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Abstract Kirsten rat sarcoma viral oncogene homologue (KRAS) is a frequent oncogenic driver of solid tumors, including non-small cell lung cancer (NSCLC). The treatment and outcomes of KRAS-mutant cancers have not been dramatically revolutionized by direct KRAS-targeted therapies because of the lack of deep binding pockets for specific small molecule inhibitors. Here, we demonstrated that the mRNA and protein levels of the class III histone deacetylase SIRT1 were upregulated by the KRASMut-Raf-MEK-c-Myc axis in KRASMut lung cancer cells and in lung tumors of a mouse model with spontaneous KrasG12D expression. KRASMut-induced SIRT1 bound to KRASMut and stably deacetylated KRASMut at lysine 104, which increased KRASMut activity. SIRT1 knockdown (K/D) or the SIRT1H363Y mutation increased KRASMut acetylation, which decreased KRASMut activity and sensitized tumors to the anticancer effects of cisplatin and erlotinib. Furthermore, in KrasG12D/+;Sirt1co/co mice, treatment with cisplatin and erlotinib robustly reduced the tumor burden and increased survival rates compared with those in spontaneous LSL-KrasG12D/+;Sirt1+/+ mice and mice in each single-drug treatment group. Then, we identified p300 as a KRASMut acetyltransferase that reinforced KRASMut lysine 104 acetylation and robustly decreased KRASMut activity. KRASMut lysine 104 acetylation by p300 and deacetylation by SIRT1 were confirmed by LC‒MS/MS. Consistent with this finding, the SIRT1 inhibitor EX527 suppressed KRASMut activity, which synergistically abolished cell proliferation and colony formation, as well as the tumor burden in KRASMut mice, when combined with cisplatin or erlotinib. Our data reveal a novel pathway critical for the regulation of KRASMut lung cancer progression and provide important evidence for the potential application of SIRT1 inhibitors and p300 activators for the combination treatment of KRASMut lung cancer patients.

Abstract Enhancing adult neurogenesis in the brain has been suggested as a potential therapeutic strategy for AD. We developed a screening platform, ATRIVIEW®, for molecules that activate neuronal differentiation of adult mouse NSCs. The most potent hit from an FDA-approved drug library was SNR1611 (trametinib), a selective MEK1/2 inhibitor. We found that trametinib increases the levels of P15INK4b and Neurog2, suggesting a mechanism by which MEK1/2 inhibition induces neuronal differentiation. Oral administration of trametinib increased adult neurogenesis in the dentate gyrus and subventricular zone of the 5XFAD AD mouse model. Surprisingly, we also found that trametinib enhanced adult neurogenesis in the cortex. Consequently, trametinib rescued AD pathologies such as neuronal loss and cognitive impairment in 5XFAD mice. Finally, trametinib induced neurogenic differentiation of NSCs derived from AD patient iPSCs, which suggests its potential therapeutic application. Altogether, we suggest that restoration of endogenous adult neurogenesis by trametinib may be a promising therapeutic approach to AD.

Breast cancer: A protein link for treatment? The role of disrupted activity of the protein BRCA1 in the progression of breast cancer has been clarified, suggesting that targeting another protein with which it interacts could offer a new route to treatment. Mutations of BRCA1 are known to predispose women to both breast and ovarian cancers. Researchers led by Sang Soo Kim (National Cancer Center, South Korea) and Rui-Hong Wang (University of Macau, China) studied the interaction with a protein called cyclin B1 that controls cell growth and division. They found that, in mitosis, BRCA1 interacts with and stabilizes cyclin B1, explaining why the loss of BRCA1 can disrupt the G2/M cell cycle control and accumulate the genetic instability. Treatment of Brca1-mutant mammary tumors with vinblastine, which alters cyclin B1 level, significantly reduced tumor progression with reduction of survival and induction of apoptosis.

On-scene resuscitation time is associated with out-of-hospital cardiac arrest (OHCA) outcomes. We developed and validated reinforcement learning models for individualized on-scene resuscitation times, leveraging nationwide Korean data. Adult OHCA patients with a medical cause of arrest were included (N = 73,905). The optimal policy was derived from conservative Q-learning to maximize survival. The on-scene return of spontaneous circulation hazard rates estimated from the Random Survival Forest were used as intermediate rewards to handle sparse rewards, while patients' historical survival was reflected in the terminal rewards. The optimal policy increased the survival to hospital discharge rate from 9.6% to 12.5% (95% CI: 12.2-12.8) and the good neurological recovery rate from 5.4% to 7.5% (95% CI: 7.3-7.7). The recommended maximum on-scene resuscitation times for patients demonstrated a bimodal distribution, varying with patient, emergency medical services, and OHCA characteristics. Our survival analysis-based approach generates explainable rewards, reducing subjectivity in reinforcement learning., (© 2024. The Author(s).)

