Genomes of Subaerial Zygnematophyceae Provide Insights into Land Plant Evolution.

The transition to a terrestrial environment, termed terrestrialization, is generally regarded as a pivotal event in the evolution and diversification of the land plant flora that changed the surface of our planet. Through phylogenomic studies, a group of streptophyte algae, the Zygnematophyceae, have recently been recognized as the likely sister group to land plants (embryophytes). Here, we report genome sequences and analyses of two early diverging Zygnematophyceae (Spirogloea muscicola gen. nov. and Mesotaenium endlicherianum) that share the same subaerial/terrestrial habitat with the earliest-diverging embryophytes, the bryophytes. We provide evidence that genes (i.e., GRAS and PYR/PYL/RCAR) that increase resistance to biotic and abiotic stresses in land plants, in particular desiccation, originated or expanded in the common ancestor of Zygnematophyceae and embryophytes, and were gained by horizontal gene transfer (HGT) from soil bacteria. These two Zygnematophyceae genomes represent a cornerstone for future studies to understand the underlying molecular mechanism and process of plant terrestrialization.

Signatures of a strange metal in a bosonic system.

Fermi liquid theory forms the basis for our understanding of the majority of metals: their resistivity arises from the scattering of well defined quasiparticles at a rate where, in the low-temperature limit, the inverse of the characteristic time scale is proportional to the square of the temperature. However, various quantum materials1-15-notably high-temperature superconductors1-10-exhibit strange-metallic behaviour with a linear scattering rate in temperature, deviating from this central paradigm. Here we show the unexpected signatures of strange metallicity in a bosonic system for which the quasiparticle concept does not apply. Our nanopatterned YBa2Cu3O7-δ (YBCO) film arrays reveal linear-in-temperature and linear-in-magnetic field resistance over extended temperature and magnetic field ranges. Notably, below the onset temperature at which Cooper pairs form, the low-field magnetoresistance oscillates with a period dictated by the superconducting flux quantum, h/2e (e, electron charge; h, Planck's constant). Simultaneously, the Hall coefficient drops and vanishes within the measurement resolution with decreasing temperature, indicating that Cooper pairs instead of single electrons dominate the transport process. Moreover, the characteristic time scale τ in this bosonic system follows a scale-invariant relation without an intrinsic energy scale: h/τ ≈ a(kBT + γµBB), where h is the reduced Planck's constant, a is of order unity7,8,11,12, kB is Boltzmann's constant, T is temperature, µB is the Bohr magneton and γ ≈ 2. By extending the reach of strange-metal phenomenology to a bosonic system, our results suggest that there is a fundamental principle governing their transport that transcends particle statistics.

Effects of PRRT2 mutation on brain gray matter networks in paroxysmal kinesigenic dyskinesia.

Although proline-rich transmembrane protein 2 is the primary causative gene of paroxysmal kinesigenic dyskinesia, its effects on the brain structure of paroxysmal kinesigenic dyskinesia patients are not yet clear. Here, we explored the influence of proline-rich transmembrane protein 2 mutations on similarity-based gray matter morphological networks in individuals with paroxysmal kinesigenic dyskinesia. A total of 51 paroxysmal kinesigenic dyskinesia patients possessing proline-rich transmembrane protein 2 mutations, 55 paroxysmal kinesigenic dyskinesia patients possessing proline-rich transmembrane protein 2 non-mutation, and 80 healthy controls participated in the study. We analyzed the structural connectome characteristics across groups by graph theory approaches. Relative to paroxysmal kinesigenic dyskinesia patients possessing proline-rich transmembrane protein 2 non-mutation and healthy controls, paroxysmal kinesigenic dyskinesia patients possessing proline-rich transmembrane protein 2 mutations exhibited a notable increase in characteristic path length and a reduction in both global and local efficiency. Relative to healthy controls, both patient groups showed reduced nodal metrics in right postcentral gyrus, right angular, and bilateral thalamus; Relative to healthy controls and paroxysmal kinesigenic dyskinesia patients possessing proline-rich transmembrane protein 2 non-mutation, paroxysmal kinesigenic dyskinesia patients possessing proline-rich transmembrane protein 2 mutations showed almost all reduced nodal centralities and structural connections in cortico-basal ganglia-thalamo-cortical circuit including bilateral supplementary motor area, bilateral pallidum, and right caudate nucleus. Finally, we used support vector machine by gray matter network matrices to classify paroxysmal kinesigenic dyskinesia patients possessing proline-rich transmembrane protein 2 mutations and paroxysmal kinesigenic dyskinesia patients possessing proline-rich transmembrane protein 2 non-mutation, achieving an accuracy of 73%. These results show that proline-rich transmembrane protein 2 related gray matter network deficits may contribute to paroxysmal kinesigenic dyskinesia, offering new insights into its pathophysiological mechanisms.

