The additive effect of metabolic syndrome on left ventricular impairment in patients with obstructive coronary artery disease assessed by 3.0 T cardiac magnetic resonance feature tracking.

BACKGROUND: Metabolic syndrome (MetS) can increase the risk of morbidity and mortality of cardiovascular disease and obstructive coronary artery disease (OCAD), which usually have a poor prognosis. This study aimed to explore the impact of MetS on left ventricular (LV) deformation and function in OCAD patients and investigate the independent factors of impaired LV function and deformation. MATERIALS AND METHODS: A total of 121 patients with OCAD and 52 sex- and age-matched controls who underwent cardiac magnetic resonance scanning were enrolled in the study. All OCAD patients were divided into two groups: OCAD with MetS [OCAD(MetS+), n = 83] and OCAD without MetS [OCAD(MetS-), n = 38]. LV functional and global strain parameters were measured and compared among the three groups. Multivariable linear regression analyses were constructed to investigate the independent factors of LV impairment in OCAD patients. Logistic regression analysis and receiver operating characteristic (ROC) curve analysis were performed to test the prediction efficiency of MetS for LV impairment. RESULTS: From controls to the OCAD(MetS-) group to the OCAD(MetS+) group, LV mass (LVM) increased, and LV global function index (LVGFI) and LV global longitudinal peak strain (GLPS) decreased (all p < 0.05). Compared with the OCAD(MetS-) group, the LV GLPS declined significantly (p = 0.027), the LVM increased (p = 0.006), and the LVGFI decreased (p = 0.043) in the OCAD(MetS+) group. After adjustment for covariates in OCAD patients, MetS was an independent factor of decreased LV GLPS (ß = - 0.211, p = 0.002) and increased LVM (ß = 0.221, p = 0.003). The logistic multivariable regression analysis and ROC analysis showed that combined MetS improved the efficiency of predicting LV GLPS reduction (AUC = 0.88) and LVM (AUC = 0.89) increase. CONCLUSIONS: MetS aggravated the damage of LV deformation and function in OCAD patients and was independently associated with LV deformation and impaired LV strain. Additionally, MetS increased the prediction efficiency of increased LVM and decreased LV GLPS. Early detection and intervention of MetS in patients with OCAD is of great significance.

HS-AFM single-molecule structural biology uncovers basis of transporter wanderlust kinetics.

The Pyrococcus horikoshii amino acid transporter GltPh revealed, like other channels and transporters, activity mode switching, previously termed wanderlust kinetics. Unfortunately, to date, the basis of these activity fluctuations is not understood, probably due to a lack of experimental tools that directly access the structural features of transporters related to their instantaneous activity. Here, we take advantage of high-speed atomic force microscopy, unique in providing simultaneous structural and temporal resolution, to uncover the basis of kinetic mode switching in proteins. We developed membrane extension membrane protein reconstitution that allows the analysis of isolated molecules. Together with localization atomic force microscopy, principal component analysis and hidden Markov modeling, we could associate structural states to a functional timeline, allowing six structures to be solved from a single molecule, and an inward-facing state, IFSopen-1, to be determined as a kinetic dead-end in the conformational landscape. The approaches presented on GltPh are generally applicable and open possibilities for time-resolved dynamic single-molecule structural biology.

SIRPB1 regulates inflammatory factor expression in the glioma microenvironment via SYK: functional and bioinformatics insights.

BACKGROUND: SIRPB1 expression is upregulated in various tumor types, including gliomas, and is known to contribute to tumor progression; nevertheless, its function in the immune milieu of gliomas is still mainly unknown. METHODS: This study, we analyzed 1152 normal samples from the GTEx database and 670 glioma samples from the TCGA database to investigate the relationship between the expression of SIRPB1 and clinicopathological features. Moreover, SIRPB1 gene knockout THP-1 cell lines were constructed using CRISPR/Cas9 and were induced into a co-culture of macrophages and glioma cells in vitro to learn more about the role of SIRPB1 in the glioma immune milieu. Lastly, we established a prognostic model to predict the effect of SIRPB1 on prognosis. RESULTS: Significantly higher levels of SIRPB1 expression were found in gliomas, which had an adverse effect on the immune milieu and correlated poorly with patient survival. SIRPB1 activation with certain antibodies results in SYK phosphorylation and the subsequent activation of calcium, MAPK, and NF-κB signaling pathways. This phenomenon is primarily observed in myeloid-derived cells as opposed to glioma cells. In vitro co-culture demonstrated that macrophages with SIRPB1 knockout showed decreased IL1RA, CCL2, and IL-8, which were recovered upon ectopic expression of SIRPB1 but reduced again following treatment with SYK inhibitor GS9973. Critically, a lower overall survival rate was linked to increased SIRPB1 expression. Making use of SIRPB1 expression along with additional clinicopathological variables, we established a nomogram that showed a high degree of prediction accuracy. CONCLUSIONS: Our study demonstrates that glioma cells can be activated by macrophages via SIRPB1, subsequently reprogramming the TME, suggesting that SIRPB1 could serve as a promising therapeutic target for gliomas.