Platinum-based neoadjuvant chemotherapy (NACT) followed by radical hysterectomy has been proposed as an alternative treatment approach for cervical cancer (CC) in stage Ib2-IIb, who had a strong desire to be treated with surgery. Our study aims to develop a model based on multimodal MRI by using radiomics and deep learning to predict the treatment response in CC patients treated with neoadjuvant chemoradiotherapy (NACRT). From August 2009 to June 2013, CC patients in stage Ib2-IIb (FIGO 2008) who received NACRT at Fujian Cancer Hospital were enrolled in our study. Clinical information, contrast-enhanced T1-weighted imaging (CE-T1WI), and T2-weighted imaging (T2WI) data were respectively collected. Radiomic features and deep abstract features were extracted from the images using radiomics and deep learning models, respectively. Then, ElasticNet and SVM-RFE were employed for feature selection to construct four single-sequence feature sets. Early fusion of two multi-sequence feature sets and one hybrid feature set were performed, followed by classification prediction using four machine learning classifiers. Subsequently, the performance of the models in predicting the response to NACRT was evaluated by separating patients into training and validation sets. Additionally, overall survival (OS) and disease-free survival (DFS) were assessed using Kaplan-Meier survival curves. Among the four machine learning models, SVM exhibited the best predictive performance (AUC=0.86). Among the seven feature sets, the hybrid feature set achieved the highest values for AUC (0.86), ACC (0.75), Recall (0.75), Precision (0.81), and F1-score (0.75) in the validation set, outperforming other feature sets. Furthermore, the predicted outcomes of the model were closely associated with patient OS and DFS (p = 0.0044; p = 0.0039). A model based on MRI images with features from multiple sequences and different methods could precisely predict the response to NACRT in CC patients. This model could assist clinicians in devising personalized treatment plans and predicting patient survival outcomes., (© 2024. The Author(s).)

It is of great significance for the engineering popularization of CO 2 -ECBM technology to evaluate the potential of CCUS source and sink and study the matching of pipeline network of deep unworkable seam. In this study, the deep unworkable seam was taken as the research object. Firstly, the evaluation method of CO 2 storage potential in deep unworkable seam was discussed. Secondly, the CO 2 storage potential was analyzed. Then, the matching research of CO 2 source and sink was carried out, and the pipe network design was optimized. Finally, suggestions for the design of pipe network are put forward from the perspective of time and space scale. The results show that the average annual CO 2 emissions of coal-fired power plants vary greatly, and the total emissions are 58.76 million tons. The CO 2 storage potential in deep unworkable seam is huge with a total amount of 762 million tons, which can store CO 2 for 12.97 years. During the 10-year period, the deep unworkable seam can store 587.6 million tons of CO 2 , and the cumulative length of pipeline is 251.61 km with requiring a cumulative capital of $ 4.26 × 10 10 . In the process of CO 2 source-sink matching, the cumulative saving mileage of carbon sink is 98.75 km, and the cumulative saving cost is $ 25.669 billion with accounting for 39.25% and 60.26% of the total mileage and cost, respectively. Based on the three-step approach, the whole line of CO 2 source and sink in Huainan coalfield can be completed by stages and regions, and all CO 2 transportation and storage can be realized. CO 2 pipelines include gas collection and distribution branch lines, intra-regional trunk lines, and interregional trunk lines. Based on the reasonable layout of CO 2 pipelines, a variety of CCS applications can be simultaneously carried out, intra-regional and inter-regional CO 2 transport network demonstrations can be built, and integrated business models of CO 2 transport and storage can be simultaneously built on land and sea. The research results can provide reference for the evaluation of CO 2 sequestration potential of China's coal bases, and lay a foundation for the deployment of CCUS clusters., (© 2024. The Author(s).)

Our objective in this study is to determine whether intra-articular injection of miRNA-1 can attenuate the progression of OA in rats by down regulating Ihh. Knee chondrocytes were isolated from male Sprague-Dawley rats aged 2-3 days. Second-generation chondrocytes were transfected with miR-1 mimic and empty vector with lipo3000 for 6 h and then stimulated with 10 ng/mL IL-1β for 24 h. OA-related and cartilage matrix genes were quantified using real-time quantitative polymerase chain reaction (RT-qPCR). Two-month-old male Sprague-Dawley rats were divided into three groups (n = 30?): sham operation group + 50 µL saline, anterior cruciate ligament transection (ACLT) group + 50 µL miR-1 agomir (concentration), and control group ACLT + 50 µL miR-1 agomir. Treatment was started one week after the operation. All animals were euthanized eight weeks after the operation. X-rays and micro-CT were used to detect imaging changes in the knee joints. FMT was used to monitor joint inflammation in vivo. Safranin O staining was used to detect morphological changes in articular cartilage. Immunohistochemistry was used to detect Col2, Col10, metalloproteinase-13 (MMP-13). RT-qPCR was used to detect gene changes includingmiR-1, Col2, Col10, MMP-13, Ihh, Smo, Gli1, Gli2, and Gli3. Overexpression of miR-1 in IL-1β-stimulated chondrocytes reduced the levels of Ihh, MMP-13, and Col10 but increased the levels of Col2 and aggrecan. Intra-articular injection of miR-1 agomir reduced osteophyte formation, inflammation, and prevented cartilage damage. RT-qPCR results indicated that the miR-1 agomir increased articular cartilage anabolism and inhibited cartilage catabonism. miR-1 can attenuate the progression of OA by downregulating Ihh., (© 2024. The Author(s).)

