Mammalian male germline development depends on a specialized gonadal somatic microenvironment. However, itsin vitro reconstruction remains challenging. Major barriers include the generation of appropriate supporting-cell lineages, organized tissue architecture, and culture conditions that sustain germ-cell maturation. Yoshino et al. established a mouse pluripotent stem cell-derived testicular organoid model. This model reconstitutes the sex-determining region Y (Sry)-SRY-box transcription factor 9 (Sox9)‑mediated sex-determination program and generates testicular somatic cell-like cells (TesLCs). When assembled with primordial germ cell-like cells (PGCLCs), TesLCs formed seminiferous tubule-like structures and supported male germline progression toward prospermatogonia and germline stem cell-like cells (GSCLCs). After transplantation into infertile recipient testes, organoid-derived GSCLCs produced fertilization-competent sperm and generated fertile offspring. The major significance of this work extends beyond sperm production. It integrates sex determination, germ-cell fate transition, and testicular niche self-organization into an experimentally tractable organoid system. This commentary discusses the technical strategy, sex-determination mechanism, value of testicular niche reconstruction, and translational limitations of this study. It also highlights its implications for in vitro gametogenesis, male infertility modeling, and reproductive medicine.

Recently,diffusion models have emerged as a promising paradigm for molecular design and optimization.However,most diffusion-based molecular generative models focus on modeling 2D graphs or 3D geom-etries,with limited research on molecular sequence diffusion models.The International Union of Pure and Applied Chemistry(IUPAC)names are more akin to chemical natural language than the simplified molecular input line entry system(SMILES)for organic compounds.In this work,we apply an IUPAC-guided conditional diffusion model to facilitate molecular editing from chemical natural language to chemical language(SMILES)and explore whether the pre-trained generative performance of diffusion models can be transferred to chemical natural language.We propose DiffIUPAC,a controllable molecular editing diffusion model that converts IUPAC names to SMILES strings.Evaluation results demonstrate that our model out-performs existing methods and successfully captures the semantic rules of both chemical languages.Chemical space and scaffold analysis show that the model can generate similar compounds with diverse scaffolds within the specified constraints.Additionally,to illustrate the model's applicability in drug design,we conducted case studies in functional group editing,analogue design and linker design.

Recently, diffusion models have emerged as a promising paradigm for molecular design and optimization. However, most diffusion-based molecular generative models focus on modeling 2D graphs or 3D geometries, with limited research on molecular sequence diffusion models. The International Union of Pure and Applied Chemistry (IUPAC) names are more akin to chemical natural language than the Simplified Molecular Input Line Entry System (SMILES) for organic compounds. In this work, we apply an IUPAC-guided conditional diffusion model to facilitate molecular editing from chemical natural language to chemical language (SMILES) and explore whether the pre-trained generative performance of diffusion models can be transferred to chemical natural language. We propose DiffIUPAC, a controllable molecular editing diffusion model that converts IUPAC names to SMILES strings. Evaluation results demonstrate that our model outperforms existing methods and successfully captures the semantic rules of both chemical languages. Chemical space and scaffold analysis show that the model can generate similar compounds with diverse scaffolds within the specified constraints. Additionally, to illustrate the model's applicability in drug design, we conducted case studies in functional group editing, analogue design and linker design.

BACKGROUND: Recent studies suggest that a healthy diet helps to prevent the development of Alzheimer disease (AD). This study aimed to investigate whether spicy food consumption is associated with cognition and cerebrospinal fluid (CSF) biomarkers of AD in the Chinese population. METHODS: We enrolled 55 AD patients and 55 age- and gender-matched cognitively normal (CN) subjects in a case-control study, as well as a cohort of 131 participants without subjective cognitive decline (non-AD) in a cross-sectional study. Spicy food consumption was assessed using the Food Frequency Questionnaire (FFQ). Associations of FFQ scores with cognition and CSF biomarkers of AD were analyzed. RESULTS: In the case-control study, spicy food consumption was lower in AD patients than that in CNs (4.0 [4.0-8.0] vs. 8.0 [4.5-10.0], P < 0.001); FFQ scores were positively associated with Mini-Mental Status Examination scores in the total sample (r = 0.218, P = 0.014). In the cross-sectional study, the association between spicy food consumption and cognition levels was verified in non-AD subjects (r = 0.264, P = 0.0023). Moreover, higher FFQ scores were significantly associated with higher β-Amyloid (1-42) (Aβ42) levels and lower phospho-tau/Aβ42 and total tau/Aβ42 ratios in the CSF of non-AD subjects (P < 0.05). CONCLUSION Spicy food consumption is closely related to higher cognition levels and reversed AD biomarkers in the CSF, suggesting that a capsaicin-rich diet might have the potential to modify the cognitive status and cerebral pathologies associated with AD.
Alzheimer Disease ; Amyloid beta-Peptides ; Biomarkers ; Case-Control Studies ; Cognition ; Cross-Sectional Studies ; Humans ; Peptide Fragments ; tau Proteins

