Exploiting hosts and vectors: viral strategies for facilitating transmission.

Viruses have developed various strategies to ensure their survival and transmission. One intriguing strategy involves manipulating the behavior of infected arthropod vectors and hosts. Through intricate interactions, viruses can modify vector behavior, aiding in crossing barriers and improving transmission to new hosts. This manipulation may include altering vector feeding preferences, thus promoting virus transmission to susceptible individuals. In addition, viruses employ diverse dissemination methods, including cell-to-cell and intercellular transmission via extracellular vesicles. These strategies allow viruses to establish themselves in favorable environments, optimize replication, and increase the likelihood of spreading to other individuals. Understanding these complex viral strategies offers valuable insights into their biology, transmission dynamics, and potential interventions for controlling infections. Unraveling interactions between viruses, hosts, and vectors enables the development of targeted approaches to effectively mitigate viral diseases and prevent transmission.

Genome sequences and population genomics reveal climatic adaptation and genomic divergence between two closely related sweetgum species.

Understanding the genetic basis of population divergence and adaptation is an important goal in population genetics and evolutionary biology. However, the relative roles of demographic history, gene flow, and/or selective regime in driving genomic divergence, climatic adaptation, and speciation in non-model tree species are not yet fully understood. To address this issue, we generated whole-genome resequencing data of Liquidambar formosana and L. acalycina, which are broadly sympatric but altitudinally segregated in the Tertiary relict forests of subtropical China. We integrated genomic and environmental data to investigate the demographic history, genomic divergence, and climatic adaptation of these two sister species. We inferred a scenario of allopatric species divergence during the late Miocene, followed by secondary contact during the Holocene. We identified multiple genomic islands of elevated divergence that mainly evolved through divergence hitchhiking and recombination rate variation, likely fostered by long-term refugial isolation and recent differential introgression in low-recombination genomic regions. We also found some candidate genes with divergent selection signatures potentially involved in climatic adaptation and reproductive isolation. Our results contribute to a better understanding of how late Tertiary/Quaternary climatic change influenced speciation, genomic divergence, climatic adaptation, and introgressive hybridization in East Asia's Tertiary relict flora. In addition, they should facilitate future evolutionary, conservation genomics, and molecular breeding studies in Liquidambar, a genus of important medicinal and ornamental values.

Association between left atrial myopathy and sarcomere mutation in patients with hypertrophic cardiomyopathy: insights into left atrial strain by MRI feature tracking.

OBJECTIVES: Left atrial (LA) myopathy, characterized by LA enlargement and mechanical dysfunction, is associated with worse prognosis in hypertrophic cardiomyopathy (HCM) while the impact of sarcomere mutation on LA myopathy remains unclear. We aimed to assess the association between LA myopathy and sarcomere mutation and to explore the incremental utility of LA strain in mutation prediction. METHODS: A total of 105 consecutive HCM patients (mean age 47.8 ± 11.9 years, 71% male) who underwent HCM-related gene screening and cardiac MRI were retrospectively enrolled. LA volume, ejection fraction and strain indices in reservoir, conduit, and booster-pump phases were investigated respectively. RESULTS: Fifty mutation-positive patients showed higher LA maximal volume index (59.4 ± 28.2 vs 43.8 ± 18.1 mL/m2, p = 0.001), lower reservoir (21.3 ± 7.9 vs 26.2 ± 6.6%, p < 0.001), and booster-pump strain (12.1 ± 5.4 vs 17.1 ± 5.0%, p < 0.001) but similar conduit strain (9.2 ± 4.5 vs 9.1 ± 4.5%, p = 0.909) compared with mutation-negative patients. In multivariate logistic regression, LA booster-pump strain was associated with sarcomere mutation (odds ratio = 0.86, 95% confidence interval: 0.77-0.96, p = 0.010) independent of maximal wall thickness, late gadolinium enhancement, and LA volume. Furthermore, LA booster-pump strain showed incremental value for mutation prediction added to Mayo II score (AUC 0.798 vs 0.709, p = 0.024). CONCLUSIONS: In HCM, mutation-positive patients suffered worse LA enlargement and worse reservoir and booster-pump functions. LA booster-pump strain was a strong factor for sarcomere mutation prediction added to Mayo II score. CLINICAL RELEVANCE STATEMENT: The independent association between sarcomere mutation and left atrial mechanical dysfunction provide new insights into the pathogenesis of atrial myopathy and is helpful to understand the adverse prognosis regarding atrial fibrillation and stroke in mutation-positive patients. KEY POINTS: • In patients with hypertrophic cardiomyopathy, left atrial (LA) reservoir and booster-pump function, but not conduit function, were significantly impaired in mutation-positive patients compared with mutation-negative patients. • LA booster-pump strain measured by MRI-derived feature tracking is feasible to predict sarcomere mutation with high incremental value added to Mayo II score.