The Internet era is an era of information explosion. By 2022, the global Internet users have reached more than 4 billion, and the social media users have exceeded 3 billion. People face a lot of news content every day, and it is almost impossible to get interesting information by browsing all the news content. Under this background, personalized news recommendation technology has been widely used, but it still needs to be further optimized and improved. In order to better push the news content of interest to different readers, users' satisfaction with major news websites should be further improved. This study proposes a new recommendation algorithm based on deep learning and reinforcement learning. Firstly, the RL algorithm is introduced based on deep learning. Deep learning is excellent in processing large-scale data and complex pattern recognition, but it often faces the challenge of low sample efficiency when it comes to complex decision-making and sequential tasks. While reinforcement learning (RL) emphasizes learning optimization strategies through continuous trial and error through interactive learning with the environment. Compared with deep learning, RL is more suitable for scenes that need long-term decision-making and trial-and-error learning. By feeding back the reward signal of the action, the system can better adapt to the unknown environment and complex tasks, which makes up for the relative shortcomings of deep learning in these aspects. A scenario is applied to an action to solve the sequential decision problem in the news dissemination process. In order to enable the news recommendation system to consider the dynamic changes in users' interest in news content, the Deep Deterministic Policy Gradient algorithm is applied to the news recommendation scenario. Opposing learning complements and combines Deep Q-network with the strategic network. On the basis of fully summarizing and thinking, this paper puts forward the mode of intelligent news dissemination and push. The push process of news communication information based on edge computing technology is proposed. Finally, based on Area Under Curve a Q-Leaning Area Under Curve for RL models is proposed. This indicator can measure the strengths and weaknesses of RL models efficiently and facilitates comparing models and evaluating offline experiments. The results show that the DDPG algorithm improves the click-through rate by 2.586% compared with the conventional recommendation algorithm. It shows that the algorithm designed in this paper has more obvious advantages in accurate recommendation by users. This paper effectively improves the efficiency of news dissemination by optimizing the push mode of intelligent news dissemination. In addition, the paper also deeply studies the innovative application of intelligent edge technology in news communication, which brings new ideas and practices to promote the development of news communication methods. Optimizing the push mode of intelligent news dissemination not only improves the user experience, but also provides strong support for the application of intelligent edge technology in this field, which has important practical application prospects., (© 2024. The Author(s).)

Background: To prevent school injuries, thorough epidemiological data is an essential foundation. We aimed to investigate the characteristics of school injuries in Asia and explore risk factors for major trauma., Methods: This retrospective study was conducted in the participating centers of the Pan-Asian Trauma Outcome Study from October 2015 to December 2020. Subjects who reported "school" as the site of injury were included. Major trauma was defined as an Injury Severity Score (ISS) value of ≥16., Results: In total, 1305 injury cases (1.0% of 127,715 events) occurred at schools. Among these, 68.2% were children. Unintentional injuries were the leading cause and intentional injuries comprised 7.5% of the cohort. Major trauma accounted for 7.1% of those with documented ISS values. Multivariable regression revealed associations between major trauma and factors, including age, intention of injury (self-harm), type of injury (traffic injuries, falls), and body part injured (head, thorax, and abdomen). Twenty-two (1.7%) died, with six deaths related to self-harm. Females represented 28.4% of injuries but accounted for 40.9% of all deaths., Conclusions: In Asia, injuries at schools affect a significant number of children. Although the incidence of injuries was higher in males, self-inflicted injuries and mortality cases were relatively higher in females., Impact: Epidemiological data and risk factors for major trauma resulting from school injuries in Asia are lacking. This study identified significant risk factors for major trauma occurring at schools, including age, intention of injury (self-harm), injury type (traffic injuries, falls), and body part injured (head, thoracic, and abdominal injuries). Although the incidence of injuries was higher in males, the incidence of self-harm injuries and mortality rates were higher in females. The results of this would make a significant contribution to the development of prevention strategies and relative policies concerning school injuries., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Genetic, environment, and behaviour factors have a role in causing sudden cardiac arrest (SCA). We aimed to determine the strength of the association between various risk factors and SCA incidence. We conducted a multicentre case-control study at 17 hospitals in Korea from September 2017 to December 2020. The cases included out-of-hospital cardiac arrest aged 19-79 years with presumed cardiac aetiology. Community-based controls were recruited at a 1:1 ratio after matching for age, sex, and urban residence level. Multivariable conditional logistic regression analysis was conducted. Among the 1016 cases and 1731 controls, 948 cases and 948 controls were analysed. A parental history of SCA, low educational level, own heart disease, current smoking, and non-regular exercise were associated with SCA incidence (Adjusted odds ratio [95% confidence interval]: 2.51 [1.48-4.28] for parental history of SCA, 1.37 [1.38-2.25] for low edication level, 3.77 [2.38-5.90] for non-coronary artery heart disease, 4.47 [2.84-7.03] for coronary artery disease, 1.39 [1.08-1.79] for current smoking, and 4.06 [3.29-5.02] for non-regular exercise). Various risk factors related to genetics, environment, and behaviour were independently associated with the incidence of SCA. Establishing individualised SCA prevention strategies in addition to general prevention strategies is warranted., (© 2023. The Author(s).)

To save time during transport, where resuscitation quality can degrade in a moving ambulance, it would be prudent to continue the resuscitation on scene if there is a high likelihood of ROSC occurring at the scene. We developed the pre-hospital real-time cardiac arrest outcome prediction (PReCAP) model to predict ROSC at the scene using prehospital input variables with time-adaptive cohort. The patient survival at discharge from the emergency department (ED), the 30-day survival rate, and the final Cerebral Performance Category (CPC) were secondary prediction outcomes in this study. The Pan-Asian Resuscitation Outcome Study (PAROS) database, which includes out-of-hospital cardiac arrest (OHCA) patients transferred by emergency medical service in Asia between 2009 and 2018, was utilized for this study. From the variables available in the PAROS database, we selected relevant variables to predict OHCA outcomes. Light gradient-boosting machine (LightGBM) was used to build the PReCAP model. Between 2009 and 2018, 157,654 patients in the PAROS database were enrolled in our study. In terms of prediction of ROSC on scene, the PReCAP had an AUROC score between 0.85 and 0.87. The PReCAP had an AUROC score between 0.91 and 0.93 for predicting survived to discharge from ED, and an AUROC score between 0.80 and 0.86 for predicting the 30-day survival. The PReCAP predicted CPC with an AUROC score ranging from 0.84 to 0.91. The feature importance differed with time in the PReCAP model prediction of ROSC on scene. Using the PAROS database, PReCAP predicted ROSC on scene, survival to discharge from ED, 30-day survival, and CPC for each minute with an AUROC score ranging from 0.8 to 0.93. As this model used a multi-national database, it might be applicable for a variety of environments and populations., (© 2023. The Author(s).)

