a powerful tool for dissecting this cellular heterogeneity. This technology enables the construction of high-precision breast cell atlases, the accurate identification of distinct cell subsets, and the reconstruction of differentiation trajectories from stem/progenitor cells to functional epithelial cells. By resolving the transcriptional regulatory networks that govern cell fate determination, intercellular communication patterns, and dynamic microenvironmental interactions, scRNA-seq has unveiled the molecular foundations of breast development and provided new perspectives on the pathogenesis of related diseases such as breast cancer and macromastia. Furthermore, scRNA-seq demonstrates significant potential for discovering early molecular markers of disease, deciphering tumor heterogeneity, and elucidating mechanisms of therapeutic resistance. The continued application of scRNA-seq for dissecting breast cell heterogeneity, combined with its integration with multi-modal data such as spatial omics, promises to provide critical evidence and new insights for revealing the molecular mechanisms of breast development-related diseases and for formulating precision therapeutic strategies.
Humans ; Single-Cell Analysis/methods* ; Female ; Breast Neoplasms/pathology* ; Sequence Analysis, RNA/methods* ; Breast/cytology*

Poly(ADP-ribosyl)ation (PARylation) is a specific form of post-translational modification (PTM) predominantly triggered by the activation of poly-ADP-ribose polymerase 1 (PARP1). However, the role and mechanism of PARylation in the advancement of acute kidney injury (AKI) remain undetermined. Here, we demonstrated the significant upregulation of PARP1 and its associated PARylation in murine models of AKI, consistent with renal biopsy findings in patients with AKI. This elevation in PARP1 expression might be attributed to trimethylation of histone H3 lysine 4 (H3K4me3). Furthermore, a reduction in PARylation levels mitigated renal dysfunction in the AKI mouse models. Mechanistically, liquid chromatography-mass spectrometry indicated that PARylation mainly occurred in receptor for activated C kinase 1 (RACK1), thereby facilitating its subsequent phosphorylation. Moreover, the phosphorylation of RACK1 enhanced its dimerization and accelerated the ubiquitination-mediated hypoxia inducible factor-1α (HIF-1α) degradation, thereby exacerbating kidney injury. Additionally, we identified a PARP1 proteolysis-targeting chimera (PROTAC), A19, as a PARP1 degrader that demonstrated superior protective effects against renal injury compared with PJ34, a previously identified PARP1 inhibitor. Collectively, both genetic and drug-based inhibition of PARylation mitigated kidney injury, indicating that the PARylated RACK1/HIF-1α axis could be a promising therapeutic target for AKI treatment.

Extensive epigenetic reprogramming involves in memory CD8+ T-cell differentiation. The elaborate epigenetic rewiring underlying the heterogeneous functional states of CD8+ T cells remains hidden. Here, we profile single-cell chromatin accessibility and map enhancer-promoter interactomes to characterize the differentiation trajectory of memory CD8+ T cells. We reveal that under distinct epigenetic regulations, the early activated CD8+ T cells divergently originated for short-lived effector and memory precursor effector cells. We also uncover a defined epigenetic rewiring leading to the conversion from effector memory to central memory cells during memory formation. Additionally, we illustrate chromatin regulatory mechanisms underlying long-lasting versus transient transcription regulation during memory differentiation. Finally, we confirm the essential roles of Sox4 and Nrf2 in developing memory precursor effector and effector memory cells, respectively, and validate cell state-specific enhancers in regulating Il7r using CRISPR-Cas9. Our data pave the way for understanding the mechanism underlying epigenetic memory formation in CD8+ T-cell differentiation.
CD8-Positive T-Lymphocytes/metabolism* ; Cell Differentiation ; Chromatin/immunology* ; Animals ; Mice ; Immunologic Memory ; Epigenesis, Genetic ; SOXC Transcription Factors/immunology* ; NF-E2-Related Factor 2/immunology* ; Mice, Inbred C57BL ; Gene Regulatory Networks ; Enhancer Elements, Genetic