Clinical characteristics and prognostic analysis of primary extranodal non-Hodgkin lymphoma of the head and neck.

OBJECTIVE: Primary extranodal non-Hodgkin's lymphoma (PE-NHL) of the head and neck is the second common site of extranodal lymphoma, accounting for approximately one-third of all extranodal non-Hodgkin's lymphoma (E-NHL). However, in recent years, large-scale PE-NHL case studies in China and worldwide are rare and not comprehensive enough. This work analyzed the clinical manifestations, pathological features, immunophenotypes and diagnosis of PE-NHL, as well as the factors affecting the treatment and prognosis. METHODS: A retrospective study was performed on 74 patients who were diagnosed with head and neck PE-NHL and treated for the first time. The clinical manifestations, pathological features, and immunophenotypes were summarized, and the factors related to the treatment and prognosis were analyzed. RESULTS: The most common site of this disease was the Waldeyer's ring, followed by the nasal cavity. Diffuse large B-cell lymphoma was the most common type, followed by extranodal NK T-cell lymphoma nasal type. The 1-year, 2-year, and 5-year progression-free survival (PFS) rates were 76.4%, 67.9%, and 59.3%. The 1-year, 2-year, and 5-year overall survival (OS) rates were 89.4%, 85.6%, and 63.2%. ECOG score ≥ 2, Ann Arbor stage III or IV and IPI risk stratification identifying patients as the high-risk group were independent risk factors affecting the OS of patients with PE-NHL of the head and neck. CONCLUSIONS: The most common site of PE-NHL in these Chinese patients was the Waldeyer's ring, but the incidence in the nasal cavity was higher than that reported in Western countries. Radiotherapy combined with chemotherapy had better efficacy than chemotherapy alone, and the prognosis depended on the ECOG score and clinical stage. IPI had a better prognostic value in patients in the high-risk group of head and neck PE-NHL.

CHRNA9 as a New Prognostic Marker and Potential Therapeutic Target in Glioma.

Background: The nicotinic acetylcholine receptor (nAChR) subunit alpha-9 (CHRNA9) is a unique cholinergic receptor, which is involved in tumor proliferation, apoptosis, metastasis and chemotherapy resistance. However, the correlation between the expression level of CHRNA9 in glioma and the clinical features and prognosis of glioma patients has not been clarified. The aim of this study was to verify the expression level of CHRNA9 in glioma and its effect on prognosis by bioinformatics methods. Methods: The RNA-seq data of glioma and normal samples were obtained from the TCGA and GTEx databases. Bioinformatics methods were utilized to analyze the differential expression of CHRNA9 between tumor samples and normal samples. The potential association between CHRNA9 and the clinicopathological features of glioma patients was also investigated. The Kaplan-Meier method and Cox regression were utilized to analyze the relationship between CHRNA9 expression level and survival time and prognostic value of glioma patients. Enrichment analysis was applied to predict gene function and signaling pathways associated with CHRNA9. Experimental verification was performed using tumor tissues and paracancerous tissues from glioma patients. Results: The results of bioinformatics analysis showed that the expression of CHRNA9 was increased in glioma tissues, correlating with poor prognosis and reduced patient survival time. Enrichment analysis suggested that CHRNA9 may interact with the JAK/STAT pathway. CHRNA9 was also found to be abnormally expressed in various other tumors and associated with the expression levels of numerous immune checkpoints in glioma. The findings from the analysis of clinical samples revealed that the expression levels of both mRNA and protein of CHRNA9 in glioma tissues were higher than those in paracancerous tissues. Similarly, the mRNA expression levels of STAT3, IL-6, and TNF-α, which are crucial factors in the STAT3 pathway, were elevated in glioma tissues compared to paracancerous tissues. Conclusion: CHRNA9 is a potential prognostic marker and immunotherapy target for glioma, with its mechanism of action potentially linked to the STAT3 pathway.

