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Abstract Background Spinal cord motor neurons (MNs) from human iPS cells (iPSCs) have wide applications in disease modeling and therapeutic development for amyotrophic lateral sclerosis (ALS) and other MN-associated neurodegenerative diseases. We need highly efficient MN differentiation strategies for generating iPSC-derived disease models that closely recapitulate the genetic and phenotypic complexity of ALS. An important application of these models is to understand molecular mechanisms of action of FDA-approved ALS drugs that only show modest clinical efficacy. Novel mechanistic insights will help us design optimal therapeutic strategies together with predictive biomarkers to achieve better efficacy. Methods We induce efficient MN differentiation from iPSCs in 4 days using synthetic mRNAs coding two transcription factors (Ngn2 and Olig2) with phosphosite modification. These MNs after extensive characterization were applied in electrophysiological and neurotoxicity assays as well as transcriptomic analysis, to study the neuroprotective effect and molecular mechanisms of edaravone, an FDA-approved drug for ALS, for improving its clinical efficacy. Results We generate highly pure and functional mRNA-induced MNs (miMNs) from control and ALS iPSCs, as well as embryonic stem cells. Edaravone alleviates H2O2-induced neurotoxicity and electrophysiological dysfunction in miMNs, demonstrating its neuroprotective effect that was also found in the glutamate-induced miMN neurotoxicity model. Guided by the transcriptomic analysis, we show a previously unrecognized effect of edaravone to induce the GDNF receptor RET and the GDNF/RET neurotrophic signaling in vitro and in vivo, suggesting a clinically translatable strategy to activate this key neuroprotective signaling. Notably, edaravone can replace required neurotrophic factors (BDNF and GDNF) to support long-term miMN survival and maturation, further supporting the neurotrophic function of edaravone-activated signaling. Furthermore, we show that edaravone and GDNF combined treatment more effectively protects miMNs from H2O2-induced neurotoxicity than single treatment, suggesting a potential combination strategy for ALS treatment. Conclusions This study provides methodology to facilitate iPSC differentiation and disease modeling. Our discoveries will facilitate the development of optimal edaravone-based therapies for ALS and potentially other neurodegenerative diseases. Graphical abstract

The COVID-19 outbreak emerged in December 2019 and has rapidly become a global pandemic. A great deal of effort has been made to find effective drugs against this disease. Chloroquine (CQ) and hydroxychloroquine (HCQ) were widely adopted in treating COVID-19, but the results were contradictive. CQ/HCQ have been used to prevent and treat malaria and are efficacious anti-inflammatory agents in rheumatoid arthritis and systemic lupus erythematosus. These drugs have potential broad-spectrum antiviral properties, but the underlying mechanisms are speculative. In this review, we re-evaluated the treatment outcomes and current hypothesis for the working mechanisms of CQ/HCQ as COVID-19 therapy with a special focus on disruption of Ca2+ signaling. In so doing, we attempt to show how the different hypotheses for CQ/HCQ action on coronavirus may interact and reinforce each other. The potential toxicity is also noted due to its action on Ca2+ and hyperpolarization-activated cyclic nucleotide-gated channels in cardiac myocytes and neuronal cells. We propose that intracellular calcium homeostasis is an alternative mechanism for CQ/HCQ pharmacology, which should be considered when evaluating the risks and benefits of therapy in these patients and other perspective applications.