【Objective】 To explore the correlation of dopamine receptor 4(DRD4) expression with clinicopathological characteristics and the prognostic significance after examining the expression of DRD4 in hepatocellular carcinoma (HCC) and non-tumor tissues; to show the effect of DRD4 agonist PD-168077 and inhibitor L-745870 on proliferation, migration and invasion of HCC cells, and to reveal its possible mechanism. 【Methods】 Immunohistochemistry and real time qPCR were implemented to detect the expression of DRD4 protein and mRNA in tumor and non-tumor tissues and prognostic significance of DRD4 expression was analyzed. To reveal the impact of PD-168077 and L-745870 on HCC cells, CCK8 and Transwell were performed; the signaling pathway was monitored by Western blot, and was verified with a specific inhibitor. 【Results】 Eighty-five(43.4%) of 196 HCC tissues had high expression of DRD4 protein; non-tumor tissues had higher expression of DRD4 mRNA in 74 pairs tissues, and DRD4 mRNA was highly expressed in non-tumor cell line Miha compared with HCC cell lines. Patients with high DRD4 expression significantly had longer recurrence free survival(RFS) and overall survival(OS), and DRD4 was an independent prognostic factor for RFS and OS in patients after HCC resection(P<0.05). PD-168077 showed a dose-dependent inhibition on proliferation, migration and invasion of HCC cells(P<0.05), while 1nmol/L of L-745870 significantly enhanced the proliferation, migration and invasion of HCC cells(P<0.05). PD-168077 inhibited the phosphorylation of ERK, while L-745870 promoted the phosphorylation of ERK. The ERK inhibitor PD98059 could reverse the effect of L-745870. 【Conclusions】 HCC patients with high DRD4 expression had better prognosis and DRD4 might be a biomarker for prognosis of HCC patients. DRD4 might become a target of targeted therapy for HCC.

Objective: To assess the clinical characteristics and identify the risk factors in the acute myocardial infarction (AMI) patients complicating with ventricular septal rupture (VSR). Methods: A retrospective study was performed on 96 AMI patients complicating with VSR, who were hospitalized in the Second Xiangya Hospital of Central South University, Hunan Provincial Peoples′ Hospital, the First Affiliated Hospital of University of South China, the Second Affiliated hospital of University of south China, Xiangtan Central Hospital from December 2007 to May 2017. There were 46 females and the age was (66.2±10.7) years (from 43 to 90 years). Patients were divided into in-hospital survival group (n=64) and in-hospital death group (n=32). The 96 patients were also divided into the early death group (survived ≤2 weeks after admission, n=50) and non-early death group (survived>2 weeks after admission, n=46). Multivariate logistic regression was used to analyze the independent risk factors of the early death. Results: Location of VSR was available in 71 patients, VSR was located at the apical or anterior septum near the apical region in 64.0% (32/50) patients with the anterior AMI, VSR was located at the posterior wall and basal inferior segment in 57.1% (12/21) patients with non-anterior AMI. Compared to the in-hospital survival group, patients in the in-hospital death group were older ((69.6±11.3) years vs. (64.6±10.1) years, P=0.031), incidence of non-ventricular aneurysm (71.9% (23/32) vs. 37.5% (24/64), P=0.001) and anterior AMI (84.4%(27/32) vs. 62.5%(40/64), P=0.028) was significantly higher in the in-hospital death group than in the in-hospital survival group. The comparison between the early death group and non-early death group showed that older age, female, no history of angina or myocardial infarction, Killip grade>Ⅲ, and non-ventricular aneurysm were related to increased risk of the early mortality in this patient cohort. Logistic regression analysis revealed that female (OR=5.109,95%CI 1.19-22.00, P=0.012), no history of angina or myocardial infarction (OR=23.34, 95%CI 3.44-158.37, P=0.001), Killip grade>Ⅲ(OR=5.35, 95%CI 1.26-22.66, P=0.019) and non-ventricular aneurysm (OR=6.30,95%CI 1.67-23.73, P=0.005) were independent risk factors for early death in this patient cohort. Conclusion The risk factors of in-hospital death include older age, non-ventricular aneurysm and anterior AMI. Female, no history of angina or myocardial infarction, Killip grade>Ⅲ and non-ventricular aneurysm are independent risk factors for the early death of AMI patients complicating VSR.