Progress in Cardiac Magnetic Resonance Feature Tracking for Evaluating Myocardial Strain in Type-2 Diabetes Mellitus.

The global prevalence of type-2 diabetes mellitus (T2DM) has caused harm to human health and economies. Cardiovascular disease is one main cause of T2DM mortality. Increased prevalence of diabetes and associated heart failure (HF) is common in older populations, so accurately evaluating heart-related injury and T2DM risk factors and conducting early intervention are important. Quantitative cardiovascular system imaging assessments, including functional imaging during cardiovascular disease treatment, are also important. The left-ventricular ejection fraction (LVEF) has been traditionally used to monitor cardiac function; it is often preserved or increased in early T2DM, but subclinical heart deformation and dysfunction can occur. Myocardial strains are sensitive to global and regional heart dysfunction in subclinical T2DM. Cardiac magnetic resonance feature-tracking technology (CMR-FT) can visualize and quantify strain and identify subclinical myocardial injury for early management, especially with preserved LVEF. Meanwhile, CMR-FT can be used to evaluate the multiple cardiac chambers involvement mediated by T2DM and the coexistence of complications. This review discusses CMR-FT principles, clinical applications, and research progress in the evaluation of myocardial strain in T2DM.

Association of Pulmonary Transit Time and Pulmonary Blood Volume From First-Pass Perfusion Cardiac MRI With Diastolic Dysfunction and Left Ventricle Deformation in Restrictive Cardiomyopathy.

BACKGROUND: Patients with restrictive cardiomyopathy (RCM) have impaired diastolic filling and hemodynamic congestion. Pulmonary transit time (PTT) and pulmonary blood volume index (PBVi) reflect the hemodynamic status, but the relationship with left ventricle (LV) dysfunction remains unclear. PURPOSE: To evaluate the PTT and PBVi in RCM patients, the association with diastolic dysfunction and LV deformation, and the effects on the occurrence of major adverse cardiac events (MACE) in RCM patients. STUDY TYPE: Retrospective. POPULATION: 137 RCM patients (88 men, age 58.80 ± 10.83 years) and 68 age- and sex-matched controls (46 men, age 57.00 ± 8.59 years). FIELD STRENGTH/SEQUENCE: 3.0T/Balanced steady-state free precession sequence, recovery prepared echo-planar imaging sequence, and phase-sensitive inversion recovery sequence. ASSESSMENT: The LV function and peak strain (PS) parameters were measured. The PTT was calculated and corrected by heart rate (PTTc). The PBVi was calculated as the product of PTTc and RV stroke volume index. STATISTICAL TESTS: Chi-squared test, student's t-test, Mann-Whitney U test, Pearson's or Spearman's correlation, multivariate linear regression, Kaplan-Meier survival analysis, and Cox regression models analysis. A P-value <0.05 was considered statistically significant. RESULTS: The PTTc showed a significant correlation with the E/A ratio (r = 0.282), and PBVi showed a significant correlation with the E/e' ratio, E/A ratio, and diastolic dysfunction stage (r = 0.222, 0.320, and 0.270). PTTc showed an independent association with LVEF, LV circumferential PS, and LV longitudinal PS (ß = 0.472, 0.299, and 0.328). In Kaplan-Meier analysis, higher PTTc and PBVi were significantly associated with MACE. In multivariable Cox regression analysis, PTTc was a significantly independent predictor of the MACE in combination with both cardiac MRI functional and tissue parameters (hazard ratio: 1.23/1.32, 95% confidence interval: 1.10-1.42/1.20-1.46). DATA CONCLUSION: PTTc and PBVi are associated with diastolic dysfunction and deteriorated LV deformation, and PTTc independently predicts MACE in patients with RCM. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

P129, a pyrazole ring-containing isolongifolanone-derivate: synthesis and investigation of anti-glioma action mechanism.