Assessment of late gadolinium enhancement in hypertrophic cardiomyopathy improves risk stratification based on current guidelines.

BACKGROUND AND AIMS: Identifying patients with hypertrophic cardiomyopathy (HCM) who are candidates for implantable cardioverter defibrillator (ICD) implantation in primary prevention for sudden cardiac death (SCD) is crucial. The aim of this study was to externally validate the 2022 European Society of Cardiology (ESC) model and other guideline-based ICD class of recommendation (ICD-COR) models and explore the utility of late gadolinium enhancement (LGE) in further risk stratification. METHODS: Seven hundred and seventy-four consecutive patients who underwent cardiac magnetic resonance imaging were retrospectively enrolled. RESULTS: Forty-six (5.9%) patients reached the SCD-related endpoint during 7.4 ± 2.5 years of follow-up. Patients suffering from SCD had higher ESC Risk-SCD score (4.3 ± 2.4% vs. 2.8 ± 2.1%, P < .001) and LGE extent (13.7 ± 9.4% vs. 4.9 ± 6.6%, P < .001). Compared with the 2014 ESC model, the 2022 ESC model showed increased area under the curve (.76 vs. .63), sensitivity (76.1% vs. 43.5%), positive predictive value (16.8% vs. 13.6%), and negative predictive value (98.1% vs. 95.9%). The C-statistics for SCD prediction of 2011 American College of Cardiology (ACC)/American Heart Association (AHA), 2014 ESC, 2020 AHA/ACC, and 2022 ESC models were .68, .64, .76 and .78, respectively. Furthermore, in patients without extensive LGE, LGE ≥5% was responsible for seven-fold SCD risk after multivariable adjustment. Whether in ICD-COR II or ICD-COR III, patients with LGE ≥5% and <15% showed significantly worse prognosis than those with LGE <5% (all P < .001). CONCLUSIONS: The 2022 ESC model performed better than the 2014 ESC model with especially improved sensitivity. LGE enabled further risk stratification based on current guidelines.

Short-Term and Imminent Rainfall Prediction Model Based on ConvLSTM and SmaAT-UNet.

Short-term precipitation forecasting methods are mainly divided into statistical forecasting, numerical model-based forecasting, and radar image extrapolation techniques. The two methods based on statistical prediction and numerical model have the disadvantages of being unstable and generating large errors. Therefore, this study proposes the use of deep learning for radar image extrapolation for precipitation forecasting, in particular by developing algorithms for ConvLSTM and SmaAT-UNet. The ConvLSTM model is a fusion of a CNN (Convolutional Neural Network) and LSTM (Long Short-Term Memory network), which solves the challenge of processing spatial sequence data, which is a task that traditional LSTM models cannot accomplish. At the same time, SmaAT-UNet enhances the traditional UNet structure by incorporating the CBAM (Convolutional Block Attention Module) attention mechanism and replacing the standard convolutional layer with depthwise separable convolution. This innovative approach aims to improve the efficiency and accuracy of short-term precipitation forecasting by improving feature extraction and data processing techniques. Evaluation and analysis of experimental data show that both models exhibit good predictive ability, with the SmaAT-UNet model outperforming ConvLSTM in terms of accuracy. The results show that the performance indicators of precipitation prediction, especially detection probability (POD) and the Critical Success index (CSI), show a downward trend with the extension of the prediction time. This trend highlights the inherent challenges of maintaining predictive accuracy over longer periods of time and highlights the superior performance and resilience of the SmaAT-UNet model under these conditions. Compared with the statistical forecasting method and numerical model forecasting method, its accuracy in short-term rainfall forecasting is improved.

Variability of BMP-2 content in DBM products derived from different long bone.

Demineralized bone matrix (DBM) has been regarded as an ideal bone substitute as a native carrier of bone morphogenetic proteins (BMPs) and other growth factors. However, the osteoinductive properties diverse in different DBM products. We speculate that the harvest origin further contributing to variability of BMPs contents in DBM products besides the process technology. In the study, the cortical bone of femur, tibia, humerus, and ulna from a signal donor were prepared and followed demineralizd into DBM products. Proteins in bone martix were extracted using guanidine-HCl and collagenase, respectively, and BMP-2 content was detected by sandwich enzyme-linked immunosorbent assay (ELISA). Variability of BMP-2 content was found in 4 different DBM products. By guanidine-HCl extraction, the average concentration in DBMs harvested from ulna, humerus, tibia, and femur were 0.613 ± 0.053, 0.848 ± 0.051, 3.293 ± 0.268, and 21.763 ± 0.344, respectively (p < 0.05), while using collagenase, the levels were 0.089 ± 0.004, 0.097 ± 0.004, 0.330 ± 0.012, and 1.562 ± 0.008, respectively (p < 0.05). In general, the content of BMP-2 in long bones of Lower limb was higher than that in long bones of upper limb, and GuHCl had remarkably superior extracted efficiency for BMP-2 compared to collagenase. The results suggest that the origin of cortical bones harvested to fabricate DBM products contribute to the variability of native BMP-2 content, while the protein extracted method only changes the measured values of BMP-2.