Differential cortical gray matter changes in early- and late-onset patients with amyotrophic lateral sclerosis.

Age at onset may be an important feature associated with distinct subtypes of amyotrophic lateral sclerosis (ALS). Little is known about the neuropathological mechanism of early-onset ALS (EO-ALS) and late-onset ALS (LO-ALS). Ninety ALS patients were divided into EO-ALS and LO-ALS group, and 128 healthy controls were matched into young controls(YCs) and old controls (OCs). A voxel-based morphometry approach was employed to investigate differences in gray matter volume (GMV). Significant age at onset-by-diagnosis interactions were found in the left parietal operculum, left precentral gyrus, bilateral postcentral gyrus, right occipital gyrus, and right orbitofrontal cortex. Post hoc analysis revealed a significant decrease in GMV in all affected regions of EO-ALS patients compared with YCs, with increased GMV in 5 of the 6 brain regions, except for the right orbitofrontal cortex, in LO-ALS patients compared with OCs. LO-ALS patients had a significantly increased GMV than EO-ALS patients after removing the aging effect. Correspondingly, GMV of the left postcentral gyrus correlated with disease severity in the 2 ALS groups. Our findings suggested that the pathological mechanisms in ALS patients with different ages at onset might differ. These findings provide unique insight into the clinical and biological heterogeneity of the 2 ALS subtypes.

14-3-3-η interacts with BCL-2 to protect human endothelial progenitor cells from ox-LDL-triggered damage.

Oxidized low-density lipoprotein (ox-LDL) causes dysfunction of endothelial progenitor cells (EPCs), and we recently reported that 14-3-3-η can attenuate the damage triggered by ox-LDL in EPCs. However, the molecular mechanisms by which 14-3-3-η protects EPCs from the damage caused by ox-LDL are not fully understood. In this study, we observed that the expression of 14-3-3-η and BCL-2 were downregulated in ox-LDL-treated EPCs. Overexpression of 14-3-3-η in ox-LDL-treated EPC significantly increased BCL-2 level, while knockdown of BCL-2 reduced 14-3-3-η expression and mitigated the protective effect of 14-3-3-η on EPCs. In addition, we discovered that 14-3-3-η colocalizes and interacts with BCL-2 in EPCs. Taken together, these data suggest that 14-3-3-η protects EPCs from ox-LDL-induced damage by its interaction with BCL-2.

Distinctive subgingival microbial signatures in older adults with different levels of cognitive function.

AIM: To examine association between subgingival microbial signatures and levels of cognitive impairment in older adults. MATERIALS AND METHODS: We analysed subgingival plaque samples and 16S ribosomal RNA sequences for microbiota among 165 participants (normal controls [NCs]: 40, subjective cognitive decline [SCD]: 40, mild cognitive impairment [MCI]: 49 and dementia: 36). RESULTS: The bacterial richness was lower among individuals with worse cognitive function, and subgingival microbial communities differed significantly among the four groups. Declining cognitive function was associated with decreasing relative abundance of genera Capnocytophaga, Saccharibacteria_genera_incertae_sedis, Lautropia and Granulicatella, and increasing abundance of genus Porphyromonas. Moreover, there were differentially abundant genera among the groups. Random forest model based on subgingival microbiota could distinguish between cognitive impairment and NC (AUC = 0.933, 95% confidence interval 0.873-0.992). Significant correlations were observed between oral microbiota and sex, Montreal Cognitive Assessment (MoCA) score and Mini-Mental State Examination score. Partial correlation analysis showed that Leptotrichia and Burkholderia were closely negatively associated with the MoCA score after adjusting for multiple covariates. Gene function was not significantly different between SCD and NC groups, whereas three homozygous genes were altered in MCI patients and two in dementia patients. CONCLUSIONS: This is the first study to demonstrate an association between the composition, function and metabolic pathways of subgingival microbiota and different levels of cognitive function among older individuals. Future cohort studies should assess its diagnostic usefulness for cognitive impairment.

Aberrant functional connectivity associated with drug response in patients with newly diagnosed epilepsy.