Purpose. Harmaline is one member of a class of tremorgenic harmala alkaloids that have been implicated in neuroprotective effects and neurodegenerative disorders. It has been reported to interact with several neurotransmitter receptors as well as ion exchangers and voltage-sensitive channels. One site of harmaline action in the brain is the inferior olive (IO). Either local or systemic harmaline injection has been reported to increase spiking rate and coherence in the inferior olive and this activation is thought to produce tremor and ataxia through inferior olivary neuron activation of target neurons in the cerebellum, but the cellular mechanism is not yet known. Methods. Here, we have performed whole cell voltage-clamp and current clamp recordings from olivary neurons in brain slices derived from newborn rats. Results. We found that both transient low-voltage activated (LVA) and sustained high voltage-activated (HVA) Ca2+ currents are significantly attenuated by 0.125 – 0.25 mM harmaline applied to the bath and that this attenuation is partially reversible. In current clamp recordings, spike-afterhyperpolarization complexes were evoked by brief positive current injections. Harmaline produced a small attenuation of spike amplitude, but large spike broadening associated with attenuation of the fast and medium afterhyperpolarization. Conclusion. Our data suggest that one mode of olivary neuron activation by harmaline involves attenuation of both HVA and LVA Ca2+ conductances and consequent attenuation of Ca2+-sensitive K+ conductances resulting in spike broadening and attenuation of the afterhyperpolarization. Both of HVA and LVA attenuation also suggests a role to regulate intracelluar Ca2+, thereby to protect neurons from apoptosis. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Super Typhoon Doksuri is a significant meteorological challenge for China this year due to its strong intensity and wide influence range, as well as significant and prolonged hazards. In this work, we studied Doksuri's main characteristics and assessed its forecast accuracy meticulously based on official forecasts, global models and regional models with lead times varying from 1 to 5 days. The results indicate that Typhoon Doksuri underwent rapid intensification and made landfall at 09:55 BJT on July 28 with a powerful intensity of 50 m s−1 confirmed by the real-time operational warnings issued by China Meteorological Administration (CMA). The typhoon also caused significant wind and rainfall impacts, with precipitation at several stations reaching historical extremes, ranking eighth in terms of total rainfall impact during the event. The evaluation of forecast accuracy for Doksuri suggests that Shanghai Multi-model Ensemble Method (SSTC) and Fengwu Model are the most effective for short-term track forecasts. Meanwhile, the forecasts from the European Centre for Medium-Range Weather Forecasts (ECMWF) and United Kingdom Meteorological Office (UKMO) are optimal for long-term predictions. It is worth noting that objective forecasts systematically underestimate the typhoon maximum intensity. The objective forecast is terribly poor when there is a sudden change in intensity. CMA-National Digital Forecast System (CMA-NDFS) provides a better reference value for typhoon accumulated rainfall forecasts, and regional models perform well in forecasting extreme rainfall. The analyses above assist forecasters in pinpointing challenges within typhoon predictions and gaining a comprehensive insight into the performance of each model. This improves the effective application of model products.

Abstract Transcription-blocking lesions (TBLs) stall elongating RNA polymerase II (Pol II), which then initiates transcription-coupled repair (TCR) to remove TBLs and allow transcription recovery. In the absence of TCR, eviction of lesion-stalled Pol II is required for alternative pathways to address the damage, but the mechanism is unclear. Using Protein-Associated DNA Damage Sequencing (PADD-seq), this study reveals that the p97-proteasome pathway can evict lesion-stalled Pol II independently of repair. Both TCR and repair-independent eviction require CSA and ubiquitination. However, p97 is dispensable for TCR and Pol II eviction in TCR-proficient cells, highlighting repair’s prioritization over repair-independent eviction. Moreover, ubiquitination of RPB1-K1268 is important for both pathways, with USP7’s deubiquitinase activity promoting TCR without abolishing repair-independent Pol II release. In summary, this study elucidates the fate of lesion-stalled Pol II, and may shed light on the molecular basis of genetic diseases caused by the defects of TCR genes.

High-k gate dielectrics have attracted a great deal of attention in the investigation of transistors due to their unique properties such as superior gate controllability. However, their integration into graphene field-effect transistors (GFETs) remains problematic and the physical mechanisms governing the performance of these devices are still not fully understood. In this study, the effects of post-annealing on GFETs utilizing the high-k HfLaO ternary oxide as the gate dielectric were comprehensively investigated. The HfLaO film was deposited on top of graphene by magnetron sputtering, and the device performance with various post-annealing temperatures was conducted. It was found that post-annealing temperature can effectively increase the dielectric constant through balancing the oxygen-vacancy defects and moisture absorption. Both the surface morphology of HfLaO and performance of GFETs were investigated, and the fabricated GFETs exhibit notable electrical performance enhancements. Specifically, GFETs with a 200 °C post-annealed HfLaO gate dielectric demonstrate the optimal device performance, featuring a minimal Dirac point voltage (VDirac) of 1.1 V and a minimal hysteresis (ΔVDirac) of 0.5 V. The extracted hole and electron mobilities are 4012 and 1366 cm2/V · s, respectively, nearly one order of magnitude higher than that of GFETs with as-deposited HfLaO. This work outperforms other existing GFETs utilizing high-k gate dielectric and chemical vapor deposition grown graphene in terms of both carrier mobility and on–off ratio. It is also noted that the excessive post-annealing temperature can negatively impact the GFET performance through introducing oxygen vacancies, increasing the surface roughness, lowering the breakdown voltage, and inducing recrystallization.