To study the vertical compressive bearing characteristics of large-diameter rock-socketed cast-in-place piles, eight manually-excavated rock-socketed cast-in-place piles were subjected to vertical compressive on-site load and pile stress tests. The test results showed that the load-displacement (Q-s) curves of the eight test piles were all slow-varying, and the settlement of the piles was less than 11 mm, which met the minimum engineering requirements. The unloading rebound rate was between 55 and 75%, and the elastic working properties of the piles were apparent. The pile axial force gradually decreased with depth, and the slope of the axial force distribution curve reached a minimum in the moderately weathered muddy siltstone layer while the pile side friction resistance reached its maximum value. Pile end friction increases with the increase of load. But the pile end resistance was inversely proportional to the single pile length-to-diameter (L/D) ratio and the depth of rock embedment for the pile. The percentage of pile side friction resistance under maximum load was 86%, indicating that these were characteristic friction piles. Based on the test results and the current Chinese code, the friction coefficient of the pile side soil layer η and the total resistance coefficient of the rock-socketed section ζ were introduced. A revision to the calculation equation for the vertical bearing capacity of the rock-socketed cast-in-place pile in the code was proposed, together with an optimization design method for large-diameter rock-socketed cast-in-place piles., (© 2023. Springer Nature Limited.)

The structures of dendrites and axons form the basis for the connectivity of neural network, but their precise relationship at single-neuron level remains unclear. Here we report the complete dendrite and axon morphology of nearly 2,000 neurons in mouse prefrontal cortex (PFC). We identified morphological variations of somata, dendrites and axons across laminar layers and PFC subregions and the general rules of somatodendritic scaling with cytoarchitecture. We uncovered 24 morphologically distinguishable dendrite subtypes in 1,515 pyramidal projection neurons and 405 atypical pyramidal projection neurons and spiny stellate neurons with unique axon projection patterns. Furthermore, correspondence analysis among dendrites, local axons and long-range axons revealed coherent morphological changes associated with electrophysiological phenotypes. Finally, integrative dendrite-axon analysis uncovered the organization of potential intra-column, inter-hemispheric and inter-column connectivity among projection neuron types in PFC. Together, our study provides a comprehensive structural repertoire for the reconstruction and analysis of PFC neural network., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Abnormal activation of Wnt/β-catenin-mediated transcription is closely associated with the malignancy of pancreatic cancer. Family with sequence similarity 83 member A (FAM83A) was shown recently to have oncogenic effects in a variety of cancer types, but the biological roles and molecular mechanisms of FAM83A in pancreatic cancer need further investigation. Here, we newly discovered that FAM83A binds directly to β-catenin and inhibits the assembly of the cytoplasmic destruction complex thus inhibiting the subsequent phosphorylation and degradation. FAM83A is mainly phosphorylated by the SRC non-receptor kinase family member BLK (B-lymphoid tyrosine kinase) at tyrosine 138 residue within the DUF1669 domain that mediates the FAM83A-β-catenin interaction. Moreover, FAM83A tyrosine 138 phosphorylation enhances oncogenic Wnt/β-catenin-mediated transcription through promoting β-catenin-TCF4 interaction and showed an elevated nucleus translocation, which inhibits the recruitment of histone deacetylases by TCF4. We also showed that FAM83A is a direct downstream target of Wnt/β-catenin signaling and correlates with the levels of Wnt target genes in human clinical pancreatic cancer tissues. Notably, the inhibitory peptides that target the FAM83A-β-catenin interaction significantly suppressed pancreatic cancer growth and metastasis in vitro and in vivo. Our results revealed that blocking the FAM83A cascade signaling defines a therapeutic target in human pancreatic cancer., (© 2022. The Author(s).)

The recently introduced orientation selective deep brain stimulation (OS-DBS) technique freely controls the direction of the electric field's spatial gradient by using multiple contacts with independent current sources within a multielectrode array. The goal of OS-DBS is to align the electrical field along the axonal track of interest passing through the stimulation site. Here we utilized OS-DBS with a planar 3-channel electrode for stimulating the rat entorhinal cortex (EC) and medial septal nucleus (MSN), two promising areas for DBS treatment of Alzheimer's disease. The brain responses to OS-DBS were monitored by whole brain functional magnetic resonance imaging (fMRI) at 9.4 T with Multi-Band Sweep Imaging with Fourier Transformation (MB-SWIFT). Varying the in-plane OS-DBS stimulation angle in the EC resulted in activity modulation of multiple downstream brain areas involved in memory and cognition. Contrary to that, no angle dependence of brain activations was observed when stimulating the MSN, consistent with predictions based on the electrode configuration and on the main axonal directions of the targets derived from diffusion MRI tractography and histology. We conclude that tuning the OS-DBS stimulation angle modulates the activation of brain areas relevant to Alzheimer's disease, thus holding great promise in the DBS treatment of the disease., (© 2022. The Author(s).)