OBJECTIVE: To analyze the local functional activity and connectivity features of the brain associated with drug response inpatients newly diagnosed with epilepsy (NDE) who are naïve to anti-seizure medication (ASM). METHODS: Recruited patients, underwent functional magnetic resonance imaging at baseline, and were assigned to the well-controlled (WC, n = 28) or uncontrolled (UC, n = 11) groups based on their response to ASM. Healthy participants were included in the control group (HC, n = 29). The amplitudes of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) were used to measure local functional activity, and voxel-wise degree centrality (DC) and seed-based functional connectivity (FC) were used to evaluate the connecting intensity of the brain areas. RESULTS: Compared to the HC and WC groups, the UC group had higher ALFF values in the left posterior central gyrus (PoCG.L) and left inferior temporal gyrus (ITG.L) and higher DC in the bilateral PoCG (Gaussian random field correction, voxel-level P < 0.001, and cluster-level P < 0.05). Both PoCG and ITG.L in the UC group showed stronger FC with multiple brain regions, mainly located in the occipital and temporal lobes, compared to the HC or WC group, while the WC group showed decreased or similar FC compared to the HC group. INTERPRETATION: Excessive enhancement of brain functional activity or connecting intensity in ASM-naïve patients with NDE may be associated with a higher risk of poor drug response.

Effect of MVF Combined with FES on Limb Function Recovery and Fine Function Rehabilitation of Hemiplegic Patients after ACI.

Background: This study assesses the efficacy of mirror visual feedback (MVF) combined with functional electrical stimulation (FES) in rehabilitating limb function and fine motor skills in hemiplegic patients after acute cerebral infarction (ACI). Given the limited research in this area, this study aims to provide insights into innovative rehabilitation techniques. Methods: A randomized controlled trial was conducted on 106 post-ACI hemiplegic patients, split into two groups of 53 each. One group received conventional training plus FES, while the other group underwent MVF combined with FES. Key metrics like walking parameters, the modified Lindmark score, center of gravity movement speed, Fugl-Meyer Motor function (FMA) score, fall index, Berg score, and Time-Up-Go Time (TUGT) were measured to evaluate the effectiveness. Results: In the study, significant improvements were observed in the observation group compared to the control group. The Modified Lindmark Scores for sensory function, motor coordination, and total scores in the observation group improved to 6.85±0.72, 15.77±2.25, and 22.62±2.78 respectively post-treatment, surpassing the control group's scores of 5.77±0.68, 13.92±1.87, and 19.69±2.45. In terms of FMA score, fall index, Berg score, and TUGT time, the observation group showed remarkable improvement: the FMA score increased from 43.69±4.51 to 67.25±7.04, the fall index decreased from 55.74±8.76 to 42.08±5.97, the Berg score rose from 31.03±6.28 to 43.11±6.71, and the TUGT time was reduced from 30.78±6.59s to 18.57±3.26s. These changes were significantly better than those in the control group, with all P = .000, indicating statistically significant improvements. Conclusion: The results indicate that the combination of MVF and FES is more effective in improving limb function, hand fine movements, and balance in hemiplegic patients post-ACI compared to FES alone. This suggests that integrating MVF with FES may be a more beneficial approach in stroke rehabilitation. Future research is advised to explore larger sample sizes and long-term effects, offering guidance for developing more effective treatment and rehabilitation plans. This study suggests that integrating mirror visual feedback and functional electrical stimulation into stroke rehabilitation could significantly enhance recovery, potentially influencing clinical practices and rehabilitation policies. Future studies should explore the long-term effects, applicability to diverse patient groups, and cost-effectiveness of these combined therapies.

Developmental validation of a novel 8-dye fluorescent typing system with 59 Y-STRs and 3 Y-indels for forensic applications.