BACKGROUND: Cyclin-dependent kinase-2 (CDK-2) is an important regulatory factor in the G1/S phase transition. CDK-2 targeting has been shown to suppress the viability of multiple cancers. However, the exploration and application of a CDK-2 inhibitor in the treatment of glioblastoma are sparse. METHODS: We synthesized P129 based on isolongifolanone, a natural product with anti-tumor activity. Network pharmacology analysis was conducted to predict the structural stability, affinity, and pharmacological and toxicological properties of P129. Binding analysis and CETSA verified the ability of P129 to target CDK-2. The effect of P129 on the biological behavior of glioma cells was analyzed by the cell counting kit-8, colony formation, flow cytometry, and other experiments. Western blotting was used to detect the expression changes of proteins involved in the cell cycle, cell apoptosis, and epithelial-mesenchymal transition. RESULTS: Bioinformatics analysis and CETSA showed that P129 exhibited good intestinal absorption and blood-brain barrier penetrability together with high stability and affinity with CDK-2, with no developmental toxicity. The viability, proliferation, and migration of human glioma cells were significantly inhibited by P129 in a dose- and time-dependent manner. Flow cytometry and western blotting analyses showed G0/G1 arrest and lower CDK-2 expression in cells treated with P129 than in the controls. The apoptotic ratio of glioma cells increased significantly with increasing concentrations of P129 combined with karyopyknosis and karyorrhexis. Apoptosis occurred via the mitochondrial pathway. CONCLUSION: The pyrazole ring-containing isolongifolanone derivate P129 exhibited promising anti-glioma activity by targeting CDK-2 and promoting apoptosis, indicating its potential importance as a new chemotherapeutic option for glioma.

Effects of diabetes mellitus on left ventricular function and deformation in patients with restrictive cardiomyopathies: a 3.0T CMR feature tracking study.

BACKGROUND: Diabetes mellitus (DM) is the most common metabolic disease worldwide and a major risk factor for adverse cardiovascular events, while the additive effects of DM on left ventricular (LV) deformation in the restrictive cardiomyopathy (RCM) cohort remain unclear. Accordingly, we aimed to investigate the additive effects of DM on LV deformation in patients with RCM. MATERIALS AND METHODS: One hundred thirty-six RCM patients without DM [RCM(DM-)], 46 with DM [RCM (DM+)], and 66 age- and sex-matched control subjects who underwent cardiac magnetic resonance (CMR) scanning were included. LV function, late gadolinium enhancement (LGE) type, and LV global peak strains (including radial, circumferential, and longitudinal directions) were measured. The determinant of reduced LV global myocardial strain for all RCM patients was assessed using multivariable linear regression analyses. The receiver operating characteristic curve (ROC) was performed to illustrate the relationship between DM and decreased LV deformation. RESULTS: Compared with the control group, RCM (DM-) and RCM(DM+) patients presented increased LV end-diastolic index and end-systolic volume index and decreased LV ejection fraction. LV GPS in all three directions and longitudinal PDSR progressively declined from the control group to the RCM(DM-) group to the RCM(DM+) group (all p < 0.05). DM was an independent determinant of impaired LV GPS in the radial, circumferential, and longitudinal directions and longitudinal PDSR (ß = - 0.217, 0.176, 0.253, and - 0.263, all p < 0.05) in RCM patients. The multiparameter combination, including DM, showed an AUC of 0.81(95% CI 0.75-0.87) to predict decreased LV GLPS and an AUC of 0.69 (95% CI 0.62-0.76) to predict decreased LV longitudinal PDSR. CONCLUSIONS: DM may have an additive deleterious effect on LV dysfunction in patients with RCM, especially diastolic dysfunction in RCM patients, indicating the importance of early identification and initiation of treatment of DM in patients with RCM.

Assessment of left atrioventricular coupling and left atrial function impairment in diabetes with and without hypertension using CMR feature tracking.