Both sarcopenia and loss of teeth are associated with aging. The purpose of this study was to investigate potential relationships between tooth loss and sarcopenia and its components in suburban community-dwelling older adults of Shanghai and Tianjin, China. The subjects were 1494 people over 60 years of age (40.7% men; aged 71.64 ± 5.97 years) from Chongming District of Shanghai and Hangu District of Tianjin. Asian Working Group for Sarcopenia(AWGS) criteria were used to define sarcopenia. Muscle mass, muscle strength, and physical performance were assessed using a bioelectrical impedance analyzer, a grip strength test, and a four-meter walk test, respectively. The subjects were divided into groups depending on self-reported loss of teeth. Our studies found no correlation between tooth loss and sarcopenia or muscle mass. However, the walking speed of female participants with at least 10 teeth lost was 0.059 m/s slower than that of participants with fewer than 10 teeth lost (p < 0.001), and grip strength was 1.577 kg lower among male participants with at least 10 teeth lost than among males with fewer than 10 teeth lost (p = 0.023). These results are consistent with the importance of good oral hygiene in preventing declines of physical performance in older adults., (© 2022. The Author(s).)

The gas sensing ability of a pure β-SiC fiber is limited due to its low-sensitivity and selectivity with poor recovery time during a gas sensing test. The combination of functional β-SiC fibers with metal-oxide (MO) can lead to excellent electronic conductivity, boosted chemical activity, and high reaction activity with the target gas and β-SiC-In 2 O 3 sensor material. Influence factors such as amounts of MO, current collectors, and gas species (CO 2 , O 2 and without gas) for the gas sensing ability of β-SiC-In 2 O 3 nanocomposite were determined at standard room temperature (25 °C) and high temperature (350 °C) conditions. The gas sensing ability of the functional β-SiC fiber was significantly enhanced by the loading of In 2 O 3 metal-oxide. In addition, the MO junction on the β-SiC fiber was mainly subjected to the Si-C-O-In bond sensor layer with an effective electron-transfer ability. The gas sensing mechanism was based on the transfer of charges, in which the sensing material acted as an absorber or a donor of charges. The sensor material could use different current- collectors to support the electron transfer and gas sensing ability of the material. A 1:0.5M SiC-In 2 O 3 coated Ni-foil current collector sensor showed better sensing ability for CO 2 and O 2 gases than other gas sensors at room temperature and high temperature conditions. The sensing result of the electrode was obtained with different current density values without or with gas purging conditions because CO 2 and O 2 gases had electron acceptor properties. During the gas sensing test, the sensor material donated electrons to target gases. The current value on the CV graph then significantly changed. Our obtained sample analysis data and the gas sensing test adequately demonstrated that MO junctions on functional β-SiC fibers could improve the sensitivity of a sensor material and particularly upgrade the sensor material for gas sensing., (© 2022. The Author(s).)

Prefrontal cortex (PFC) is the cognitive center that integrates and regulates global brain activity. However, the whole-brain organization of PFC axon projections remains poorly understood. Using single-neuron reconstruction of 6,357 mouse PFC projection neurons, we identified 64 projectome-defined subtypes. Each of four previously known major cortico-cortical subnetworks was targeted by a distinct group of PFC subtypes defined by their first-order axon collaterals. Further analysis unraveled topographic rules of soma distribution within PFC, first-order collateral branch point-dependent target selection and terminal arbor distribution-dependent target subdivision. Furthermore, we obtained a high-precision hierarchical map within PFC and three distinct functionally related PFC modules, each enriched with internal recurrent connectivity. Finally, we showed that each transcriptome subtype corresponds to multiple projectome subtypes found in different PFC subregions. Thus, whole-brain single-neuron projectome analysis reveals organization principles of axon projections within and outside PFC and provides the essential basis for elucidating neuronal connectivity underlying diverse PFC functions., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

In perovskite solar cells, the interfaces between the perovskite and charge-transporting layers contain high concentrations of defects (about 100 times that within the perovskite layer), specifically, deep-level defects, which substantially reduce the power conversion efficiency of the devices 1-3 . Recent efforts to reduce these interfacial defects have focused mainly on surface passivation 4-6 . However, passivating the perovskite surface that interfaces with the electron-transporting layer is difficult, because the surface-treatment agents on the electron-transporting layer may dissolve while coating the perovskite thin film. Alternatively, interfacial defects may not be a concern if a coherent interface could be formed between the electron-transporting and perovskite layers. Here we report the formation of an interlayer between a SnO 2 electron-transporting layer and a halide perovskite light-absorbing layer, achieved by coupling Cl-bonded SnO 2 with a Cl-containing perovskite precursor. This interlayer has atomically coherent features, which enhance charge extraction and transport from the perovskite layer, and fewer interfacial defects. The existence of such a coherent interlayer allowed us to fabricate perovskite solar cells with a power conversion efficiency of 25.8 per cent (certified 25.5 per cent)under standard illumination. Furthermore, unencapsulated devices maintained about 90 per cent of their initial efficiency even after continuous light exposure for 500 hours. Our findings provide guidelines for designing defect-minimizing interfaces between metal halide perovskites and electron-transporting layers., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Epidural spinal cord stimulation (ESCS) is widely used for chronic pain treatment, and is also a promising tool for restoring motor function after spinal cord injury. Despite significant positive impact of ESCS, currently available protocols provide limited specificity and efficiency partially due to the limited number of contacts of the leads and to the limited flexibility to vary the spatial distribution of the stimulation field in respect to the spinal cord. Recently, we introduced Orientation Selective (OS) stimulation strategies for deep brain stimulation, and demonstrated their selectivity in rats using functional MRI (fMRI). The method achieves orientation selectivity by controlling the main direction of the electric field gradients using individually driven channels. Here, we introduced a similar OS approach for ESCS, and demonstrated orientation dependent brain activations as detected by brain fMRI. The fMRI activation patterns during spinal cord stimulation demonstrated the complexity of brain networks stimulated by OS-ESCS paradigms, involving brain areas responsible for the transmission of the motor and sensory information. The OS approach may allow targeting ESCS to spinal fibers of different orientations, ultimately making stimulation less dependent on the precision of the electrode implantation.