Objective This study aimed to explore the spatial heterogeneity and risk factors for dental caries in 12-year-old children in Shanxi province,China. Methods The data encompassed 3,721 participants from the two most recent oral health surveys conducted across 16 districts in Shanxi Province in 2015 and 2018.Eighteen specific variables were analyzed to examine the interplay between socioeconomic factors,medical resources and environmental conditions.The Geo-detector model was employed to assess the impacts and interactions of these ecological factors. Results Socioeconomic factors(Q=0.30,P<0.05)exhibited a more substantial impact compared to environmental(Q=0.19,P<0.05)and medical resource factors(Q=0.25,P<0.05).Notably,the urban population percentage(UPP)demonstrated the most significant explanatory power for the spatial heterogeneity in caries prevalence,as denoted by its highest q-value(q=0.51,P<0.05).Additionally,the spatial distribution's heterogeneity of caries was significantly affected by SO2 concentration(q=0.39,P<0.05)and water fluoride levels(q=0.27,P<0.05)among environmental factors. Conclusion The prevalence of caries exhibited spatial heterogeneity,escalating from North to South in Shanxi Province,China,influenced by socioeconomic factors,medical resources,and environmental conditions to varying extents.

Objective:To explore the genetic etiology of two patients with Gitelman syndrome (GS).Methods:Two patients who had presented at the Linyi People′s Hospital in January and June 2022 respectively were selected as the study subjects. Peripheral blood samples of them were collected and subjected to whole exome sequencing (WES). Electrolyte levels in their serum and urine were detected. Candidate variants were verified by Sanger sequencing. PyMOL software was used to predict the impact of the variants on the protein structure.Results:Patient 1 was a 27-year-old female with decreased serum levels of sodium, potassium, chloride and magnesium, along with decreased urine chloride and calcium. WES revealed that she has harbored compound heterozygous variants of the SLC12A3 gene, namely c. 1456G>A (p.D486N) and c. 179C>T (p.T60M). The former was inherited from her mother and known to be pathogenic. Patient 2 was a 4-year-old male with lower serum sodium, chloride and magnesium levels, and his serum potassium level was found to be critically low. He was found to harbor compound heterozygous variants of c. 602-16G>A and c. 805_806insTTGGCGTGGTCTCGGTCA (p.V268_T269insIGVVSV) of the SLC12A3 gene, which were inherited from his mother and father, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics, both variants were predicted to be pathogenic (PVS1+ PM2_Supporting+ PP3; PVS1+ PM2_Supporting+ PM4). Conclusion:The above heterozygous variants of the SLC12A3 gene probably underlay the GS in these patients.

OBJECTIVE: To explore the genetic etiology for a Chinese pedigree affected with Lesch-Nyhan syndrome. METHODS: Members of the pedigree who had visited the Genetic Counseling Clinic of Linyi People's Hospital on February 10, 2022 were selected as the study subjects. Clinical data and family history of the proband were collected, and trio-whole exome sequencing (trio-WES) was carried out for the proband and his parents. Candidate variants were verified by Sanger sequencing. RESULTS: Trio-WES revealed that both the proband and his cousin brother had harbored a hemizygous c.385-1G>C variant in intron 4 of the HPRT1 gene, which was unreported previously. A heterozygous c.385-1G>C variant of the HPRT1 gene was also found in the proband's mother, grandmother, two aunts, and a female cousin, whilst all phenotypically normal males in his pedigree were found to have a wild type for the locus, which has conformed to an X-linked recessive inheritance. CONCLUSION The heterozygous c.385-1G>C variant of the HPRT1 gene probably underlay the Lesch-Nyhan syndrome in this pedigree.
Male ; Humans ; Female ; Lesch-Nyhan Syndrome/genetics* ; Pedigree ; East Asian People ; Heterozygote ; Introns ; Mutation