PURPOSE: The study was designed to assess the effect of co-occurrence of diabetes mellitus (DM) and hypertension on the deterioration of left atrioventricular coupling index (LACI) and left atrial (LA) function in comparison to individuals suffering from DM only. METHODS: From December 2015 to June 2022, we consecutively recruited patients with clinically diagnosed DM who underwent cardiac magnetic resonance (CMR) at our hospital. The study comprised a total of 176 patients with DM, who were divided into two groups based on their blood pressure status: 103 with hypertension (DM + HP) and 73 without hypertension (DM-HP). LA reservoir function (reservoir strain (εs), total LA ejection fraction (LAEF)), conduit function (conduit strain (εe), passive LAEF), booster-pump function (booster strain (εa) and active LAEF), LA volume index (LAVI), LV global longitudinal strain (LVGLS), and LACI were evaluated and compared between the two groups. RESULTS: After adjusting for age, sex, body surface area (BSA), and history of current smoking, total LAEF (61.16 ± 14.04 vs. 56.05 ± 12.72, p = 0.013) and active LAEF (43.98 ± 14.33 vs. 38.72 ± 13.51, p = 0.017) were lower, while passive LAEF (33.22 ± 14.11 vs. 31.28 ± 15.01, p = 0.807) remained unchanged in the DM + HP group compared to the DM-HP group. The DM + HP group had decreased εs (41.27 ± 18.89 vs. 33.41 ± 13.94, p = 0.006), εe (23.69 ± 12.96 vs. 18.90 ± 9.90, p = 0.037), εa (17.83 ± 8.09 vs. 14.93 ± 6.63, p = 0.019), and increased LACI (17.40±10.28 vs. 22.72±15.01, p = 0.049) when compared to the DM-HP group. In patients with DM, multivariate analysis revealed significant independent associations between LV GLS and εs (ß=-1.286, p < 0.001), εe (ß=-0.919, p < 0.001), and εa (ß=-0.324, p = 0.036). However, there was no significant association observed between LV GLS and LACI (ß=-0.003, p = 0.075). Additionally, hypertension was found to independently contribute to decreased εa (ß=-2.508, p = 0.027) and increased LACI in individuals with DM (ß = 0.05, p = 0.011). CONCLUSIONS: In DM patients, LV GLS showed a significant association with LA phasic strain. Hypertension was found to exacerbate the decline in LA booster strain and increase LACI in DM patients, indicating potential atrioventricular coupling index alterations.

Primary intracranial lymphomas-incidence and survival: a population-based study.

Biopsy is recommended for patients with primary intracranial lymphoma to confirm the diagnosis, but the effect of tumor resection is still controversial. We conducted this retrospective study to better understand the epidemiology of primary intracranial lymphoma in the USA and explore the relationship between surgical resection and prognosis. Data regarding primary intracranial lymphoma, including incidence, were extracted from the SEER database. We analyzed the difference in incidence between different groups of people. We explored the effect of surgery on the survival of patients by the Kaplan-Meier method and evaluated the possible prognostic indicators by multivariate Cox proportional hazards models. The incidence significantly increased with age. The non-Hispanic Asian or Pacific Islander population exhibited the highest incidence, and the incidence was significantly higher in males than females. A total of 6428 cases were included in the cohort study, and most of the patients were diagnosed in the sixth to seventh decade of life. Sixty percent of tumors were supratentorial tumors. Surgery, especially total resection, significantly improved overall survival and cancer-specific survival. The survival of female patients, patients diagnosed before reaching 60 years of age, patients diagnosed after 2010, and patients with supratentorial lymphomas was better than that of their counterparts. The survival of patients with diffuse large B-cell lymphoma was worse than that of their counterparts. We conducted a comprehensive retrospective analysis of patients with primary intracranial lymphoma. We analyzed the difference in incidence between different groups of people. Surgery significantly improved overall and cancer-specific survival. The results of our research can help clinicians and patients better understand the epidemiology and management of primary intracranial lymphoma.

A concerted ATPase cycle of the protein transporter AAA-ATPase Bcs1.