Hulless barley (Hordeum vulgare L. var. nudum) is a barley variety that has loose husk cover of the caryopses. Because of the ease in processing and edibility, hulless barley has been locally cultivated and used as human food. For example, in Tibetan Plateau, hulless barley is the staple food for human and essential livestock feed. Although the draft genome of hulless barley has been sequenced, the assembly remains fragmented. Here, we reported an improved high-quality assembly and annotation of the Tibetan hulless barley genome using more than 67X PacBio long-reads. The N50 contig length of the new assembly is at least more than 19 times larger than other available barley assemblies. The new genome assembly also showed high gene completeness and high collinearity of genome synteny with the previously reported barley genome. The new genome assembly and annotation will not only remove major hurdles in genetic analysis and breeding of hulless barley, but will also serve as a key resource for studying barley genomics and genetics.

Previous studies indicated serious soil arsenic (As) pollution of large spatial extent related to tungsten mining. We performed systematic analyses of magnetic parameters and As contents of a slag covered soil profile close to the abandoned tungsten mine in southern China, in order to discuss the feasibility of using sensitive, non-destructive, and cost-effective magnetic methods for monitoring the soil arsenic content in such arsenic pollution areas. The results indicate that arsenic sulfide entered from slags into the underlying soil and changed to iron arsenate and moveable arsenic ion. The arsenic ions were transported from the upper to the lower part of the soil profile, leading to more serious arsenic pollution at lower levels of the section. Pedogenesis and oxidation of the entered iron and arsenic sulfide resulted in coexistence of magnetite/maghemite and hematite, with different contributions at depths of 125-195 cm, 60-125 cm, and 0-60 cm. The arsenic content is significant positively correlated with the hematite concentration given by the magnetic parameter HIRM and negatively correlated with the S -300 ratio that measures the relative contributions of magnetite(+maghemite) and hematite. The S -300 ratio is effective for semi-quantification of soil arsenic content, and may be also used for soil arsenic pollution assessment and monitoring in similar settings of tungsten mining.

In China, the knowledge of the underlying causes of heterogeneous distribution pattern of dengue fever in different high-risk areas is limited. A comparative study will help us understand the influencing factors of dengue in different high-risk areas. In the study, we compared the effects of climate, mosquito density and imported cases on dengue fever in two high-risk areas using Generalized Additive Model (GAM), random forests and Structural Equation Model (SEM). GAM analysis identified a similar positive correlation between imported cases, density of Aedes larvae, climate variables and dengue fever occurrence in the studied high-risk areas of both Guangdong and Yunnan provinces. Random forests showed that the most important factors affecting dengue fever occurrence were the number of imported cases, BI and the monthly average minimum temperature in Guangdong province; whereas the imported cases, the monthly average temperature and monthly relative humidity in Yunnan province. We found the rainfall had the indirect effect on dengue fever occurrence in both areas mediated by mosquito density; while the direct effect in high-risk areas of Guangdong was dominated by temperature and no obvious effect in Yunnan province by SEM. In total, climate factors and mosquito density are the key drivers on dengue fever incidence in different high-risk areas of China. These findings could provide scientific evidence for early warning and the scientific control of dengue fever in high-risk areas.

Hematopoietic stem/progenitor cells (HSPC) in zebrafish emerge from the aortic hemogenic endothelium (HE) and migrate towards the caudal hematopoietic tissue (CHT), where they expand and differentiate during definitive hematopoiesis. Phospholipase C gamma 1 (Plcγ1) has been implicated for hematopoiesis in vivo and in vitro and is also required to drive arterial and HSPC formation. Genetic mutation in plcg1 -/- (y10 allele) completely disrupts the aortic blood flow, specification of arterial fate, and HSPC formation in zebrafish embryos. We previously demonstrated that ginger treatment promoted definitive hematopoiesis via Bmp signaling. In this paper, we focus on HSPC development in plcg1 -/- mutants and show that ginger/10-gingerol (10-G) can rescue the expression of arterial and HSPC markers in the HE and CHT in plcg1 -/- mutant embryos. We demonstrate that ginger can induce scl/runx1 expression, and that rescued HE fate is dependent on Bmp and Notch. Bmp and Notch are known to regulate nitric oxide (NO) production and NO can induce hematopoietic stem cell fate. We show that ginger produces a robust up-regulation of NO. Taken together, we suggest in this paper that Bmp, Notch and NO are potential players that mediate the effect of ginger/10-G for rescuing the genetic defects in blood vessel specification and HSPC formation in plcg1 -/- mutants. Understanding the molecular mechanisms of HSPC development in vivo is critical for understanding HSPC expansion, which will have a positive impact in regenerative medicine.

Almost half of the groundwater in the Pearl River Delta (PRD) contains salt water originally derived from paleo-seawater due to the Holocene transgression, which then generates intense physicochemical gradients in the mixing zone between freshwater and saltwater. Although some studies have been conducted on the hydrological and geochemical characteristics of groundwater in the PRD to monitor the intrusion of seawater, little attention has been paid to the microbial community of this particular region. In this study, we implemented a high-throughput sequencing analysis to characterize the microbial communities along a salinity gradient in the PRD aquifer, China. Our results indicated that the microbial community composition varied significantly depending on the salinity of the aquifer. The presence of abundant anaerobic microorganisms of the genera Desulfovibrio and Methanococcus in certain saltwater samples may be responsible for the gas generation of H 2 S and CH 4 in the stratum. In saline water samples (TDS > 10 g/L), the linear discriminant analysis effect size (LEfSe) analysis found two biomarkers that usually live in marine environments, and the aquifers of the PRD still contained large quantity of saltwater, indicating that the impact of the paleo-seawater has lasted to this day. The predictive metagenomic analysis revealed that the metabolic pathways present in the groundwater samples studied, included the degradation of pesticides and refractory organics (dichlorodiphenyltrichloroethane (DDT), atrazine and polycyclic aromatic hydrocarbons), matter cycling (methane, nitrogen and sulfur), and inorganic ion and mineral metabolites. This study can help enhance our understanding of the composition of the microbial assemblages and its implications as an environmental indicator in an aquifer affected by saltwater intrusion.