OBJECTIVETo compare screw's inserting angle through the 11th and 12th rib in treating L1 burst fracture, explore effects on inserting screw and postoperative angle.

METHODSFrom October 2007 to October 2010, 108 patients with L1 brust fracture treated through anterior approach were analyzed,including 68 males and 40 females, aged from 21 to 64 years (mean 38.22 years). All patients were divided into the 11th (A, 51 cases) and 12th (B, 57 cases) approach. The data of operation time,blood loss, duration of incision pain, JOA score, Oswestry score, VAS score, quality of life (SF-36), recovery of nervous function, coronal Cobb angle, included angle between screw and plate were observed.

RESULTSAll patients were followed up for 9 to 37 months, mean 23 months. The operation time, blood loss, duration of incision pain, in group A were lower than group B (P<0.05), JOA score, Oswestry score, VAS score, SF-36, recovery of nervous function had no significant differences (P>0.05). There were no differences in Cobb angle before operation, but had significance after operation (P=0.000). There were statistically significance between two group in angle between screw and plate (P=0.000, P=0.003).

CONCLUSIONThe 11th rib approach for the treatment of L1 burst fracture has less effects on screw, less trauma and less angle between screw and plate.

Adult ; Bone Screws ; Female ; Fracture Fixation, Internal ; adverse effects ; instrumentation ; Humans ; Male ; Middle Aged ; Postoperative Complications ; Recovery of Function ; Rib Fractures ; diagnostic imaging ; physiopathology ; surgery ; Ribs ; surgery ; Spinal Cord ; physiopathology ; Tomography, X-Ray Computed ; Young Adult

OBJECTIVETo evaluate the ancillary diagnostic value of IgH gene rearrangements in those B-cell lymphoproliferative disorder cases whom are difficult in making a final diagnosis.

METHODSIgH gene clonal rearrangements were retrospectively analyzed in a total of 77 diagnostically difficult B-cell lympho-proliferative patients. Standardized BIOMED-2 system IgH gene clonality assay kit targeting FR1, FR2, FR3 was used, followed by heteroduplex-polyacrylamide gel electrophoresis (PAGE) and silver nitrate staining.

RESULTSThe final diagnoses of the 77 cases were: 12 cases of reactive lymphoid hyperplasia, 20 cases of atypical lymphoid hyperplasia or suspicious lymphoma, and 45 cases of B-cell lymphoma. Detection rates of at least one positive reaction were 2/12, 11/20 (55%), 36/45 (80%) in the three groups, respectively. In B-cell lymphomas, the clonality detection rate of FR1, FR2 and FR3 was 60% (27/45), 60% (27/45) and 56% (25/45), respectively. The type distribution were: 20 marginal zone lymphomas, including 18 extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, 7 diffuse large B-cell lymphomas, 7 follicular lymphomas, 1 mantle-cell lymphoma, 1 Burkitt's lymphoma, 4 plasma cell neoplasms and 5 unclassified B-cell lymphomas. Rearrangements of FR1, FR2 or FR3 were not detected in 9 (20%) of the B cell lymphoma cases, nevertheless, one of them had developed liver lesion later, and was confirmed finally to be B cell lymphoma. Fourteen patients of reactive lymphoid hyperplasia with positive IgH gene clonal rearrangements, and atypical lymphoid hyperplasia had follow-up history available. Four of them were diagnosed as lymphoid malignancies upon further biopsy, and in three of them, clonal IgH gene rearrangements were detected.

CONCLUSIONSB-cell lymphoproliferative disorder requiring a detection of clonal IgH gene rearrangement for making a final diagnosis. Combined detections of three IgH FR1, FR2 and FR3 rearrangements provide important ancillary diagnostic value in confirming suspected B-cell lympho-proliferative disorders. It is important to take an additional biopsy or to follow-up those patients who that have a detectable IgH gene clonal rearrangement but without apparent morphological evidence of lymphoma. For cases with a negative IgH gene rearrangements, it might be necessary to perform clonality analysis for other forms of gene rearrangements including IgH or IgK and IgL in order to further improve the detection sensitivity.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Female ; Follow-Up Studies ; Gene Rearrangement, B-Lymphocyte, Heavy Chain ; Humans ; Lymphoma, B-Cell ; diagnosis ; genetics ; pathology ; Lymphoma, B-Cell, Marginal Zone ; diagnosis ; genetics ; pathology ; Lymphoma, Follicular ; diagnosis ; genetics ; pathology ; Lymphoma, Large B-Cell, Diffuse ; diagnosis ; genetics ; pathology ; Lymphoproliferative Disorders ; diagnosis ; genetics ; pathology ; Male ; Middle Aged ; Neoplasms, Plasma Cell ; diagnosis ; genetics ; pathology ; Pseudolymphoma ; diagnosis ; genetics ; pathology ; Retrospective Studies ; Young Adult

OBJECTIVETo develop a rapid and specific method for hepatitis C virus ( HCV) genotyping using reverse dot blot hybridization technique and investigate the distribution of HCV genotypes and subtypes in Guangdong.