OBJECTIVES: With the increasing detection rate of lung nodules, the qualitative problem of lung nodules has become one of the key clinical issues. This study aims to evaluate the value of combining dynamic contrast-enhanced (DCE) MRI based on time-resolved imaging with interleaved stochastic trajectories-volume interpolated breath hold examination (TWIST-VIBE) with T₁ weighted free-breathing star-volumetric interpolated breath hold examination (T₁WI star-VIBE) in identifying benign and malignant lung nodules. METHODS: We retrospectively analyzed 79 adults with undetermined lung nodules before the operation. All nodules of patients included were classified into malignant nodules (n=58) and benign nodules (n=26) based on final diagnosis. The unenhanced T₁WI-VIBE, the contrast-enhanced T₁WI star-VIBE, and the DCE curve based on TWIST-VIBE were performed. The corresponding qualitative [wash-in time, wash-out time, time to peak (TTP), arrival time (AT), positive enhancement integral (PEI)] and quantitative parameters [volume transfer constant (Ktrans), interstitium-to-plasma rate constant (Kep), and fractional extracellular space volume (Ve)] were evaluated. Besides, the diagnostic efficacy (sensitivity and specificity) of enhanced CT and MRI were compared. RESULTS: There were significant differences in unenhanced T₁WI-VIBE hypo-intensity, and type of A, B, C DCE curve type between benign and malignant lung nodules (all P<0.001). Pulmonary malignant nodules had a shorter wash-out time than benign nodules (P=0.001), and the differences of the remaining parameters were not statistically significant (all P>0.05). After T₁WI star-VIBE contrast-enhanced MRI, the image quality was further improved. Compared with enhanced CT scan, the sensitivity (82.76% vs 80.50%) and the specificity (69.23% vs 57.10%) based on MRI were higher than that of CT (both P<0.001). CONCLUSIONS T₁WI star-VIBE and dynamic contrast-enhanced MRI based on TWIST-VIBE were helpful to improve the image resolution and provide more information for clinical differentiation between benign and malignant lung nodules.
Adult ; Humans ; Retrospective Studies ; Magnetic Resonance Imaging ; Plasma ; Tomography, X-Ray Computed ; Lung

Objective:To investigate the clinical characteristics of choledocholithiasis com-bined with periampullary diverticulum and influencing factor for difficult cannulation of endoscopic retrograde cholangiopancreatography (ERCP).Methods:The retrospective case-control study was conducted. The clinical data of 1 920 patients who underwent ERCP for choledocholithiasis in 15 medical centers, including the First Hospital of Lanzhou University, et al, from July 2015 to December 2017 were collected. There were 915 males and 1 005 females, aged (63±16)years. Of 1 920 patients, there were 228 cases with periampullary diverticulum and 1 692 cases without periampullary diverticulum. Observation indicators: (1) clinical characteristics of patients with choledocholithiasis; (2) intraoperative and postoperative situations of patients undergoing ERCP for choledocholithiasis; (3) influencing factor analysis for difficult cannulation in patients undergoing ERCP for choledocholithiasis. Measurement data with normal distribution were represented as Mean±SD, and comparison between groups was conducted using the independent sample t test. Measurement data with skewed distribution were represented as M(range) or M( Q1, Q3), and com-parison between groups was conducted using the Wilcoxon rank sum test. Count data were described as absolute numbers or percentages, and comparison between groups was conducted using the chi-square test or Fisher exact probability. The Logistic regression model was used for univariate and multivariate analyses. Results:(1) Clinical characteristics of patients with choledocholithiasis. Age, body mass index, cases with complications as chronic obstructive pulmonary disease, diameter of common bile duct, cases with diameter of common bile duct as <8 mm, 8?12 mm, >12 mm, diameter of stone, cases with number of stones as single and multiple were (69±12)years, (23.3±3.0)kg/m 2, 16, (14±4)mm, 11, 95, 122, (12±4)mm, 89, 139 in patients with choledocholithiasis combined with periampullary diverticulum, versus (62±16)years, (23.8±2.8)kg/m 2, 67, (12±4)mm, 159, 892, 641, (10±4)mm, 817, 875 in patients with choledocholithiasis not combined with periampullary diver-ticulum, showing significant differences in the above indicators between the two groups ( t=?7.55, 2.45, χ2=4.54, t=?4.92, Z=4.66, t=?7.31, χ2=6.90, P<0.05). (2) Intraoperative and postoperative situations of patients undergoing ERCP for choledocholithiasis. The balloon expansion diameter, cases with intraoperative bleeding, cases with hemorrhage management of submucosal injection, hemostatic clip, spray hemostasis, electrocoagulation hemostasis and other treatment, cases with endoscopic plastic stent placement, cases with endoscopic nasal bile duct drainage, cases with mechanical lithotripsy, cases with stone complete clearing, cases with difficult cannulation, cases with delayed intubation, cases undergoing >5 times of cannulation attempts, cannulation time, X-ray exposure time, operation time were 10.0(range, 8.5?12.0)mm, 56, 6, 5, 43, 1, 1, 52, 177, 67, 201, 74, 38, 74, (7.4±3.1)minutes, (6±3)minutes, (46±19)minutes in patients with choledocholithiasis combined with periampullary diverticulum, versus 9.0(range, 8.0?11.0)mm, 243, 35, 14, 109, 73, 12, 230, 1 457, 167, 1 565, 395, 171, 395, (6.6±2.9)minutes, (6±5)minutes, (41±17)minutes in patients with choledocholithiasis not combined with periampullary diverticulum, showing significant differences in the above indicators between the two groups ( Z=6.31, χ2=15.90, 26.02, 13.61, 11.40, 71.51, 5.12, 9.04, 8.92, 9.04, t=?3.89, 2.67, ?3.61, P<0.05). (3) Influencing factor analysis for difficult cannulation in patients undergoing ERCP for choledocholithiasis. Results of multivariate analysis showed total bilirubin >30 umol/L, number of stones >1, combined with periampullary diverticulum were indepen-dent risk factors for difficult cannulation in patients with periampullary diverticulum who underwent ERCP for choledocholithiasis ( odds ratio=1.31, 1.48, 1.44, 95% confidence interval as 1.06?1.61, 1.20?1.84, 1.06?1.95, P<0.05). Results of further analysis showed that, of 1 920 patients undergoing ERCP for choledocholithiasis, the incidence of postoperative pancreatitis was 17.271%(81/469) and 8.132%(118/1 451) in the 469 cases with difficult cannulation and 1 451 cases without difficult cannula-tion, respectively, showing a significant difference between them ( χ2=31.86, P<0.05). In the 1 692 patients with choledocholithiasis not combined with periampullary diverticulum, the incidence of postopera-tive pancreatitis was 17.722%(70/395) and 8.250%(107/1 297) in 395 cases with difficult cannula-tion and 1 297 cases without difficult cannulation, respectively, showing a significant difference between them ( χ2=29.00, P<0.05). In the 228 patients with choledocholithiasis combined with peri-ampullary diverticulum, the incidence of postoperative pancreatitis was 14.865%(11/74) and 7.143%(11/154) in 74 cases with difficult cannulation and 154 cases without difficult cannulation, respectively, showing no significant difference between them ( χ2=3.42, P>0.05). Conclusions:Compared with patients with choledocholithiasis not combined with periampullary divertioulum, periampullary divertioulum often occurs in choledocholithiasis patients of elderly and low body mass index. The proportion of chronic obstructive pulmonary disease is high in choledocholithiasis patients with periampullary diverticulum, and the diameter of stone is large, the number of stone is more in these patients. Combined with periampullary diverticulum will increase the difficult of cannulation and the ratio of patient with mechanical lithotripsy, and reduce the ratio of patient with stone complete clearing without increasing postoperative complications of choledocholithiasis patients undergoing ERCP. Total bilirubin >30 μmol/L, number of stones >1, combined with periampullary diverticulum are independent risk factors for difficult cannulation in patients of periampullary diverticulum who underwent ERCP for choledocholithiasis.