Uneven regional development has long been a focal issue for both academia and policymakers, with numerous studies over the past decades actively engaging in discussions on measuring regional development disparities. Generally, most existing studies measure the Human Development Index (HDI) using relatively simple indicators, with a focus on national and provincial scales. As a crucial component of regional development, counties can directly reflect the regional characteristics of socio-economic progress. This study employs a multi-dimensional approach to develop an improved Human Development Index (improved HDI) system, using machine learning techniques to establish the relationship between nighttime light (NTL) data and the improved HDI. Subsequently, NTL data are utilized to infer the spatial distribution characteristics of the improved HDI across China’s county-level regions. The improved HDI for county-level areas in the Ningxia Hui Autonomous Region was validated using a machine learning model, resulting in a Pearson correlation coefficient of 0.93. The adjusted R-squared value for the linear fit was 0.86, and the residuals were relatively balanced, ensuring the accuracy of the simulations. This study reveals that 1439 county-level units, representing 50% of all county-level units in China, have development levels at or above the medium level. At the provincial and national levels, the improved HDI shows significant clustering, characterized by a multi-center pattern with declining diffusion. The spatial distribution of the improved Human Development Index remains closely associated with the natural geographic background and socio-economic development levels of the county regions. Lower HDI values are predominantly found in the inland areas of central and western China, often in ecologically sensitive areas, inter-provincial border zones, and mountainous regions of mainland China, sometimes forming contiguous distribution patterns. This underscores the need for the government and society to focus more on these specific geographic development areas, promoting continuous improvements in health, education, and living standards to achieve coordinated regional development.

Abstract A novel recursive cascaded full‐resolution residual network (RCFRR‐Net) for abdominal four‐dimensional computed tomography (4D‐CT) image registration was proposed. The entire network was end‐to‐end and trained in the unsupervised approach, which meant that the deformation vector field, which presented the ground truth, was not needed during training. The network was designed by cascading three full‐resolution residual subnetworks with different architectures. The training loss consisted of the image similarity loss and the deformation vector field regularization loss, which were calculated based on the final warped image and the fixed image, allowing all cascades to be trained jointly and perform the progressive registration cooperatively. Extensive network testing was conducted using diverse datasets, including an internal 4D‐CT dataset, a public DIRLAB 4D‐CT dataset, and a 4D cone‐beam CT (4D‐CBCT) dataset. Compared with the iteration‐based demon method and two deep learning‐based methods (VoxelMorph and recursive cascaded network), the RCFRR‐Net achieved consistent and significant gains, which demonstrated that the proposed method had superior performance and generalization capability in medical image registration. The proposed RCFRR‐Net was a promising tool for various clinical applications.

China's economy has achieved remarkable success, while it has also paid a high environmental cost. Environmental pollution not only causes great economic losses, but also severely restricts the development of society. Both theory and practice demonstrate that financial development plays a significant role in environmental governance, but the internal mechanism of its impacts has remained to be explored. It is vital to investigate the influence mechanism of financial development on the environmental quality in order to accomplish sustainable economic development through finance and enhance environmental quality concurrently. This paper, using mediating model, spatial Durbin and spatial error model, constructs a theoretical framework financial development on environmental quality from two dimensions, i.e., Financial Interrelations Ratio (FIR) and Financial Efficiency (FE), based on panel data of 234 cities in China from 2010 to 2019. And the results are as follows: (1) the improvement of Financial Interrelations Ratio (FIR) and Financial Efficiency (FE) had not yet reached the level of environmental pollution improvement; (2) in terms of mechanism, the rise of the level of financial development promoted economic growth, but inhibited the optimization of industrial structure, which increased industrial pollution emissions and deteriorates environmental quality; (3) urban environment had significant spatial dependence; (4) the impact of financial development on environmental quality in eastern region has been transformed into an improvement effect, while it still shows a deteriorating effect in central and western regions. Some policy recommendations related to the use of financial development to improve environmental quality are proposed at last, which will help to promote ecological protection and high quality synergistic economic development in China.

By considering the uncertainties in the initial field, model physical processes, and lateral boundary conditions, the Shanghai Weather And Risk Model System-Ensemble Prediction System (SWARMS-EN) is constructed. According to the prediction results of typhoon Muifa (2022), the daily track error of SWARMS-EN within 5 days is 70.6 km, 142.2 km, 129.1 km, 174.5 km, and 203.5 km, respectively. When compared with the Typhoon Ensemble Data Assimilation and Prediction System (TEDAPS) and the Global Ensemble Forecast System (GEFS) of the National Centers for Environmental Prediction (NCEP) in homogeneous conditions, SWARMS-EN performs better than TEDAPS within 72 h and better than GEFS beyond 72 h in track forecasting. This indicates an improvement in forecasting accuracy. The ensemble spread within two days is less than the root mean square error (RMSE), according to an analysis of the relationship between ensemble RMSE and spread, which shows that SWARMS-EN has no apparent systematic bias overall. The system has improved the ensemble RMSE and spread, indicating that it can better represent the uncertainty of the forecast and produce more reliable forecasts. Additionally, SWARMS-EN provides the landfall forecast five days in advance. The ensemble-based analysis suggests that the large-scale circulation is the primary factor contributing to the forecast differences among members, and the strong steering flow provides an indication of the landfalling forecast. The analysis of the ensemble characteristics of the initial field indicates that the initial perturbation between the wind field and the temperature field in the dynamically unstable region (such as near a tropical cyclone) exhibits flow dependence, and the small perturbation shows continuity throughout the entire troposphere. The distribution of ensemble spread and disturbance energy exhibited a reasonable growth stage as the forecast lead time increased. Disturbance internal energy dominated the lower troposphere, while the upper troposphere was mainly characterized by disturbance kinetic energy. Disturbance kinetic energy played a leading role in the evolution process. This conclusion further confirms the importance of paying attention to the initial small perturbations near TC in order to optimize the initial perturbation.