An 8-dye fluorescence-labeling forensic Y-chromosomal short tandem repeats (Y-STRs) kit, the 62-plex Y-STR multiplex amplification system, was developed and optimized. The system was validated by testing PCR conditions, stutter ratios (SR) and peak height ratios, sensitivity, mixture samples, precision and accuracy, species-specificity, and inhibition studies according to the Scientific Working Group on DNA Analysis Methods guidelines. PCR-based studies showed that the recommended PCR conditions were optimized for this kit. In the sensitivity study, a full profile was obtained from template DNA with a quantity of u125 pg. Consistent profiles were obtained from three different laboratories. The SRs in all loci were less than 15%, and nice balance and suitable average peak height were shown. No peaks were detected in the profiles of common animal species and microorganisms. In the male-male mixture studies, all loci were observed at a ratio of 1:8, and in the male-female mixture study, all alleles could be profiled at a ratio of 1:500 if the male DNA inputs were ≥0.5 ng/µL. An inhibitor study demonstrated that the kit had varying degrees of resistance to the presence of common inhibitors. Population study demonstrated the 62-plex Y-STR Kit improved the power of discrimination in unrelated Chinese Han males (n = 192). When haplotype diversity was 1, the probability of discrimination power of the 62-plex Y-STR Kit was 0.9948, which is suitable for forensic investigations. The results show that the developed 8-dye fluorescence labeling 62 loci system is sensitive, robust, convenient, and highly informative for forensic applications.

Correlation between AI-based CT organ features and normal lung dose in adjuvant radiotherapy following breast-conserving surgery: a multicenter prospective study.

BACKGROUND: Radiation pneumonitis (RP) is one of the common side effects after adjuvant radiotherapy in breast cancer. Irradiation dose to normal lung was related to RP. We aimed to propose an organ features based on deep learning (DL) model and to evaluate the correlation between normal lung dose and organ features. METHODS: Patients with pathology-confirmed invasive breast cancer treated with adjuvant radiotherapy following breast-conserving surgery in four centers were included. From 2019 to 2020, a total of 230 patients from four nationwide centers in China were screened, of whom 208 were enrolled for DL modeling, and 22 patients from another three centers formed the external testing cohort. The subset of the internal testing cohort (n = 42) formed the internal correlation testing cohort for correlation analysis. The outline of the ipsilateral breast was marked with a lead wire before the scanning. Then, a DL model based on the High-Resolution Net was developed to detect the lead wire marker in each slice of the CT images automatically, and an in-house model was applied to segment the ipsilateral lung region. The mean and standard deviation of the distance error, the average precision, and average recall were used to measure the performance of the lead wire marker detection model. Based on these DL model results, we proposed an organ feature, and the Pearson correlation coefficient was calculated between the proposed organ feature and ipsilateral lung volume receiving 20 Gray (Gy) or more (V20). RESULTS: For the lead wire marker detection model, the mean and standard deviation of the distance error, AP (5 mm) and AR (5 mm) reached 3.415 ± 4.529, 0.860, 0.883, and 4.189 ± 8.390, 0.848, 0.830 in the internal testing cohort and external testing cohort, respectively. The proposed organ feature calculated from the detected marker correlated with ipsilateral lung V20 (Pearson correlation coefficient, 0.542 with p < 0.001 in the internal correlation testing cohort and 0.554 with p = 0.008 in the external testing cohort). CONCLUSIONS: The proposed artificial Intelligence-based CT organ feature was correlated with normal lung dose in adjuvant radiotherapy following breast-conserving surgery in patients with invasive breast cancer. TRIAL REGISTRATION: NCT05609058 (08/11/2022).

Integration of transcriptomics and metabolomics provides metabolic and functional insights into reduced insulin secretion in MIN6 ß-cells exposed to deficient and excessive arginine.

Previous work demonstrated that arginine is one of the strongest insulin secretagogues. However, knowledge of the mechanisms linking chronic arginine metabolism with ß-cell function and insulin secretion is relatively limited. After preliminary selection of concentration according to the cell proliferation, the MIN6 pancreatic ß-cells were randomly assigned to culture in 0.04 mM (low-arginine, LA), 0.4 mM (standard-arginine, SA), or 8 mM arginine (high-arginine, HA) for 24 h. Following the treatment, a combination of transcriptomics and metabolomics, together with a series of molecular biological tests were performed to investigate the responses of ß-cells to varied arginine availability. Our results showed that HA treatment reduced the chronic insulin releases, and LA and HA treatments decreased the glucose-stimulated insulin secretions (GSIS) of ß-cells relative to the SA group (p < .05). Transcriptomics analysis indicated that LA administration significantly inhibited oxidative phosphorylation and ATP metabolic process but promoted DNA repair and mRNA processing in ß-cells, while HA administration affected ammonium ion metabolic process and mRNA export (p < .05). Both LA and HA regulated the expressions of genes involved in DNA replication, cell-cycle phase transition, and response to oxidative stress (p < .05). Protein-protein interaction and transcription factor analyses suggested that Trp53 and Nr4a2 genes may play key roles during arginine stimulation. On the contrary, metabolomics analysis demonstrated that the differentially expressed metabolites (DEM) of MIN6 ß-cells induced by LA were mainly enriched in glycerophospholipid metabolism, linoleic acid metabolism, and purine metabolism, while most DEMs between LA vs. SA comparison belonged to amino acid metabolism. When combined the three groups, co-expression analysis suggested that insulin secretions had strong associations with L-pyroglutamic acid, L-glutamate, and creatine concentrations, while intracellular insulin contents were mainly correlated to L-arginine, argininosuccinic acid, and phosphorylcholine. At last, integrated analysis of transcriptomics and metabolomics showed that glycerophospholipid metabolism, biosynthesis of unsaturated fatty acids, and amino acid metabolism were the most relevant pathways in ß-cells exposed to abnormal arginine supply. This descriptive bioinformatics analysis suggested that the disturbed carbohydrate, lipid, and amino acid metabolisms, as well as the increased apoptosis and elevated oxidative stress, contributed to the reduced insulin secretion and lower GSIS in ß-cells induced by LA or HA treatments, while some underlying mechanisms need to be further explored.