Impaired hearing and cognition are disabling conditions among older adults. Research has presented inconsistent conclusions regarding hearing impairment posing a risk for cognitive impairment. We aimed to assess this from published evidence via searching PubMed and Embase, from the inception of the databases indexed to December 2, 2016. For those high-quality studies retrieved, relative risk (RR) and 95% confidence intervals (CIs) were combined to estimate the risk of cognitive impairment. Eleven cohort studies were included in the present study. Pooled results found that elderly people with disabled peripheral and central hearing function had a higher risk of cognitive impairment (for moderate/severe peripheral hearing impairment: RR = 1.29, 95% CI: 1.04-1.59 during a follow-up ≤6 years. RR = 1.57, 95% CI: 1.13-2.20 during a follow-up >6 years; for severe central hearing impairment, RR = 3.21, 95% CI: 1.19-8.69) compared to those with normal hearing function. We also recorded a dose-response trend for cognitive impairment as hearing thresholds rose. No evident bias from potential confounding factors was found with one exception: the length for clinical follow-up. Although results are preliminary because qualifying studies were few, statistical findings were consistent with older people identified as having greater levels of hearing loss, having a corresponding higher risk of cognitive impairment.

A wireless magnetoelastic (ME) biosensor immobilized with E2 glycoprotein was first developed to detect classical swine fever virus (CSFV) E2 antibody. The detection principle is that a sandwich complex of CSFV E2 - rabbit anti-CSFV E2 antibody - alkaline phosphatase (AP) conjugated goat anti-rabbit IgG formed on the ME sensor surface, with biocatalytic precipitation used to amplify the mass change of antigen-antibody specific binding reaction, induces a significant change in resonance frequency of the biosensor. Due to its magnetostrictive feature, the resonance vibrations and resonance frequency can be actuated and wirelessly monitored through magnetic fields. The experimental results show that resonance frequency shift increases with the augmentation of the CSFV E2 antibody concentration. Scanning electron microscopy (SEM), energy-dispersive spectroscopy (EDS) and fluorescence microscopy analysis proved that the modification and detection process were successful. The biosensor shows a linear response to the logarithm of CSFV E2 antibody concentrations ranging from 5 ng/mL to 10 μg/mL, with a detection limit (LOD) of 2.466 ng/mL and the sensitivity of 56.2 Hz/μg·mL -1 . The study provides a low-cost yet highly-sensitive and wireless method for selective detection of CSFV E2 antibody.

Neuron-microglia interactions have a crucial role in maintaining the neuroimmune system. The balance of neuroimmune system has emerged as an important process in the pathophysiology of depression. However, how neuron-microglia interactions contribute to major depressive disorders has been poorly understood. Herein, we demonstrated that microglia-derived synaptic changes induced antidepressive-like behavior by using microglia-specific signal transducer and activator of transcription 3 (STAT3) knockout (KO) (STAT3 fl/fl ;LysM-Cre +/- ) mice. We found that microglia-specific STAT3 KO mice showed antidepressive-like behavior in the forced swim, tail suspension, sucrose preference, and open-field tests. Surprisingly, the secretion of macrophage colony-stimulating factor (M-CSF) was increased from neuronal cells in the brains of STAT3 fl/fl ;LysM-Cre +/- mice. Moreover, the phosphorylation of antidepressant-targeting mediators and brain-derived neurotrophic factor expression were increased in the brains of STAT3 fl/fl ;LysM-Cre +/- mice as well as in neuronal cells in response to M-CSF stimulation. Importantly, the miniature excitatory postsynaptic current frequency in the medial prefrontal cortex was increased in STAT3 fl/fl ;LysM-Cre +/- mice and in the M-CSF treatment group. Collectively, microglial STAT3 regulates depression-related behaviors via neuronal M-CSF-mediated synaptic activity, suggesting that inhibition of microglial STAT3 might be a new therapeutic strategy for depression.

Epithelial organs undergo steady-state turnover throughout adult life, with old cells being continually replaced by the progeny of stem cell divisions. To avoid hyperplasia or atrophy, organ turnover demands strict equilibration of cell production and loss. However, the mechanistic basis of this equilibrium is unknown. Here we show that robustly precise turnover of the adult Drosophila intestine arises through a coupling mechanism in which enterocyte apoptosis breaks feedback inhibition of stem cell division. Healthy enterocytes inhibit stem cell division through E-cadherin, which prevents secretion of mitogenic epidermal growth factors (EGFs) by repressing transcription of the EGF maturation factor rhomboid. Individual apoptotic enterocytes promote divisions by loss of E-cadherin, which releases cadherin-associated β-catenin (Armadillo in Drosophila) and p120-catenin to induce rhomboid. Induction of rhomboid in the dying enterocyte triggers activation of the EGF receptor (Egfr) in stem cells within a discrete radius. When we blocked apoptosis, E-cadherin-controlled feedback suppressed divisions, and the organ retained the same number of cells. When we disrupted feedback, apoptosis and divisions were uncoupled, and the organ developed either hyperplasia or atrophy. Together, our results show that robust cellular balance hinges on the obligate coupling of divisions to apoptosis, which limits the proliferative potential of a stem cell to the precise time and place at which a replacement cell is needed. In this way, localized cell-cell communication gives rise to tissue-level homeostatic equilibrium and constant organ size.