Maintaining proper mechanical strength and tissue volume is important for bone growth at the site of a bone defect. In this study, potassium magnesium phosphate hexahydrate (KMgPO4·6H2O, MPC) was applied to gelma-methacrylate hydrogel (GelMA) to prepare GelMA/MPC composites (GMPCs). Among these, 5 GMPC showed the best performance in vivo and in vitro. These combinations significantly enhanced the mechanical strength of GelMA and regulated the degradation and absorption rate of MPC. Considerably better mechanical properties were noted in 5 GMPC compared with other concentrations. Better bioactivity and osteogenic ability were also found in 5 GMPC. Magnesium ions (Mg2+) are bioactive and proven to promote bone tissue regeneration, in which the enhancement efficiency is closely related to Mg2+ concentrations. These findings indicated that GMPCs that can release Mg2+ are effective in the treatment of bone defects and hold promise for future in vivo applications.

Triple negative breast cancer is distinguished by its high malignancy, aggressive invasion, rapid progression, easy recurrence, and distant metastases. Additionally, it has a poor prognosis, a high mortality, and is unresponsive to conventional endocrine and targeted therapy, making it a challenging problem for breast cancer treatment and a hotspot for scientific research. Recent research has revealed that certain miRNA can directly or indirectly affect the occurrence, progress and recurrence of TNBC. Their expression levels have a significant impact on TNBC diagnosis, treatment and prognosis. Some miRNAs can serve as biomarkers for TNBC diagnosis and prognosis. This article summarizes the progress of miRNA research in TNBC, discusses their roles in the occurrence, invasion, metastasis, prognosis, and chemotherapy of TNBC, and proposes a treatment strategy for TNBC by interfering with miRNA expression levels.

Bone defect repair poses significant challenges in orthopedics, thereby increasing the demand for bone substitutes. Magnesium phosphate cements (MPCs) are widely used for bone defect repair because of their excellent mechanical properties and biodegradability. However, high crystallinity and uncontrolled magnesium ion (Mg2+) release limit the surface bioactivity of MPCs in bone regeneration. Here, we fabricate chondroitin sulfate (CS) as a surface coating via the lyophilization method, namely CMPC. We find that the CS coating is uniformly distributed and improves the mechanical properties of MPC through anionic electrostatic adsorption, while mediating degradation-related controlled ion release of Mg2+. Using a combination of in vitro and in vivo analyses, we show that the CS coating maintained cytocompatibility while increasing the cell adhesion area of MC3T3-E1s. Furthermore, we display accelerated osteogenesis and angiogenesis of CMPC, which are related to appropriate ion concentration of Mg2+. Our findings reveal that the preparation of a lyophilized CS coating is an effective method to promote surface bioactivity and mediate Mg2+ concentration dependent osteogenesis and angiogenesis, which have great potential in bone regeneration.

Summary: Cellular circadian clocks direct a daily transcriptional program that supports homeostasis and resilience. Emerging evidence has demonstrated age-associated changes in circadian functions. To define age-dependent changes at the systems level, we profile the circadian transcriptome in the hypothalamus, lung, heart, kidney, skeletal muscle, and adrenal gland in three age groups. We find age-dependent and tissue-specific clock output changes. Aging reduces the number of rhythmically expressed genes (REGs), indicative of weakened circadian control. REGs are enriched for the hallmarks of aging, adding another dimension to our understanding of aging. Analyzing differential gene expression within a tissue at four different times of day identifies distinct clusters of differentially expressed genes (DEGs). Increased variability of gene expression across the day is a common feature of aged tissues. This analysis extends the landscape for understanding aging and highlights the impact of aging on circadian clock function and temporal changes in gene expression.