Bcs1, a homo-heptameric transmembrane AAA-ATPase, facilitates folded Rieske iron-sulfur protein translocation across the inner mitochondrial membrane. Structures in different nucleotide states (ATPγS, ADP, apo) provided conformational snapshots, but the kinetics and structural transitions of the ATPase cycle remain elusive. Here, using high-speed atomic force microscopy (HS-AFM) and line scanning (HS-AFM-LS), we characterized single-molecule Bcs1 ATPase cycling. While the ATP conformation had ~5600 ms lifetime, independent of the ATP-concentration, the ADP/apo conformation lifetime was ATP-concentration dependent and reached ~320 ms at saturating ATP-concentration, giving a maximum turnover rate of 0.17 s-1. Importantly, Bcs1 ATPase cycle conformational changes occurred in concert. Furthermore, we propose that the transport mechanism involves opening the IMS gate through energetically costly straightening of the transmembrane helices, potentially driving rapid gate resealing. Overall, our results establish a concerted ATPase cycle mechanism in Bcs1, distinct from other AAA-ATPases that use a hand-over-hand mechanism.

Intrinsically disordered regions in TRPV2 mediate protein-protein interactions.

Transient receptor potential (TRP) ion channels are gated by diverse intra- and extracellular stimuli leading to cation inflow (Na+, Ca2+) regulating many cellular processes and initiating organismic somatosensation. Structures of most TRP channels have been solved. However, structural and sequence analysis showed that ~30% of the TRP channel sequences, mainly the N- and C-termini, are intrinsically disordered regions (IDRs). Unfortunately, very little is known about IDR 'structure', dynamics and function, though it has been shown that they are essential for native channel function. Here, we imaged TRPV2 channels in membranes using high-speed atomic force microscopy (HS-AFM). The dynamic single molecule imaging capability of HS-AFM allowed us to visualize IDRs and revealed that N-terminal IDRs were involved in intermolecular interactions. Our work provides evidence about the 'structure' of the TRPV2 IDRs, and that the IDRs may mediate protein-protein interactions.

OH Radical-Induced Oxidation in Nucleosides and Nucleotides Unraveled by Tandem Mass Spectrometry and Infrared Multiple Photon Dissociation Spectroscopy.

OH⋅-induced oxidation products of DNA nucleosides and nucleotides have been structurally characterized by collision-induced dissociation tandem mass spectrometry (CID-MS2 ) and Infrared Multiple Photon Dissociation (IRMPD) spectroscopy. CID-MS2 results have shown that the addition of one oxygen atom occurs on the nucleobase moiety. The gas-phase geometries of +16 mass increment products of 2'-deoxyadenosine (dA(O)H+ ), 2'-deoxyadenosine 5'-monophosphate (dAMP(O)H+ ), 2'-deoxycytidine (dC(O)H+ ), and 2'-deoxycytidine 5'-monophosphate (dCMP(O)H+ ) are extensively investigated by IRMPD spectroscopy and quantum-chemical calculations. We show that a carbonyl group is formed at the C8 position after oxidation of 2'-deoxyadenosine and its monophosphate derivative. For 2'-deoxycytidine and its monophosphate derivative, the oxygen atom is added to the C5 position to form a C-OH group. IRMPD spectroscopy has been employed for the first time to provide direct structural information on oxidative lesions in DNA model systems.

Rapid increases in BMI waist to height ratio during adolescence and subsequent neurobehavioral deficits.

OBJECTIVE: The aim of this study was to explore prospective relationships between changing patterns of BMI/waist to height ratio (WHtR) during adolescence and subsequent neurobehavioral development. METHODS: In this prospective cohort study, randomized stratified sampling was used to recruit six middle schools and 609 students in Shanghai, China. In Grades 6, 7, and 9, the Youth Self Report scale was used to assess student neurobehavioral status and anthropometric measurements were conducted to calculate BMI z scores and WHtRs. Longitudinal data were analyzed using latent class mixture modeling to delineate trajectories of BMI z scores ("stable," "decreasing," "rapidly increasing") and WHtRs ("stable," "rapidly increasing"), and their associations with neurobehavioral status in Grade 9 were assessed. RESULTS: In Grades 6 through 9 (ages 11-15 years), the prevalence of overall obesity and abdominal obesity ranged from 10.7% to 13.0% and 13.0% to 19.8%, respectively. Compared with the stable BMI z score trajectory, the rapidly increasing BMI z score trajectory was longitudinally associated with delinquent behavior, aggressive behavior, and externalizing problems (incidence rate ratio: 1.564-1.613, adjusted p < 0.05). Compared with the stable WHtR trajectory, the rapidly increasing WHtR trajectory significantly predicted increased risks of social problems and delinquent behavior (incidence rate ratios: 1.776-1.967, adjusted p < 0.05). Significant associations of the rapidly increasing BMI z score/WHtR trajectories with subsequent neurobehavioral deficits were observed among girls (adjusted p < 0.05) but not among boys (adjusted p > 0.05). CONCLUSIONS: Rapid increases in BMI or WHtR during adolescence could predict subsequent neurobehavioral deficits, especially for externalizing behaviors. Timely intervention for weight control may be considered to promote adolescent mental health.