Objective:To analyze the prevention and treatment of Kaschin-Beck disease in Fu County, Shaanxi Province, so as to provide basis for consolidating the results of Kaschin-Beck disease prevention and control and the treatment of patients with Kaschin-Beck disease.Methods:The epidemiological investigation of data and clinical data Kaschin-Beck disease from 1954 to 2022 were collected from the Fu County Institute for Endemic Disease Prevention and Control and People's Hospital of Fu County in Shaanxi Province, respectively. The retrospective study was used to investigate the prevention and control of Kaschin-Beck disease in Fu County through the adoption of comprehensive measures such as relocation, grain exchange, water improvement, conversion of farmland to forest and so on.Results:In 1954, there were 6 endemic townships and 127 endemic villages of Kaschin-Beck disease in Fu County, with a total population of 78 781. A total of 16 327 patients with Kaschin-Beck disease were detected by X-ray examination, with a detection rate of 20.72%, including 5 434 patients without clinical symptoms. There were 5 850 patients with clinical grade Ⅰ, 3 725 patients with clinical grade Ⅱ and 1 318 patients with clinical grade Ⅲ. In 1975, the first general survey of Kaschin-Beck disease was conducted in the whole county, with a total population of 101 341. A total of 9 575 patients with Kaschin-Beck disease were detected by X-ray examination, with a detection rate of 9.45%, including 3 247 cases without clinical symptoms. Among the patients with symptoms, there were 3 704 cases of clinical grade Ⅰ, 2 006 cases of clinical grade Ⅱ and 618 cases of clinical grade Ⅲ. The patients with Kaschin-Beck disease were mainly local residents, accounting for 93.92% (8 993/9 575). In 1997, 27 320 students aged 7 to 16 years in 342 schools of 15 townships were examined and found that there were 169 cases without clinical symptoms with X-ray changes, only 2 cases with clinical grade Ⅰ, and the detection rate decreased to 0.63%. In 1997, Fu County began to encourage relocation and grain exchange to prevent Kaschin-Beck disease. The relocation targets were mainly the seriously ill villages with new cases among children and poor living conditions. By 1999, a total of 100 households and 469 people were relocated, and by 2020, 1 569 households and 5 334 people were relocated. In 1997 and 1998, measures were taken to improve water quality in 43 natural villages in 6 townships, with 1 591 households and 7 375 people benefiting. In 2010, a general survey of Kaschin-Beck disease was conducted in 15 townships of Fu County, with a total population of 135 858, and 3 424 patients with Kaschin-Beck disease were detected by X-ray examination, with a detection rate of 2.52%. There were 2 885 cases with clinical symptoms, including 1 584 cases with clinical grade Ⅰ, 1 024 cases with clinical grade Ⅱ and 277 cases with clinical grade Ⅲ. Among them, 32 561 minors under 16 years old were examined, and 49 patients with Kaschin-Beck disease were detected by X-ray examination, with a detection rate of 0.15%, and all of them were clinical gradeⅠ patients. In 2014, a total of 73 600 people were surveyed in 170 endemic villages of Fu county, and 2 885 patients with Kaschin-Beck disease were detected by X-ray examination, with a detection rate of 3.92%. Compared with 2010, the number of patients with Kaschin-Beck disease increased zero, and there were no underage patients under the age of 16 for 4 consecutive years. By the end of 2016, 666.67 hm 2 of farmland had been converted to forest in Fu County, involving 9 townships (including communities), 33 administrative villages and 1 993 households. In 2018, another general survey of Kaschin-Beck disease was conducted in Fu County, with a total population of 157 362. A total of 2 308 patients were detected by X-ray examination, with a detection rate of 1.47%. Among them, there were 1 270 cases of clinical grade Ⅰ, 870 cases of clinical grade Ⅱ and 168 cases of clinical grade Ⅲ, and there were no patients with Kaschin-Beck disease under 16 years old in the county for 8 consecutive years (2011-2018). In the same year, 22 cases of Kaschin-Beck disease joint replacement were completed in Fu County, and by January 2022, about 60 cases had completed joint replacement. Conclusion:The prevention and control of Kaschin-Beck disease in Fu County has achieved remarkable results through comprehensive measures such as relocation, grain exchange, water improvement and conversion of farmland to forest.