Dysregulated SYVN1 promotes CAV1 protein ubiquitination and accentuates ischemic stroke.

BACKGROUND: Stroke is a major cause of death and severe disability, and there remains a substantial need for the development of therapeutic agents for neuroprotection in acute ischemic stroke (IS) to protect the brain against damage before and during recanalization. Caveolin-1 (CAV1), an integrated protein that is located at the caveolar membrane, has been reported to exert neuroprotective effects during IS. Nevertheless, the mechanism remains largely unknown. Here, we explored the upstream modifiers of CAV1 in IS. METHODS: E3 ubiquitin ligases of CAV1 that are differentially expressed in IS were screened using multiple databases. The transcription factor responsible for the dysregulation of E3 ubiquitin-protein ligase synoviolin (SYVN1) in IS was predicted and verified. Genetic manipulations by lentiviral vectors were applied to investigate the effects of double-strand-break repair protein rad21 homolog (RAD21), SYVN1, and CAV1 in a middle cerebral artery occlusion (MCAO) mouse model and mouse HT22 hippocampal neurons induced by oxygen-glucose deprivation (OGD). RESULTS: SYVN1 was highly expressed in mice with MCAO, and knockdown of SYVN1 alleviated IS injury in mice, as evidenced by limited infarction volume, the lower water content in the brain, and repressed apoptosis and inflammatory response. RAD21 inhibited the transcription of SYVN1, thereby reducing the ubiquitination modification of CAV1. Overexpression of RAD21 elicited a neuroprotective role as well in mice with MCAO and HT22 induced with OGD, which was overturned by SYVN1. CONCLUSION: Transcriptional repression of SYVN1 by RAD21 alleviates IS in mice by reducing ubiquitination modification of CAV1.

[Astragali Radix-Curcumae Rhizoma inhibits colon cancer progression and enhances 5-FU efficacy by regulating hypoxia-inducible factors and tumor stem cells].

The animal and cell models were used in this study to investigate the mechanism of Astragali Radix-Curcumae Rhizoma(HQEZ) in inhibiting colon cancer progression and enhancing the efficacy of 5-fluorouracil(5-FU) by regulating hypoxia-inducible factors and tumor stem cells. The animal model was established by subcutaneous transplantation of colon cancer HCT116 cells in nude mice, and 24 successfully modeled mice were randomized into model, 5-FU, HQEZ, and 5-FU+HQEZ groups. The tumor volume was measured every two days. Western blot was employed to measure the protein levels of epidermal growth factor receptor(EGFR), dihydropyrimidine dehydrogenase(DPYD), and thymidylate synthase(TYMS), the key targets of the hypoxic core region, as well as the hypoxia-inducible factors HIF-1α and HIF-2α and the cancer stem cell surface marker CD133 and SRY-box transcription factor 2(SOX2). The results of animal experiments showed that HQEZ slowed down the tumor growth and significantly increased the tumor inhibition rate of 5-FU. Compared with the model group, HQEZ significantly down-regulated the protein levels of EGFR and DPYD, and 5-FU+HQEZ significantly down-regulated the protein levels of EGFR and TYMS in tumors. Compared with the model group, HQEZ significantly down-regulated the protein levels of HIF-1α, HIF-2α, SOX2, and CD133 in the hypoxic core region. Compared with the 5-FU group, 5-FU+HQEZ lowered the protein levels of HIF-1α, HIF-2α, and SOX2. The cell experiments showed that the protein le-vels of HIF-1α and HIF-2α in HCT116 cells elevated significantly after low oxygen treatment. Compared with 5-FU(1.38 µmol·L~(-1)) alone, HQEZ(40 mg·mL~(-1)) and 5-FU+HQEZ significantly down-regulated the protein levels of HIF-1α, HIF-2α, and TYMS. In conclusion, HQEZ can inhibit the expression of hypoxia-responsive molecules in colon cancer cells and reduce the properties of cancer stem cells, thereby enhancing the therapeutic effect of 5-FU on colon cancer.