Atypical teratoid/rhabdoid tumour with CDK6 amplification in a child: a case report and literature review.

Atypical teratoid/rhabdoid tumours (AT/RTs) are rare central nervous system neoplasms that frequently occur in infants and children and have a very poor prognosis. In recent years, molecular analysis of AT/RTs has shown that biallelic inactivation of SMARCB1 (INI1, SNF5, BAF47) or SMARCA4 (BRG1) frequently occurs. Here, we present a case of basal ganglia AT/RT with SMARCB1 gene deficiency and CDK6 gene amplification in a 5-year-old child. A 5-year-old boy was hospitalized due to a 1-week history of frontal and parietal headache. Magnetic resonance imaging (MRI) demonstrated a 3 cm × 2 cm × 1.5 cm heterogeneous enhanced mass located at the right basal ganglia that partially protruded into the right lateral ventricle. The lesion was successfully resected under electrophysiological monitoring and neuronavigation. The postoperative pathological examination implied an AT/RT diagnosis, with loss of SMARCB1 protein, SMARCB1 gene deficiency and CDK6 gene amplification. Unfortunately, the patient died due to respiratory and circulatory failure at 5 weeks after the operation. To date, standard regimens have not yet been established due to the lack of large-scale prospective studies for AT/RT. The p16-RB signalling pathway should be considered as a potential target for AT/RT treatment modalities. Apart from traditional regimens, targeted therapies, especially CDK4/6 inhibitors, are likely a promising therapeutic option for AT/RT treatment.

A pentameric TRPV3 channel with a dilated pore.

Transient receptor potential (TRP) channels are a large, eukaryotic ion channel superfamily that control diverse physiological functions, and therefore are attractive drug targets1-5. More than 210 structures from more than 20 different TRP channels have been determined, and all are tetramers4. Despite this wealth of structures, many aspects concerning TRPV channels remain poorly understood, including the pore-dilation phenomenon, whereby prolonged activation leads to increased conductance, permeability to large ions and loss of rectification6,7. Here, we used high-speed atomic force microscopy (HS-AFM) to analyse membrane-embedded TRPV3 at the single-molecule level and discovered a pentameric state. HS-AFM dynamic imaging revealed transience and reversibility of the pentamer in dynamic equilibrium with the canonical tetramer through membrane diffusive protomer exchange. The pentamer population increased upon diphenylboronic anhydride (DPBA) addition, an agonist that has been shown to induce TRPV3 pore dilation. On the basis of these findings, we designed a protein production and data analysis pipeline that resulted in a cryogenic-electron microscopy structure of the TRPV3 pentamer, showing an enlarged pore compared to the tetramer. The slow kinetics to enter and exit the pentameric state, the increased pentamer formation upon DPBA addition and the enlarged pore indicate that the pentamer represents the structural correlate of pore dilation. We thus show membrane diffusive protomer exchange as an additional mechanism for structural changes and conformational variability. Overall, we provide structural evidence for a non-canonical pentameric TRP-channel assembly, laying the foundation for new directions in TRP channel research.

Homework, sleep insufficiency and adolescent neurobehavioral problems: Shanghai Adolescent Cohort.