Objective : To evaluate the vertical distance between the maxillary first molars (MFMs) and the maxillary sinus floor (MSF) and its interrelationship with sex, age, and vertical facial pattern in skeletal ClassⅡ patients to provide a reference for clinical orthodontic treatment. Methods: Sixty teenagers and sixty adults with skeletal Class Ⅱ malocclusion who met the inclusion criteria were selected to evaluate the vertical relationship between the MFMs and the MSF on cone-beam CT (CBCT) images. The vertical distance between the roots of the MFMs and the MSF was measured. Statistical analysis was used to assess differences between patients by sex, age, and vertical facial pattern. Results: The contact percent of the roots of MFMs and MSF was 85% and 56% in skeletal Class Ⅱ teenagers and adults, respectively. The contact percent and penetration percent of the roots with MSF were higher in teenagers than in adults（P<0.05）. The penetration percent of the high-angle (HA) and the normal-angle(NA) groups was 34.1% and 36.6% respectively, which was significantly higher than that in the low-angle (LA) group(20.8%)（P<0.05）. The difference between the distance of the bilateral MFMs and the MSF was not significant in skeletal Class Ⅱ patients (P>0.05); No significant difference was found between different sexes of skeletal Class Ⅱ patients when comparing the distance of the MFMs and the MSF (P>0.05). The MFMs of skeletal Class Ⅱ teenagers were closer to the MSF than those of adults (P<0.05). In the adult group, the distance was not significantly different in different vertical facial patterns (P>0.05). In the teenager group, the MFMs were more closely related to the MSF in the NA and HA groups than in the LA group. Among them, the difference between the mesiobuccal roots and distalbuccal roots was significantly different (P<0.05). There was no significant difference between the groups of the palatal roots (P>0.05). Conclusion The MFMs were closer to the MSF in skeletal Class Ⅱ teenagers than in adults. The distance between the MFMs and MSF was associated with the vertical facial pattern in skeletal Class Ⅱ teenagers, while it was not associated with the vertical facial pattern in adult patients.