To explore the effect of corn peptide on enhancing exercise performance and preventing overtraining-induced myocardial injury, 40 male mice were divided into normal control, swimming training control, swimming training with low, medium, and high-dose corn peptide groups for 8-week interventions. After interventions, exhaustive swimming time and blood lactate were determined to evaluate exercise performance. Creatine kinase (CK) and CK-MB levels were determined by ELISA. The proteins associated with autophagy and apoptosis in myocardial tissue were evaluated by Western blot. Results indicated that corn peptide could effectively prolong exhaustive swimming time, and accelerate blood lactate elimination, suggesting its enhancing exercise performance and alleviating exercise fatigue. Meanwhile, it could also reduce serum CK and CK-MB levels, up-regulate Atg7 and Beclin1, increase LC3-II/LC3-I ratio, and down-regulate p62 and Bax. Therefore, corn peptide cooperated with regular swimming training can enhance exercise performance and execute overtraining-induced myocardial protection through activating autophagy and inhibiting apoptosis.

Circadian rhythms are maintained by a cell-autonomous, transcriptional–translational feedback loop known as the molecular clock. While previous research suggests a role of the molecular clock in regulating skeletal muscle structure and function, no mechanisms have connected the molecular clock to sarcomere filaments. Utilizing inducible, skeletal muscle specific, Bmal1 knockout (iMSBmal1-/-) mice, we showed that knocking out skeletal muscle clock function alters titin isoform expression using RNAseq, liquid chromatography–mass spectrometry, and sodium dodecyl sulfate-vertical agarose gel electrophoresis. This alteration in titin’s spring length resulted in sarcomere length heterogeneity. We demonstrate the direct link between altered titin splicing and sarcomere length in vitro using U7 snRNPs that truncate the region of titin altered in iMSBmal1-/- muscle. We identified a mechanism whereby the skeletal muscle clock regulates titin isoform expression through transcriptional regulation of Rbm20, a potent splicing regulator of titin. Lastly, we used an environmental model of circadian rhythm disruption and identified significant downregulation of Rbm20 expression. Our findings demonstrate the importance of the skeletal muscle circadian clock in maintaining titin isoform through regulation of RBM20 expression. Because circadian rhythm disruption is a feature of many chronic diseases, our results highlight a novel pathway that could be targeted to maintain skeletal muscle structure and function in a range of pathologies.

It is generally considered that protein supplementation and resistance exercise significantly increase muscle mass and muscle growth. As the hydrolysis products of proteins, peptides may play the crucial role on muscle growth. In this study, male rats were orally administrated 0.4 g/kg body weight of pea peptide combined with 8 weeks of moderate intensity resistance exercise training. After treatment, the body gains, upper limb grip, muscle thickness, and wet weight of biceps brachii were tested, and the cross-sectional area of biceps brachii muscle fiber and the types of muscle fibers were determined by HE staining, immunofluorescence staining, and lactate dehydrogenase activity, respectively. Western blot analysis was used to investigate the level of growth-signaling pathway-related proteins. The results showed that pea peptide supplementation combined with resistance exercise training significantly increased body weight, upper limb grip, muscle thickness, wet weight of biceps brachii, and cross-sectional area of muscle fiber. Meanwhile, pea peptide supplementation obviously elevated the ratio of fast-twitch fiber (type II) and the expression of muscle growth-signaling pathway-related proteins. In addition, the PP2 oligopeptide in pea peptide with the amino acid sequence of LDLPVL induced a more significant promotion on C2C12 cell growth than other oligopeptides.

The consumption of bamboo leaf flavonoids (BLFs) as novel dietary antioxidants has increased owing to their beneficial biological and pharmacological functions. This study assessed the in vivo effects of BLFs on antioxidant capacity, as well as caecal microbiota, serum metabolome, and health status. The Gallus gallus domesticus model and the oral administration approach were used with four treatment groups (basal diet, basal diet with 20 mg bacitracin/kg, basal diet with 50 mg BLF/kg, and basal diet with 250 mg BLF/kg). Ultra-high-performance liquid chromatography triple-quadrupole mass spectrometry analysis indicated that vitexin, fumaric acid, orientin, isoorientin, and p-coumaric acid were the predominant BLF components. From days 1 to 21, BLF increased the average daily gain and decreased the feed:gain of broilers. Moreover, BLF enhanced the serum antioxidant capacity and immune responses. Further, 16S rRNA sequencing showed that BLF modulated the caecal microbial community structure, which was dominated by Betaproteobacteriales, Erysipelatoclostridium, Parasutterella, Lewinella, Lactobacillus, and Candidatus Stoquefichus in BLF broilers. Among the 22 identified serum metabolites in BLF broilers, sphinganine, indole-3-acetaldehyde retinol, choline, 4-methylthio-2-oxobutanoic acid, and L-phenylalanine were recognised as biomarkers. In summary, BLFs appeared to modulate the caecal microbiome, alter the serum metabolome, and indirectly improve antioxidant capacity and health status.