METHODSThe primers and the probes targeting the 5'untranslated region (5'UTR) and core region of HCV genotypes 1b, 2a, 3a, 3b and 6a were designed, and the RT-PCR reverse dot blot hybridization (PCR-RDH) method for HCV genotyping was established. A total of 115 patients with hepatitis C were genotyped using this method, and 38 of them were also genotyped by sequencing and phylogenetic analysis to evaluate the accuracy and specificity of the method.

RESULTSOf the 115 patients, 111 were successfully genotyped to be 1b, 2a, 3a, 3b, 6a and mix-infection of 1b/2a at frequencies of 56.8%, 8.1 %, 3.6%, 5.4%, 25.2% and 0.9% respectively, and all the 15 healthy control samples showed negative results. The accuracy and reliability of the genotyping method of PCR-RDH was confirmed in 38 cases by amplification of HCV core and NS5B regions followed by DNA sequencing and phylogenetic analysis.

CONCLUSIONThis method for HCV genotyping, with high reliability and specificity, is suitable for clinical and epidemiological investigations. The prevalence of HCV genotypes 1b and 2a decreases while 1b remains the dominant genotype in Guangdong, where the prevalence of 6a significantly increases as compared with that 10 years ago.

Genes, Viral ; Genotype ; Genotyping Techniques ; methods ; Hepacivirus ; classification ; genetics ; Hepatitis C ; virology ; Humans ; Immunoblotting ; Nucleic Acid Hybridization ; Reverse Transcriptase Polymerase Chain Reaction

OBJECTIVETo study the genetic aberrations and their pathologic significance in follicular lymphoma (FL).

METHODSParaffin-embedded tissue samples of 55 cases of FL, 28 cases of other small B-cell lymphomas and 10 cases of reactive follicular hyperplasia were retrieved. Nested polymerase chain reaction (PCR) was used to detect clonal rearrangement of immunoglobulin heavy chain gene (IgH) in FL and other small B-cell lymphomas. The translocation t (14; 18) was studied by PCR and dual-color fluorescence in-situ hybridization (FISH) in FL. Cases of reactive follicular hyperplasia were used as controls.

RESULTSAmongst the 55 cases studied, 49 cases were nodal and 6 cases were extranodal. There were 33 males and 22 females. The male-to-female ratio was 1.5:1. The median age of the patients was 57 years. Twenty-five cases belonged to histologic grade 1, while 19 cases were grade 2 and 11 cases were grade 3. Beta-actin DNA was detected in 50 cases of FL. Amongst those 50 cases, clonal IgH rearrangement was present in 34 (68%). Twenty-four cases (48%) and 25 cases (50%) were positive for FR3A and FR2 respectively. Fifteen cases (30%) showed dual positivity for both FR3A and FR2. Thirty-four cases (68%) demonstrated clonal IgH rearrangement. As for other small B-cell lymphomas, 25 cases were positive for beta-actin. FR3A and FR2 were detected in 18 and 17 cases respectively. Clonal IgH rearrangement was demonstrated in 24 cases. In contrast, none of the 4 cases of reactive follicular hyperplasia showed the clonal rearrangement pattern. Amongst the 44 cases of nodal FL analyzed, t (14; 18) was detected in 15 cases (with 14 cases in MBR and 1 case in mcr). In general, FISH was superior to PCR in detecting t (14; 18) using paraffin-embedded tissue samples.

CONCLUSIONSThe detection rate of clonal IgH rearrangement in FL is lower than that in other small B-cell lymphomas. Demonstration of t (14; 18) in paraffin-embedded tissue samples by FISH helps in diagnosis of FL. FISH is superior to PCR, as the technique is more sensitive and less labor intensive.

Actins ; metabolism ; Adult ; Aged ; Chromosomes, Human, Pair 14 ; genetics ; Chromosomes, Human, Pair 18 ; genetics ; Female ; Gene Rearrangement, B-Lymphocyte, Heavy Chain ; genetics ; Humans ; In Situ Hybridization, Fluorescence ; methods ; Lymphoma, B-Cell ; genetics ; metabolism ; Lymphoma, Follicular ; genetics ; metabolism ; Male ; Middle Aged ; Paraffin Embedding ; Polymerase Chain Reaction ; methods ; Translocation, Genetic