Cardiac MRI Risk Stratification for Dilated Cardiomyopathy with Left Ventricular Ejection Fraction of 35% or Higher.

Background Studies over the past 15 years have demonstrated that a considerable number of patients with dilated cardiomyopathy (DCM) who died from sudden cardiac death (SCD) had a left ventricular (LV) ejection fraction (LVEF) of 35% or higher. Purpose To identify clinical and cardiac MRI risk factors for adverse events in patients with DCM and LVEF of 35% or higher. Materials and Methods In this retrospective study, consecutive patients with DCM and LVEF of 35% or higher who underwent cardiac MRI between January 2010 and December 2017 were included. The primary end point was a composite of SCD or aborted SCD. The secondary end point was a composite of all-cause mortality, heart transplant, or hospitalization for heart failure. The risk factors for the primary and secondary end points were identified with multivariable Cox analysis. Results A total of 466 patients with DCM and LVEF of 35% or higher (mean age, 44 years ± 14 [SD]; 358 men) were included. During a mean follow-up of 79 months ± 30 (SD) (range, 7-143 months), 40 patients reached the primary end point and 61 reached the secondary end point. In the adjusted analysis, age (hazard ratio [HR], 1.03 per year [95% CI: 1.00, 1.05]; P = .04), family history of SCD (HR, 3.4 [95% CI: 1.3, 8.8]; P = .01), New York Heart Association (NYHA) class III or IV (HR vs NYHA class I or II, 2.1 [95% CI: 1.1, 3.9]; P = .02), and myocardial scar at late gadolinium enhancement (LGE) MRI greater than or equal to 7.1% of the LV mass (HR, 4.4 [95% CI: 2.4, 8.3]; P < .001) were associated with SCD or aborted SCD. For the composite secondary end point, LGE greater than or equal to 7.1% of the LV mass (HR vs LGE <7.1%, 2.0 [95% CI: 1.2, 3.4]; P = .01), left atrial maximum volume index, and reduced global longitudinal strain were independent predictors. Conclusion For patients with dilated cardiomyopathy and left ventricular (LV) ejection fraction of 35% or higher, cardiac MRI-defined myocardial scar greater than or equal to 7.1% of the LV mass was associated with sudden cardiac death (SCD) or aborted SCD. © RSNA, 2022 Online supplemental material is available for this article.

Risk Stratification and Outcomes in Patients With Pulmonary Hypertension: Insights into Right Ventricular Strain by MRI Feature tracking.

BACKGROUND: Despite a recommended multidimensional approach for pulmonary hypertension (PH) risk stratification and guidance of treatment decisions, this may not always be achievable in patients with advanced disease. One issue is the lack of an imaging modality to assess right ventricular (RV) structure and function abnormalities. PURPOSE: To explore the risk stratification and prognostic value of cardiac MR feature tracking (MR-FT)-derived RV strain. STUDY TYPE: Retrospective. POPULATION: A total of 80 patients with idiopathic pulmonary artery hypertension (N = 52) or chronic thromboembolic PH (N = 28). FIELD STRENGTH: A 1.5 T or 3.0 T, balanced steady-state free precession sequence. ASSESSMENT: All patients underwent laboratory testing, right heart catheterization, and MR imaging (and in 37 cases, a cardiopulmonary exercise test was also performed) within a 1-month period. Cardiac functional parameters and both global longitudinal strain (GLS) and global circumferential strain (GCS) were analyzed. Patients were stratified into low, intermediate, and high-risk groups by guideline suggested stratified values of risk factors. The combined endpoint was death or hospitalization for congestive heart failure assessed during follow-up since the date of MR examination. STATISTICAL TESTS: Kolmogorov-Smirnov's test, independent-sample t-tests, Wilcoxon's rank-sum tests, one-way analysis of variance, χ2 tests or Fisher's exact test, receiver operating characteristic analysis, Kaplan-Meier survival analysis, and Cox regression analysis. A P value < 0.05 was considered statistically significant. RESULTS: The median follow-up duration was 3.4 years. Thirty-five patients presented with combined endpoint including 10 cardiac deaths. RV structural and deformation impairments were significantly associated with combined endpoint (ejection fraction: 31.3% ± 13.2% vs. 38.0% ± 14.8%, hazard ratio [HR: 0.974; GLS: -14.5 [-18.6, -10.9] % vs. -20.4 [-26.0, -13.2] %, HR: 1.071; GCS: -9.8 [-14.5, -7.3] % vs. -12.3 [-19.9, -8.4] %, HR: 1.059). There were significant differences in RVGLS among low, intermediate, and high-risk groups (-19.3% ± 7.2% vs. -17.3% ± 9.4% vs. -11.5% ± 4.4% by cardiac functional class, -21.8% ± 7.3% vs. -19.4% ± 8.2% vs. -12.7 ± 5.3% by NT-proBNP, -19.7% ± 7.7 vs. -15.8% ± 6.5% vs. -12.6% ± 8.2% by cardiac index). DATA CONCLUSION: RV deformation may aid risk stratification in patients with PH, providing crucial information for RV remodeling, pulmonary hemodynamic condition and exercise capacity. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Degradation of HIF-1α induced by curcumol blocks glutaminolysis and inhibits epithelial-mesenchymal transition and invasion in colorectal cancer cells.