BACKGROUND: The prospective associations between homework burdens and adolescent neurobehavioral problems, and whether sleep-durations mediated and sex modified such associations remained unclear. METHODS: Using Shanghai-Adolescent-Cohort study, 609 middle-school students were recruited and investigations took place at Grade 6, 7 and 9. Information on homework burdens (defined by homework completion-time and self-perceived homework difficulty), bedtime/wake-up-time and neurobehavioral problems was collected. Two patterns of comprehensive homework burdens ('high' vs. 'low') were identified by latent-class-analysis and two distinct neurobehavioral trajectories ('increased-risk' vs. 'low-risk') were formed by latent-class-mixture-modeling. RESULTS: Among the 6th-9th graders, the prevalence-rates of sleep-insufficiency and late-bedtime ranged from 44.0 %-55.0 % and 40.3 %-91.6 %, respectively. High homework burdens were concurrently associated with increased-risks of neurobehavioral problems (IRRs: 1.345-1.688, P < 0.05) at each grade, and such associations were mediated by reduced sleep durations (IRRs for indirect-effects: 1.105-1.251, P < 0.05). High homework burden at the 6th-grade (ORs: 2.014-2.168, P < 0.05) or high long-term (grade 6-9) homework burden (ORs: 1.876-1.925, P < 0.05) significantly predicted increased-risk trajectories of anxiety/depression and total-problems, with stronger associations among girls than among boys. The longitudinal associations between long-term homework burdens and increased-risk trajectories of neurobehavioral problems were mediated by reduced sleep-durations (ORs for indirect-effects: 1.189-1.278, P < 0.05), with stronger mediation-effects among girls. LIMITATIONS: This study was restricted to Shanghai adolescents. CONCLUSIONS: High homework burden had both short-term and long-term associations with adolescent neurobehavioral problems, with stronger associations among girls, and sleep-insufficiency may mediate such associations in a sex-specific manner. Approaches targeting appropriate homework-load/difficulty and sleep restoration may help prevent adolescent neurobehavioral problems.

Statins and risk of venous thromboembolic diseases: A two-sample mendelian randomization study.

BACKGROUND AND AIMS: In observational studies, statins have been suggested to have protective effects on venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE). To this aim, we performed a two-sample mendelian randomization (MR) analysis to determine whether these associations were causal. METHODS AND RESULTS: Data on the single nucleotide polymorphisms (SNPs) related to statin medication were obtained from the FinnGen study, and data for VTE, PE and DVT of lower extremities (LEDVT) were from the UK Biobank study, respectively. Inverse variance weighted (IVW) method was used as the principal analysis of MR, and sensitivity analysis was performed to detect horizontal pleiotropy and heterogeneity. MR estimates showed an inverse causal association between statin medication and the risk of VTE (odds ratio [OR]: 0.999, 95% CI: 0.998-1.000, P = 0.004), PE (OR: 0.999, 95% CI: 0.999-1.000, P = 0.011) and LEDVT (OR: 0.999, 95% CI: 0.999-1.000, P = 0.008). CONCLUSION: Our findings provide direct evidence that statins might decrease the risk of VTE, PE and LEDVT in agreement with observational studies. The specific mechanism of statin therapy for venous thromboembolism needs to be further studied.

Radiomics based on enhanced CT for differentiating between pulmonary tuberculosis and pulmonary adenocarcinoma presenting as solid nodules or masses.

PURPOSE: To investigate the incremental value of enhanced CT-based radiomics in discriminating between pulmonary tuberculosis (PTB) and pulmonary adenocarcinoma (PAC) presenting as solid nodules or masses and to develop an optimal radiomics model. METHODS: A total of 128 lesions (from 123 patients) from three hospitals were retrospectively analyzed and were randomly divided into training and test datasets at a ratio of 7:3. Independent predictors in subjective image features were used to develop the subjective image model (SIM). The plain CT-based and enhanced CT-based radiomics features were screened by the correlation coefficient method, univariate analysis, and the least absolute shrinkage and selection operator, then used to build the plain CT radiomics model (PRM) and enhanced CT radiomics model (ERM), respectively. Finally, the combined model (CM) combining PRM and ERM was established. In addition, the performance of three radiologists and one respiratory physician was evaluated. The areas under the receiver operating characteristic curve (AUCs) were used to assess the performance of each model. RESULTS: The differential diagnostic capability of the ERM (training: AUC = 0.933; test: AUC = 0.881) was better than that of the PRM (training: AUC = 0.861; test: AUC = 0.756) and the SIM (training: AUC = 0.760; test: AUC = 0.611). The CM was optimal (training: AUC = 0.948; test: AUC = 0.917) and outperformed the respiratory physician and most radiologists. CONCLUSIONS: The ERM was more helpful than the PRM for identifying PTB and PAC that present as solid nodules or masses, and the CM was the best.