Brain network structural connectome abnormalities among youth with attention-deficit/hyperactivity disorder at varying risk for bipolar I disorder: a cross-sectional graph-based magnetic resonance imaging study.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is highly prevalent among youth with or at familial risk for bipolar-I disorder (BD-I), and ADHD symptoms commonly precede and may increase the risk for BD-I; however, associated neuropathophysiological mechanisms are not known. In this cross-sectional study, we sought to investigate brain structural network topology among youth with ADHD, with and without familial risk of BD-I. METHODS: We recruited 3 groups of psychostimulant-free youth (aged 10-18 yr), namely youth with ADHD and at least 1 biological parent or sibling with BD-I (high-risk group), youth with ADHD who did not have a first- or second-degree relative with a mood or psychotic disorder (low-risk group) and healthy controls. We used graph-based network analysis of structural magnetic resonance imaging data to investigate topological properties of brain networks. We also evaluated relationships between topological metrics and mood and ADHD symptom ratings. RESULTS: A total of 149 youth were included in the analysis (49 healthy controls, 50 low-risk youth, 50 high-risk youth). Low-risk and high-risk ADHD groups exhibited similar differences from healthy controls, mainly in the default mode network and central executive network. We found topological alterations in the salience network of the high-risk group, relative to both low-risk and control groups. We found significant abnormalities in global network properties in the high-risk group only, compared with healthy controls. Among both low-risk and high-risk ADHD groups, nodal metrics in the right triangular inferior frontal gyrus correlated positively with ADHD total and hyperactivity/impulsivity subscale scores. LIMITATIONS: The cross-sectional design of this study could not determine the relevance of these findings to BD-I risk progression. CONCLUSION: Youth with ADHD, with and without familial risk for BD-I, exhibit common regional abnormalities in the brain connectome compared with healthy youth, whereas alterations in the salience network distinguish these groups and may represent a prodromal feature relevant to BD-I risk.

A pre-treatment CT-based weighted radiomic approach combined with clinical characteristics to predict durable clinical benefits of immunotherapy in advanced lung cancer.

OBJECTIVES: To develop a pre-treatment CT-based predictive model to anticipate inoperable lung cancer patients' progression-free survival (PFS) to immunotherapy. METHODS: This single-center retrospective study developed and cross-validated a radiomic model in 185 patients and tested it in 48 patients. The binary endpoint is the durable clinical benefit (DCB, PFS ≥ 6 months) and non-DCB (NDCB, PFS < 6 months). Radiomic features were extracted from multiple intrapulmonary lesions and weighted by an attention-based multiple-instance learning model. Aggregated features were then selected through L2-regularized ridge regression. Five machine-learning classifiers were conducted to build predictive models using radiomic and clinical features alone and then together. Lastly, the predictive value of the model with the best performance was validated by Kaplan-Meier survival analysis. RESULTS: The predictive models based on the weighted radiomic approach showed superior performance across all classifiers (AUCs: 0.75-0.82) compared with the largest lesion approach (AUCs: 0.70-0.78) and the average sum approach (AUCs: 0.64-0.80). Among them, the logistic regression model yielded the most balanced performance (AUC = 0.87 [95%CI 0.84-0.89], 0.75 [0.68-0.82], 0.80 [0.68-0.92] in the training, validation, and test cohort respectively). The addition of five clinical characteristics significantly enhanced the performance of radiomic-only model (train: AUC 0.91 [0.89-0.93], p = .042; validation: AUC 0.86 [0.80-0.91], p = .011; test: AUC 0.86 [0.76-0.96], p = .026). Kaplan-Meier analysis of the radiomic-based predictive models showed a clear stratification between classifier-predicted DCB versus NDCB for PFS (HR = 2.40-2.95, p < 0.05). CONCLUSIONS: The adoption of weighted radiomic features from multiple intrapulmonary lesions has the potential to predict long-term PFS benefits for patients who are candidates for PD-1/PD-L1 immunotherapies. KEY POINTS: • Weighted radiomic-based model derived from multiple intrapulmonary lesions on pre-treatment CT images has the potential to predict durable clinical benefits of immunotherapy in lung cancer. • Early line immunotherapy is associated with longer progression-free survival in advanced lung cancer.