Colorectal cancer (CRC) has high morbidity and mortality. Epithelial-mesenchymal transition (EMT) is associated with CRC progression and metastasis. Glutaminolysis is essential for malignancy of cancer cells. Here, we examined the effects of curcumol on CRC EMT. We observed that curcumol suppressed invasion and migration in human CRC cells associated with upregulation of epithelial markers E-cadherin and Zonula occludens 1 and downregulation of mesenchymal markers N-cadherin and Vimentin as well as EMT-related transcription factors Snail and Twist. Curcumol increased intracellular levels of glutamine but decreased intracellular levels of glutamate, α-ketoglutarate, ATP, glutathione, and tricarboxylic acid cycle metabolites, suggesting interruption of glutaminolysis. Next, curcumol repressed glutaminase 1 (Gls1) mRNA and protein expression, and overexpression of Gls1 promoted EMT and abolished curcumol effects on CRC cell EMT. Molecular examinations showed that curcumol stimulated protein degradation of hypoxia-inducible factor-1α (HIF-1α) and prevented its nuclear accumulation in CRC cells. HIF-1α agonist deferoxamine (DFO) promoted HIF-1α binding to Gls1 promoter and increased Gls1 expression but abolished curcumol's inhibitory effects on Gls1 expression. DFO also enhanced EMT and invasion and migration in CRC cells and eliminated curcumol effects. Furthermore, mouse CRC models were established with in vivo overexpression of HIF-1α and Gls1. Curcumol effectively inhibited CRC growth, metastasis, and EMT in mice, which was abrogated by overexpression of HIF-1α or Gls1. Altogether, stimulation of HIF-1α degradation was required for curcumol to disrupt EMT and repress invasion and migration in CRC cells through inhibiting Gls1-mediated glutaminolysis. Curcumol could be a promising candidate for intervention of CRC metastasis. • Curcumol inhibits EMT and blocks glutaminolysis in CRC cells. • Inhibition of Gls1 is required for curcumol blockade of glutaminolysis and EMT. • Curcumol induces HIF-1α degradation leading to inhibition of Gls1 and blockade of glutaminolysis and EMT. • Curcumol suppresses CRC growth and metastasis via inhibiting HIF-1α, glutaminolysis and EMT in mice.

Clinical outcomes of conventional HDR intracavitary brachytherapy combined with complementary applicator-guided intensity modulated radiotherapy boost in patients with bulky cervical tumour.

OBJECTIVE: To investigate the clinical outcomes and toxicity in patients with locally advanced cervical cancer treated with supplementary applicator guided-intensity modulated radiation therapy (IMRT) based on conventional intracavitary brachytherapy (IC/IMRT). DESIGN: A retrospective cohort study. SETTING: Sichuan Cancer Hospital & Institute, Sichuan Cancer Centre, China. POPULATION: Large high-risk clinical target volume (HR-CTV) volume (>40 ml) at the time of brachytherapy cervical cancer patients were recruited. METHODS: This study is a retrospective analysis of 76 patients with locally advanced cervical cancer (FIGO IIB-IVA) treated with concurrent chemoradiotherapy followed by IC/IMRT between June 2010 and October 2016. External radiotherapy (45 Gy in 25 fractions) was adminstered with cisplatin chemotherapy treatment before IC/IMRT. The IMRT plan was optimised using the ICBT plan base dose plan by an inverse dose optimisation tool which allows the use of DVH constraints on the total dose of ICBT. A seven-field gantry angle IMRT plan was devised to avoid hotspots when optimising the boost plan. The prescription dose for HR-CTV and IR-CTV were 6 and 5 Gy per fraction for five fractions, respectively. RESULTS: Mean HR-CTV was 65.8 ± 23.6 ml at the time of brachytherapy. D90 for HR-CTV and IR-CTV were 88.7 ± 3.6 Gy and 78.1 ± 2.5 Gy. D2cc for bladder, rectum, sigmoid and small intestine were 71.8 ± 3.8, 64.6 ± 4.9, 63.9 ± 5.3 and 56.7 ± 8.7 Gy, respectively. Median follow-up was 85 months (47.9-124.2 months). Five-year local recurrence-free survival rate, metastasis recurrence-free survival rate, disease-free survival rate and cancer-special survival rate were 87.6, 82.4, 70.9 and 76.3%, respectively. The grade 1 + 2 gastrointestinal and urinary late toxicities were 15.8 and 21.1%, and grade 3 late toxicities were 3.9 and 5.2%, respectively. Neither acute nor late grade 4 gastrointestinal or urinary toxicities were seen. CONCLUSIONS: The combination of ICBT with an applicator-guided supplementary IMRT boost achieved excellent local control and overall survival with low toxicity for bulky residual cervical tumour.