BackgroundNeoadjuvant chemoradiotherapy (nCRT) before total mesorectal excision (TME) and followed systemic chemotherapy is widely accepted as the standard therapy for locally advanced rectal cancer (LARC). This meta-analysis was to evaluate the current evidence regarding nCRT in combination with induction or consolidation chemotherapy for rectal cancer in terms of oncological outcomes.MethodsA systematic search of medical databases (PubMed, EMBASE and Cochrane Library) was conducted up to the end of July 1, 2021. This meta-analysis was performed to evaluate the efficacy of TNT in terms of pathological complete remission (pCR), nCRT or surgical complications, R0 resection, local recurrence, distant metastasis, disease-free survival (DFS) and overall survival (OS) in LARC.ResultsEight nRCTs and 7 RCTs, including 3579 patients were included in the meta-analysis. The rate of pCR was significantly higher in the TNT group than in the nCRT group, (OR 1.85, 95% CI 1.39-2.46, p < 0.0001), DFS (HR 0.80, 95% CI 0.69-0.92, p = 0.001), OS (HR 0.75, 95% CI 0.62-0.89, p = 0.002), nCRT complications (OR 1.05, 95% CI 0.77-1.44, p = 0.75), surgical complications (OR 1.02, 95% CI 0.83-1.26, p = 0.83), local recurrence (OR 1.82, 95% CI 0.95-3.49, p = 0.07), distant metastasis (OR 0.77, 95% CI 0.58-1.03, p = 0.08) did not differ significantly between the TNT and nCRT groups.ConclusionTNT appears to have advantages over standard therapy for LARC in terms of pCR, R0 resection, DFS, and OS, with comparable nCRT and postoperative complications, and no increase in local recurrence and distant metastasis.

The track forecasts of tropical cyclones (TC) in the western North Pacific (WNP) basin during 2021 typhoon season with five global models and four regional models are evaluated here. The results show that the average direct position errors (DPEs) of the global and regional models are approximately 80, 150, 200, 300, and 400 km at 24 h, 48 h, 72 h, 96 h, and 120 h lead-times, respectively. The European Centre for Medium-Range Weather Forecasts Integrated Forecasting System (ECMWF-IFS) achieved the best track forecast performance at each lead among the five global models. Among the four regional models, The China Meteorological Administration Tropical Regional Atmosphere Model for the South China Sea (CMA-TRAMS) attained the smallest DPEs within a 72 h lead, while The Hurricane Weather Research and Forecasting (HWRF) achieved the best track forecast performance at 96 h and 120 h leads. Most of the models produced an obvious westward systematic bias on track forecast from a 24 h to a 120 h lead. Further correlation and cluster analyses indicate that initial TC intensity and size and environmental steering flow can be regarded as good predictors for TC DPEs. TCs with a stronger initial intensity, a bigger initial size, and a larger environmental steering flow in general attain a smaller DPE, and the improvements may go up to 36% at short lead-time.

Abstract The present study investigates relative contributions of large‐scale environmental factors on interannual, intraseasonal, and synoptic time scales to tropical cyclone (TC) genesis over the eastern North Pacific (ENP) during TC seasons of 1979–2013 from the perspective of TC genesis time and position. Conditional sorting displays that the synoptic component is more important in the contribution of lower‐level vorticity and mid‐level specific humidity to TC genesis compared to interannual and intraseasonal components. The convection contributes to TC genesis mainly through synoptic and intraseasonal components. Synoptic‐scale tropical disturbances mainly obtain barotropic eddy energy from climatological mean flows. TCs appear most frequently when vertical wind shear anomalies are between 0 and 3 m s−1, in which interannual and intraseasonal westerly wind anomalies make a positive contribution due to climatological easterly wind shear. When total SST exceeds 28°C, the interannual component of sea surface temperature (SST) is positive, and then it has a positive contribution to TC genesis. In addition, there are notable differences of relative contributions of different time scale components of large‐scale factors among the ENP, northern Atlantic Ocean, and western North Pacific.