Energy-adjusted dietary inflammatory index and cognitive function in Chinese older adults: a population-based cross-sectional study.

Diet can regulate systemic inflammation, which may play an important role in the development and progression of cognitive impairment and dementia. To explore the relationship between the dietary inflammatory potential and cognitive ability. A total of 2307 adults aged 60 years or older were recruited from the Fujian Provincial Hospital (Fujian, China). Dietary inflammatory properties were analyzed using the energy-adjusted dietary inflammatory index (E-DII). The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used to assess cognitive function. Logistic regression and restricted cubic spline (RCS) were fit to assess the associations between variables. The MCI subjects with the highest E-DII scores had a higher risk of AD compared to subjects with the lowest E-DII scores (OR = 1.98, 95%CI = 1.49-2.64, P for trend < 0.001). Subjects with the highest E-DII levels were at increased risk of cognitive impairment compared to those with the lowest E-DII levels (OR = 1.56, 95%CI = 1.25-1.93, P for trend < 0.001). The link between E-DII and cognitive impairment was significant in a nonlinear dose response analysis (P for nonlinear = 0.001). Higher E-DII scores were associated with an increased risk of developing AD or cognitive impairment. These findings may contribute to the effective prevention of cognitive impairment by constructing a multidisciplinary synergistic prevention strategy and controlling dietary inflammation levels.

FtMt reduces oxidative stress-induced trophoblast cell dysfunction via the HIF-1α/VEGF signaling pathway.

BACKGROUND: Preeclampsia (PE) is a complication of pregnancy that causes long-term adverse outcomes for the mother and fetus and may even lead to death. Oxidative stress caused by the imbalance of oxidants and antioxidants in the placenta has been considered as one of the key mechanisms of preeclampsia (together with inflammation, etc.), in which the placental mitochondria play an important role. The expression of hypoxia-inducible factor-1 (HIF-1α) and vascular endothelial growth factor (VEGF) is known to be increased in patients with PE. Mitochondrial ferritin (FtMt) is known to protect the mitochondria from oxidative stress, although its specific role in PE remains unclear. METHODS: We used qRT-PCR and western blotting to detect the expression levels of FtMt, HIF-1α, and VEGF in placental tissues from patients with PE. Human chorionic trophoblast cells were also administered with hypoxia treatment, followed by the detection of cell proliferation, invasion and angiogenic capacity by CCK8, Transwell, and endothelial cell angiogenesis assays; we also detected the expression of HIF-1α and VEGF in these cells. Finally, overexpression or inhibitory FtMt lentiviral vectors, along with negative control vectors, were constructed and transfected into hypoxia-treated human chorionic trophoblast cells; this was followed by analyses of cell function. RESULTS: The expression levels of FtMt, HIF-1α and VEGF in the PE group were higher than those in the control group (P < 0.05). Following hypoxia, there was an increase in the expression levels of HIF-1α and VEGF protein in trophoblast cells. There was also an increase in invasion ability and vascular formation ability along with a reduction in cell proliferation ability. These effects were reversed by transfecting cells with the knockout FtMt lentivirus vector. The differences were statistically significant. CONCLUSION: Analyses showed that FtMt plays a key role in the vascular regulation of PE trophoblast cells after hypoxia possibly acting via the HIF-1α/VEGF signaling pathway. These results provide us an enhanced understanding of the pathogenesis of PE and suggest that the HIF-1α/VEGF signaling pathway represents a new target for the treatment of PE.

Seeing beyond the tumor: computed tomography image-based radiomic analysis helps identify ovarian clear cell carcinoma subtype in epithelial ovarian cancer.