Mining novel genomic regions and candidate genes of heading and flowering dates in bread wheat by SNP- and haplotype-based GWAS.

Bread wheat (Triticum aestivum L.) is a global staple crop vital for human nutrition. Heading date (HD) and flowering date (FD) are critical traits influencing wheat growth, development, and adaptability to diverse environmental conditions. A comprehensive study were conducted involving 190 bread wheat accessions to unravel the genetic basis of HD and FD using high-throughput genotyping and multi-environment field trials. Seven independent quantitative trait loci (QTLs) were identified to be significantly associated with HD and FD using two GWAS methods, which explained a proportion of phenotypic variance ranging from 1.43% to 9.58%. Notably, QTLs overlapping with known vernalization genes Vrn-D1 were found, validating their roles in regulating flowering time. Moreover, novel QTLs on chromosome 2A, 5B, 5D, and 7B associated with HD and FD were identified. The effects of these QTLs on HD and FD were confirmed in an additional set of 74 accessions across different environments. An increase in the frequency of alleles associated with early flowering in cultivars released in recent years was also observed, suggesting the influence of molecular breeding strategies. In summary, this study enhances the understanding of the genetic regulation of HD and FD in bread wheat, offering valuable insights into crop improvement for enhanced adaptability and productivity under changing climatic conditions. These identified QTLs and associated markers have the potential to improve wheat breeding programs in developing climate-resilient varieties to ensure food security. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-023-01422-z.

Hotair promotes the migration and proliferation in ovarian cancer by miR-222-3p/CDK19 axis.

Previous studies in our laboratory have reported that miR-222-3p was a tumor-suppressive miRNA in OC. This study aims to further understand the regulatory role of miR-222-3p in OC and provide a new mechanism for its prevention and treatment. We first found that miR-222-3p inhibited the migration and proliferation of OC cells. Then, we observed CDK19 was highly expressed in OC and inversely correlated with miR-222-3p. Besides, we observed that miR-222-3p directly binds to the 3'-UTR of CDK19 and inhibits CDK19 translation, thus inhibiting OC cell migration and proliferation in vitro and repressed tumor growth in vivo. We also observed the inhibitory effect of Hotair on miR-222-3p in OC. In addition, Hotair could promote the proliferation and migration of OC cells in vitro and facilitate the growth and metastasis of tumors in vivo. Moreover, Hotair was positively correlated with CDK19 expression. These results suggest Hotair indirectly up-regulates CDK19 through sponging miR-222-3p, which enhances the malignant behavior of OC. This provides a further understanding of the mechanism of the occurrence and development of OC.

Posterolateral approach for posterior malleolus fixation in ankle fractures: functional and radiological outcome based on Bartonicek classification.