Abstract When passing by Taiwan, Typhoon Meranti (2016) was deflected northwards and shrank on infrared images, while its intensity maintained above 50 m⋅s–1 with the radius of maximum wind (RMW) smaller than 30 km. In this paper, satellite and ground‐based dual‐Doppler data were adopted to document Meranti's inner core evolution after its interaction with Taiwan's topography. It was found that the eyewall of Meranti was highly asymmetric on radar reflectivity with maximum on the down motion left side during its landfalling stage in Taiwan Strait, whereas the environmental vertical shear (about 3 m⋅s–1) was not favorable for asymmetry of this strength. As Meranti was very close to Taiwan's southern tip when passing by, its deep convection distribution, especially part on the down motion right side, was impaired by the topography of Central Mountain Range, thus contributed to this asymmetry. The eyewall at 1645 UTC was examined in detail, and it was found that the primary circulation with weaker azimuth perturbations remained intact at this time, while vertical circulation differed with direction. Besides, there was a low level northeast‐southwest flow through the eye, same as the direction of Taiwan Strait. Perhaps this radial inflow, along with the primary circulation, had contributed to the maintenance of asymmetry in reflectivity, so the eyewall did not recover in the Strait despite the weak wind shear. In addition, stronger storm‐relative wind asymmetry in the mid‐troposphere was observed. This wind asymmetry was in favor of track deflection, so was the diabatic heating associated the rainfall asymmetry. The channel wind, along with downslope wind from Taiwan, may help to maintain the intensity of Meranti and the smaller RMW, which needed further investigation with high resolution numerical models.

ABSTRACT: The forecasts of tropical cyclones (TC) in 2016 from 5 official guidances, 5 global models, 3 regional models and 6 ensemble systems were assessed to study the current capabilities of track and intensity forecasts for the western North Pacific. In 2016, the position errors for each official agency were under 85, 150 and 250 km at the lead times of 24, 48, and 72 h, respectively, indicating the performance of track forecasts was a little worse than that in 2015. For each lead time, decreases were seen for each quantile value of the global models from 2010 to 2015; however, this progress in forecasts was stagnated or was reversed in 2016, especially for long lead times. A new error tracking tool, called a “Track Error Rose”, was used to visualize the spatial distributions of the track forecast error relative to the observed TC center. The results show that as lead time increases, the moving speed of most global model TC forecasts becomes slower than those of the observations, and the largest track error often appears to the south of the observation position. In 2016, JMA-GSM, NCEP-GFS, STI-GRAPES and UKMO-MetUM made considerable progress in their intensity forecasts at lead times of 24 and 48 h, and the EPS intensity forecasts made significant progress compared to those of 2015. Keywords: tropical cyclone, track, intensity, forecast verification

In the present study we show that the master myogenic regulatory factor, MYOD1, is a positive modulator of molecular clock amplitude and functions with the core clock factors for expression of clock-controlled genes in skeletal muscle. We demonstrate that MYOD1 directly regulates the expression and circadian amplitude of the positive core clock factor Bmal1. We identify a non-canonical E-box element in Bmal1 and demonstrate that is required for full MYOD1-responsiveness. Bimolecular fluorescence complementation assays demonstrate that MYOD1 colocalizes with both BMAL1 and CLOCK throughout myonuclei. We demonstrate that MYOD1 and BMAL1:CLOCK work in a synergistic fashion through a tandem E-box to regulate the expression and amplitude of the muscle specific clock-controlled gene, Titin-cap (Tcap). In conclusion, these findings reveal mechanistic roles for the muscle specific transcription factor MYOD1 in the regulation of molecular clock amplitude as well as synergistic regulation of clock-controlled genes in skeletal muscle.

This study reveals a connection of summer–fall (JJASO) tropical cyclone (TC) genesis over the western North Pacific (WNP) to preceding boreal spring (MAM) North America snow cover (NASC). Sea surface temperature (SST) anomalies in the tropical central Pacific and subtropical eastern Pacific play a crucial role in relaying influence of the MAM NASC on the following JJASO WNP TC genesis frequency. The increased NASC leads to a decrease in upward sensible heat flux and the atmospheric cooling over the North America. The atmospheric cooling enhances the meridional thermal contrast and geopotential height gradient, which is favorable for the occurrence of lower-level westerly wind anomalies and positive precipitation anomalies over the tropical eastern Pacific. The lower-level northeasterly wind anomalies over the subtropical northeastern Pacific as a Gill-type atmospheric response to positive precipitation anomalies induce ocean surface cooling via the enhanced wind speed. A positive feedback between the northeasterly wind anomalies and negative SST anomalies leads to a westward extension of the easterly flows to the western Pacific. The easterly wind anomalies along with the negative specific humidity anomalies and negative lower-level vorticity anomalies, and enhanced vertical wind shear suppress the TC genesis over the WNP during JJASO.