OBJECTIVE: To develop and validate a model that can preoperatively identify the ovarian clear cell carcinoma (OCCC) subtype in epithelial ovarian cancer (EOC) using CT imaging radiomics and clinical data. MATERIAL AND METHODS: We retrospectively analyzed data from 282 patients with EOC (training set = 225, testing set = 57) who underwent pre-surgery CT examinations. Patients were categorized into OCCC or other EOC subtypes based on postoperative pathology. Seven clinical characteristics (age, cancer antigen [CA]-125, CA-199, endometriosis, venous thromboembolism, hypercalcemia, stage) were collected. Primary tumors were manually delineated on portal venous-phase images, and 1218 radiomic features were extracted. The F-test-based feature selection method and logistic regression algorithm were used to build the radiomic signature, clinical model, and integrated model. To explore the effects of integrated model-assisted diagnosis, five radiologists independently interpreted images in the testing set and reevaluated cases two weeks later with knowledge of the integrated model's output. The diagnostic performances of the predictive models, radiologists, and radiologists aided by the integrated model were evaluated. RESULTS: The integrated model containing the radiomic signature (constructed by four wavelet radiomic features) and three clinical characteristics (CA-125, endometriosis, and hypercalcinemia), showed better diagnostic performance (AUC = 0.863 [0.762-0.964]) than the clinical model (AUC = 0.792 [0.630-0.953], p = 0.295) and the radiomic signature alone (AUC = 0.781 [0.636-0.926], p = 0.185). The diagnostic sensitivities of the radiologists were significantly improved when using the integrated model (p = 0.023-0.041), while the specificities and accuracies were maintained (p = 0.074-1.000). CONCLUSION: Our integrated model shows great potential to facilitate the early identification of the OCCC subtype in EOC, which may enhance subtype-specific therapy and clinical management.

Identification and integrated analysis of lncRNAs and miRNAs in IPEC-J2 cells provide novel insight into the regulation of the innate immune response by PDCoV infection.

BACKGROUND: Noncoding RNAs (ncRNAs), including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), are pivotal regulators involved in the pathogenic mechanism of multiple coronaviruses. Porcine deltacoronavirus (PDCoV) has evolved multiple strategies to escape the innate immune response of host cells, but whether ncRNAs are involved in this process during PDCoV infection is still unknown. RESULTS: In this study, the expression profiles of miRNAs, lncRNAs and mRNAs in IPEC-J2 cells infected with PDCoV at 0, 12 and 24 hours postinfection (hpi) were identified through small RNA and RNA sequencing. The differentially expressed miRNAs (DEmiRNAs), lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) were screened from the comparison group of IPEC-J2 cells at 0 and 12 hpi as well as the comparison group of IPEC-J2 cells at 12 and 24 hpi. The target genes of these DEncRNAs were predicted. The bioinformatics analysis of the target genes revealed multiple significantly enriched functions and pathways. Among them, the genes that were associated with innate immunity were specifically screened. The expression of innate immunity-related ncRNAs and mRNAs was validated by RT-qPCR. Competing endogenous RNA (ceRNA) regulatory networks among innate immunity-related ncRNAs and their target mRNAs were established. Moreover, we found that the replication of PDCoV was significantly inhibited by two innate immunity-related miRNAs, ssc-miR-30c-3p and ssc-miR-374b-3p, in IPEC-J2 cells. CONCLUSIONS: This study provides a data platform to conduct studies of the pathogenic mechanism of PDCoV from a new perspective and will be helpful for further elucidation of the functional role of ncRNAs involved in PDCoV escaping the innate immune response.

microRNA-155-5p initiates childhood acute lymphoblastic leukemia by regulating the IRF4/CDK6/CBL axis.