INTRODUCTION: Posterolateral approach has been advocated for the treatment of ankle fractures involving the posterior malleolus and satisfactory results were demonstrated in several studies. The Bartonicek classification based on 3-dimensional CT scanning was commonly used for treatment recommendation of posterior malleolar fracture (PMF). The aim of this retrospective study was to evaluate the clinical effect of the posterolateral approach for the treatment of PMF and present outcomes of patients with different types of Bartonicek classification. METHOD: We retrospectively reviewed the clinical outcomes of 72 patients with ankle fractures involving posterior malleolus (PM) from January 2016 to December 2018. Posterior malleolus fractures (PMFs) were all directly reduced and fixed by a posterolateral approach using lag screws and/or buttress plates. AOFAS score and VAS pain score were used as the primary functional outcome measures. The radiographic evaluation included the quality of the reduction and Kellgren-Lawrence (KL) osteoarthritis classification. According to the CT-based Bartonicek classification, all patients were classified into three groups: 42 type II, 18 type III and 12 type IV. Bartonicek type II patients were further divided into subtype IIa 19 cases, subtype IIb 16 cases and subtype IIc 7 cases. The radiological and functional outcomes were analyzed among different types and subtypes of Bartonicek classification. RESULTS: Sixty-eight patients (94.5%) achieved good or excellent reduction of PMF after surgery. The mean AOFAS score was 81.35 ± 6.15 at 6 months and 90.56 ± 4.98 at the final follow-up, respectively. The VAS score was 6.62 ± 1.03 one week after surgery, and 1.20 ± 0.92 at the final follow-up. Radiological evaluation at the final follow-up showed that primary bone union was achieved in all patients and 65 patients (88.9%) got no (KL grade 0) or just doubtable (KL grade 1) post-traumatic osteoarthritis. AOFAS scores decreased significantly with the severity of Bartonicek classification at 6 month (p < 0.001) and final follow-up (p < 0.05), while there was no statistical difference of VAS pain score among different types of Bartonicek classification. Reduction quality and the presence of osteoarthritis was not correlated to Bartonicek classification either. Besides, AOFAS scores at the final follow-up were statistically different among three subtypes of Bartonicek type II fractures (p < 0.05), and Bartonicek subtype IIa fractures had the highest AOFAS scores as 93 ± 4.99. Presence and severity of osteoarthritis was lower in patients with subtype IIa PMF compared to other subtype groups, this finding was statistically significant (p < 0.05). CONCLUSION: The posterolateral approach could achieve good clinical outcomes in the treatment of posterior malleolus fracture. Patients with a Bartonicek type II fracture had a better functional outcome measured by the AOFAS score compared to other types. Bartonicek type IIa fractures got a higher AOFAS score and a lower incidence of osteoarthritis at the final follow-up than the other two subtypes. Classification of PMFs according to the Bartonicek classification was reliable.

Comprehensive network analysis of dysregulated genes revealed MNX1-AS1/hsa-miR-4697-3p/HOXB13 axis in ovarian cancer chemotherapy response.

Poor chemotherapy response is the main obstacle of ovarian cancer (OC) treatment. Platinum-refractory and -resistant patients are associated with a worse outcome than platinum-sensitive and partially sensitive patients, but the comprehensive similarities and differences among them are not yet clear. In this study, we analyzed the data of patients with different chemotherapy response in The Cancer Genome Atlas. We found a minority of altered genes were overlapped in refractory and resistant groups, as did the enriched pathways and Gene Ontology terms. We noticed that the neural signaling and drug metabolism enzymes were more significantly enriched and the protein-protein interaction supported these results. The transcription analysis highlighted PDX1 as the common and central transcription factor in both refractory and resistant groups. The competing endogenous RNA (ceRNA) network shared no common ceRNA pairs, indicating a major difference in noncoding RNA post-transcriptional regulation. In the end, we validated the expression, regulation, binding, and effect on chemotherapy response for selected MNX1-AS1/hsa-miR-4697-3p/HOXB13 in OC cell lines. Our study offered a novel and comprehensive insight into chemotherapy response, and potential targets for improving chemotherapy response in OC.

HDAC5, negatively regulated by miR-148a-3p, promotes colon cancer cell migration.

Histone deacetylases (HDACs) are involved in many processes including tumor cell growth and proliferation and regulation of gene expression. To clarify the role of class IIa HDACs in the metastasis of colon adenocarcinoma, we used the class IIa HDAC inhibitor TMP269 and found that it effectively inhibited the migration ability of colon adenocarcinoma cells. Next, we silenced the member of class IIa HDACs and confirmed that the migratory ability of colon adenocarcinoma cells was significantly inhibited by silencing HDAC5 or HDAC7. HDAC5 plays a variety of roles in human cancers. Here, we examined the role of HDAC5 in colon adenocarcinoma. The results indicated that HDAC5 was highly expressed in tumor tissues and negatively correlated with the expression of miR-148a-3p. Moreover, the expression of HDAC5 was correlated with tumor progression. HDAC5 markedly increased the invasion and migration of cancer cells in vitro, an effect that could be inhibited by overexpression of miR-148a-3p. Following an intraperitoneal injection of colon adenocarcinoma cells in athymic nude mice, HDAC5 promoted tumor implant. Together, these findings showed that HDAC5 overexpression in colon adenocarcinoma is consistent with tumor progression and tumor cell migration and the impact of HDAC5 overexpression is reduced by miR-148a-3p.

Fine mapping and candidate gene analysis of dwarf gene Rht14 in durum wheat (Triticum durum).