ABSTRACT: The operational track and intensity forecast errors of tropical cyclones (TCs) over the western North Pacific in 2015 were evaluated on the basis of RSMC-Tokyo’s “best-track” dataset. The results showed that position errors for each official agency were under 80 km, 130 km, 180 km, 260 km and 370 km at 24, 48, 72, 96 and 120 hr lead time. Stepped decreases in the values of each quantile were made at every lead times and have been made by global models from 2010 to 2015, especially for long lead time. The results of the Track Forecast Integral Deviation (TFID) show a clearly decreasing trend for most global models, indicating that the TC forecast tracks became increasingly similar to the observations. In 2015, the intensity forecast skill scores for both global and regional models were almost negative. However, the skill of EPSs’ intensity forecasting has made significant progress in the past year. Keywords: tropical cyclone, track, intensity, forecast verification, skill scores

Skeletal muscle comprises a family of diverse tissues with highly specialized functions. Many acquired diseases, including HIV and COPD, affect specific muscles while sparing others. Even monogenic muscular dystrophies selectively affect certain muscle groups. These observations suggest that factors intrinsic to muscle tissues influence their resistance to disease. Nevertheless, most studies have not addressed transcriptional diversity among skeletal muscles. Here we use RNAseq to profile mRNA expression in skeletal, smooth, and cardiac muscle tissues from mice and rats. Our data set, MuscleDB, reveals extensive transcriptional diversity, with greater than 50% of transcripts differentially expressed among skeletal muscle tissues. We detect mRNA expression of hundreds of putative myokines that may underlie the endocrine functions of skeletal muscle. We identify candidate genes that may drive tissue specialization, including Smarca4, Vegfa, and Myostatin. By demonstrating the intrinsic diversity of skeletal muscles, these data provide a resource for studying the mechanisms of tissue specialization.

ABSTRACT: The track forecasts of five ensemble prediction systems (JMA-WEPS, CMA-GEFS, ECMWF-EPS, NCEP-GEFS and MSC-CENS, respectively) in 2014 are evaluated in this paper. First, on the assumption of bivariate normal distribution, a probability ellipse based on ensemble spread is proposed to represent forecast uncertainties, and then the ellipse and ensemble mean are used to evaluate the five different systems. It is found that the probability ellipse of ECMWF-EPS is smaller, with a high hit ratio, and its mean track errors are just a little larger than those of NCEP-GEFS within 48 h, meaning overall it outperforms the other four systems. Meanwhile, the performance of CMA-GEFS is found to be the poorest. Keywords: tropical cyclone, ensemble forecast, track verification, probability ellipse

In an attempt to find the correlation of aberrant expression of long intergenic noncoding RNAs (lincRNAs) with cancer, twenty-five samples of breast cancer tissue and respective adjacent normal tissue were studied for the expression of lincRNAs by RNA-seq. Among the 538 lincRNAs studied, 124 lincRNAs were exclusively expressed in cancer adjacent tissues and 62 lincRNAs were exclusively expressed in the cancer tissues. Furthermore, the expression of 134 lincRNAs was higher while 272 lower in breast cancer tissue compared with adjacent tissue. The expression of four selected lincRNAs (BC2, BC4, BC5, and BC8) was validated by semi-quantitative and real-time PCR. It was revealed that expression of lincRNA-BC5 was positively correlated with patients' age, pathological stage, and progesterone receptor concentration, while lincRNA-BC8 was negatively correlated with progesterone receptor expression. Higher expression of lincRNA-BC4 was seen in advanced breast cancer grade. LincRNA-BC2 showed no specific changes in the pathological features studied. Interactions between selected lincRNAs and breast cancer associated proteins were highly suggested by RPIseq based on the specific secondary structure. The results demonstrated that this group of lincRNAs was aberrantly expressed in breast cancer. They might play important roles in the function of oncogenes or tumor suppressors affecting the development and progression of breast cancer.

Activation of the Wnt/β-catenin pathway has been observed in at least 1/3 of hepatocellular carcinomas (HCC), and a significant number of these have mutations in the β-catenin gene. Therefore, effective inhibition of this pathway could provide a novel method to treat HCC. The purposed of this study was to determine whether FH535, which was previously shown to block the β-catenin pathway, could inhibit β-catenin activation of target genes and inhibit proliferation of Liver Cancer Stem Cells (LCSC) and HCC cell lines. Using β-catenin responsive reporter genes, our data indicates that FH535 can inhibit target gene activation by endogenous and exogenously expressed β-catenin, including the constitutively active form of β-catenin that contains a Serine37Alanine mutation. Our data also indicate that proliferation of LCSC and HCC lines is inhibited by FH535 in a dose-dependent manner, and that this correlates with a decrease in the percentage of cells in S phase. Finally, we also show that expression of two well-characterized targets of β-catenin, Cyclin D1 and Survivin, is reduced by FH535. Taken together, this data indicates that FH535 has potential therapeutic value in treatment of liver cancer. Importantly, these results suggest that this therapy may be effective at several levels by targeting both HCC and LCSC.