Acute lymphoblastic leukemia (ALL) is a common malignancy in children. In this study, we aimed to explore putative mechanisms of microRNA-155-5p (miR-155-5p) involvement in childhood ALL (cALL) via interactions with casitas B-lineage lymphoma (CBL), interferon regulatory factor 4 (IRF4), and cyclin-dependent kinase 6 (CDK6). Bioinformatic analysis was performed initially to identify differentially expressed genes in cALL. The expression levels of miR-155-5p, CBL, IRF4, and CDK6 in peripheral blood lymphocytes from clinical ALL samples were determined using RT-qPCR and Western blot assays. A dual-luciferase reporter gene assay was used to ascertain a possible targeting relationship between miR-155-5p and CBL, CCK-8 assay and flow cytometry were used to measure cell activity and apoptosis of ALL cells. Co-IP was performed to investigate the interaction between CBL and IRF4 and the ubiquitination level of IRF4. Furthermore, in vivo validation was performed inducing xenograft tumor models with ALL cells in nude mice. As indicated by bioinformatic analysis, miR-155-5p and CDK6 were upregulated and CBL was downregulated in ALL. miR-155-5p was found to target CBL to inhibit CBL expression. miR-155-5p promoted the proliferation of ALL cells and inhibited their apoptosis by inhibiting the expression of CBL, which otherwise degraded IRF4 protein through ubiquitination, leading to inhibited CDK6 expression. Collectively, the results show that miR-155-5p can promote the development of cALL via the regulation on CBL-mediated IRF4/CDK6 axis.

Opportunities and hurdles to European market access for multi-herbal traditional Chinese medicine products: An analysis of EU regulations for combination herbal medicinal products.

TCM herbal remedies are popular among European patients. However, a very limited number of TCM products have been approved as herbal medicinal products (HMPs) in Europe. Multi-herbal TCM products, the most prevalent form of medication in TCM practice, are even rare. This indicates multi-herbal TCM products are facing considerable obstacles in the access to EU market. To further identify such obstacles, we make a systematic analysis of current advances in both EU herbal monographs and combination HMPs granted in member states and present main features of the regulation as well as challenges for multi-herbal TCM products. The results show the EU is open to combination HMPs based on TCM or other non-European traditions. The regulation allows appropriate flexibility in the range of drug extraction rations, variation in concentrations of extraction solvent and number of herbal drugs presented in the product, if plausible pharmacological effects could be justified. Meanwhile, to guarantee the safety and efficacy based on medicinal usage, especially to justify the rationale or plausibility of the combination, is the key element for well-established use or traditional use combination HMPs. Additionally, EU herbal monographs also have great value in their marketing procedure. Nonetheless, there are many challenges in the European market access of multi-herbal TCM products which lies in quality control, safety and efficacy evaluation and others e.g., practical standard for full marketing authorization. Enforced scientific research and communication among research institutions, industries and authorities are necessary to further facilitate the access of multi-herbal TCM products to EU market. The results of this article may provide guidance for HMPs based on TCM or other non-European traditions with intention to entering EU market.

CT-based radiomics to predict muscle invasion in bladder cancer.

OBJECTIVES: This study investigated the feasibility of a computed tomography (CT)-based radiomics prediction model to evaluate muscle invasive status in bladder cancer. METHODS: Patients who underwent CT urography at two medical centers from October 2014 to May 2020 and had bladder urothelial carcinoma confirmed by postoperative histopathology were retrospectively enrolled. In total, 441 cases were collected and randomized into a training cohort (n = 293), an internal testing cohort (n = 73), and an external testing cohort (n = 75). The images were first filtered, and then, 1218 features were extracted. The best features related to muscle invasiveness of bladder cancer were identified by ANOVA. A prediction model was built by using the logistic regression method. Statistical analysis was performed by plotting the receiver operating characteristic curve. Indicators of the diagnostic performance of the prediction model, including sensitivity, specificity, accuracy, and area under curve (AUC), were evaluated. RESULTS: In the training, internal testing, and external testing cohorts, the prediction model diagnosed muscle-invasive bladder cancer with AUCs of 0.885 (95% confidence interval [95% CI] 0.841-0.929), 0.820 (95% CI 0.698-0.941), and 0.784 (95% CI 0.674-0.893), respectively. In the internal testing cohort, the sensitivity, specificity, and accuracy of the model were 0.667 (95% CI 0.387-0.870), 0.845 (95% CI 0.721-0.922), and 0.782 (95% CI 0.729-0.827), respectively. In the external testing cohort, the sensitivity, specificity, and accuracy of the model were 0.742 (95% CI 0.551-0.873), 0.750 (95% CI 0.594-0.863), and 0.782 (95% CI 0.729-0.827), respectively. CONCLUSIONS: CT-based radiomics prediction model can evaluate muscle invasiveness of bladder cancer before surgery with a good diagnostic performance. KEY POINTS: • CT-based radiomics model can evaluate muscle invasive status in bladder cancer. • The radiomics model shows good diagnostic performance to differentiate muscle-invasive bladder cancer from non-muscle-invasive bladder cancer. • This preoperative CT-based prediction method might complement MR evaluation of bladder cancer and supplement biopsy.