Semi-dwarf and dwarf genes were widely used in wheat breeding for improving lodging resistant and increasing yield. Rht14 dwarf gene was identified and deployed in durum wheat, where it showed advantage on important agronomic potential. The reciprocal F2 populations derived of Castelporziano (CP) and Langdon (L) were used for mapping of Rht14, which was located in intervals 4.8 cM and 10.38 cM by KASP (Kompetitive Allele Specific PCR) markers, respectively, where corresponding to 312-454 Mbp on chromosome 6A, and finally, it was mapped to the genomic region of 402 ~ 408 Mbp in Durum Wheat Svevo RefSeq Rel. 1.0 (i.e., 405 ~ 411 Mbp in Chinese Spring RefSeq v.1.0) using recombinants by indel markers. The expression of TdGA2oxA9 was higher in dwarf line than tall lines and the bioactive GA1 was lower. No sequence difference was observed in the promoter and coding region of GA2oxA9 between the dwarf and tall parent, while obvious DNA methylation difference was found in its promoter. Two methylation-related genes with high confidence located in the candidate region and expressed differently between the tall and dwarf ones. This study proposed that Rht14 might regulate the expression of GA2oxA9 by DNA methylation in its promoter, which provided a way to clone Rht14 and to further investigate the mechanism behind.

Upregulated lncARAT in Schwann cells promotes axonal regeneration by recruiting and activating proregenerative macrophages.

BACKGROUND: Axonal regeneration following peripheral nerve injury (PNI) depends on the complex interaction between Schwann cells (SCs) and macrophages, but the mechanisms underlying macrophage recruitment and activation in axonal regeneration remain unclear. METHODS: RNA sequencing (RNA-seq) was conducted to identify differentially expressed long noncoding RNAs (DElncRNAs) between crushed sciatic nerves and intact contralateral nerves. The putative role of lncRNAs in nerve regeneration was analyzed in vitro and in vivo. RESULTS: An lncRNA, called axon regeneration-associated transcript (lncARAT), was upregulated in SCs and SC-derived exosomes (SCs-Exo) after sciatic nerve injury. LncARAT contributed to axonal regeneration and improved motor function recovery. Mechanistically, lncARAT epigenetically activated C-C motif ligand 2 (CCL2) expression by recruiting KMT2A to CCL2 promoter, resulting in increased histone 3 lysine 4 trimethylation (H3K4me3) and CCL2 transcription in SCs. CCL2 facilitated the infiltration of macrophages into the injured nerves. Meanwhile, lncARAT-enriched exosomes were released from SCs and incorporated into macrophages. LncARAT functioned as an endogenous sponge to adsorb miRNA-329-5p in macrophages, resulting in increased suppressor of cytokine signaling (SOCS) 2 expression, which induced a proregenerative function of macrophages through a signal transducer and activator of transcription (STAT) 1/6-dependent pathway. CONCLUSIONS: LncARAT may represent a promising therapeutic avenue for peripheral nerve repair.

The fine mapping of dwarf gene Rht5 in bread wheat and its effects on plant height and main agronomic traits.

MAIN CONCLUSION: Rht5 was narrowed to an approximately 1 Mb interval and had pleiotropic effects on plant height, spike length and grain size. TraesCS3B02G025600 was predicted as the possible candidate gene. Plant height is an important component related to plant architecture, lodging resistance, and yield performance. The utilization of dwarf genes has made great contributions to wheat breeding and production. In this study, two F2 populations derived from the crosses of Jinmai47 and Ningchun45 with Marfed M were employed to identify the genetic region of reduce plant height 5 (Rht5), and their derived lines were used to evaluate its effects on plant height and main agronomic traits. Rht5 was fine-mapped between markers Kasp-25 and Kasp-23, in approximately 1 Mb region on chromosome 3BS, which harbored 17 high-confidence annotated genes based on the reference genome of Chinese Spring (IWGSC RefSeq v1.1). TraesCS3B02G025600 were predicted as the possible candidate gene based on its differential expression and sequence variation between dwarf and tall lines and parents. The results of phenotypic evaluation showed that Rht5 had pleiotropic effects on plant height, spike length, culm diameter, grain size and grain yield. The plant height of Rht5 dwarf lines was reduced by an average of 32.67% (32.53 cm) and 27.84% (33.62 cm) in the Jinmai47 and Ningchun45 population, respectively. While Rht5 showed significant and negative pleiotropic effects on culm diameter, aboveground biomass, grain yield, spike length, spikelet number, grain number per spike, grain size, grain weight and filling degree of basal second internode. The culm lodging resistance index (CLRI) of dwarf lines was significantly higher than that of tall lines in the two population. In conclusion, these results lay a foundation for understanding the dwarfing mechanism of Rht5.