Many drugs have progressed through preclinical and clinical trials and have been available - for years in some cases - before being recalled by the FDA for unanticipated toxicity in humans. One reason for such poor translation from drug candidate to successful use is a lack of model systems that accurately recapitulate normal tissue function of human organs and their response to drug compounds. Moreover, tissues in the body do not exist in isolation, but reside in a highly integrated and dynamically interactive environment, in which actions in one tissue can affect other downstream tissues. Few engineered model systems, including the growing variety of organoid and organ-on-a-chip platforms, have so far reflected the interactive nature of the human body. To address this challenge, we have developed an assortment of bioengineered tissue organoids and tissue constructs that are integrated in a closed circulatory perfusion system, facilitating inter-organ responses. We describe a three-tissue organ-on-a-chip system, comprised of liver, heart, and lung, and highlight examples of inter-organ responses to drug administration. We observe drug responses that depend on inter-tissue interaction, illustrating the value of multiple tissue integration for in vitro study of both the efficacy of and side effects associated with candidate drugs.

Thiamine is critical for cellular function, as its phosphorylated and active form, thiamine diphosphate (TDP), acts as coenzyme for three key enzymes in glucose metabolism. Mutations in thiamine transporter, TDP synthesizing enzyme or carrier, including solute carrier family 19 member 3 (SLC19A3), thiamine pyrophosphokinase (TPK1) and solute carrier family 25 member 19 (SLC25A19), have been associated with developmental neurological disorders, including microcephaly and Leigh syndrome. However, little is known about how thiamine metabolism regulates neuronal morphology at the cellular level. Here, using primary rat hippocampal neuronal cultures, we showed that reducing the expression of Tpk1, Slc25a19 or Slc19a3 in individual neurons significantly reduced dendrite complexity, as measured by total dendritic branch tip number (TDBTN) and total dendritic branch length (TDBL). The specificity of the RNAi effects were verified by overexpression of RNAi resistant human constructs. Importantly, changes in both TDBTN and TDBL tightly correlated with reduction in soma size, demonstrating coordinated regulation of soma and dendrite growth by thiamine. The requirement of thiamine metabolism for coordinated somata and dendrite growth is highly consistent with the microcephaly and neurodegenerative phenotypes observed in thiamine loss-of-function diseases.

Regulation of intracellular Ca 2+ signaling is a major determinant of CD8 + T cell responsiveness, but the mechanisms underlying this regulation of Ca 2+ levels, especially in naïve CD8 + T cells, are not fully defined. Here, we showed that microRNA-150 (miR-150) controls intracellular Ca 2+ levels in naïve CD8 + T cells required for activation by suppressing TMEM20, a negative regulator of Ca 2+ extrusion. miR-150 deficiency increased TMEM20 expression, which resulted in increased intracellular Ca 2+ levels in naïve CD8 + T cells. The subsequent increase in Ca 2+ levels induced expression of anergy-inducing genes, such as Cbl-b, Egr2, and p27, through activation of NFAT1, as well as reduced cell proliferation, cytokine production, and the antitumor activity of CD8 + T cells upon antigenic stimulation. The anergy-promoting molecular milieu and function induced by miR-150 deficiency were rescued by reinstatement of miR-150. Additionally, knockdown of TMEM20 in miR-150-deficient naïve CD8 + T cells reduced intracellular Ca 2+ levels. Our findings revealed that miR-150 play essential roles in controlling intracellular Ca 2+ level and activation in naïve CD8 + T cells, which suggest a mechanism to overcome anergy induction by the regulation of intracellular Ca 2+ levels.

The purpose of this study was to 1) identify microbial compositional changes on chicken carcasses during processing, 2) determine the antimicrobial efficacy of peracetic acid (PAA) and Amplon (blend of sulfuric acid and sodium sulfate) at a poultry processing pilot plant scale, and 3) compare microbial communities between chicken carcass rinsates and recovered bacteria from media. Birds were collected from each processing step and rinsates were applied to estimate aerobic plate count (APC) and Campylobacter as well as Salmonella prevalence. Microbiome sequencing was utilized to identify microbial population changes over processing and antimicrobial treatments. Only the PAA treatment exhibited significant reduction of APC at the post chilling step while both Amplon and PAA yielded detectable Campylobacter reductions at all steps. Based on microbiome sequencing, Firmicutes were the predominant bacterial group at the phyla level with over 50% frequency in all steps while the relative abundance of Proteobacteria decreased as processing progressed. Overall microbiota between rinsate and APC plate microbial populations revealed generally similar patterns at the phyla level but they were different at the genus level. Both antimicrobials appeared to be effective on reducing problematic bacteria and microbiome can be utilized to identify optimal indicator microorganisms for enhancing product quality.

A growing body of research suggests daily low-dose aspirin (ASA) reduces heart diseases and colorectal cancers. However, the major limitation to the use of aspirin is its side effect to cause ulceration and bleeding in the gastrointestinal tract. Preclinical studies have shown that ginger constituents ameliorate ASA-induced gastric ulceration. We here report the design and synthesis of a novel prodrug of aspirin, [6]-gingerol aspirinate (GAS). Our data show that GAS exerts enhanced anti-cancer properties in vitro and superior gastroprotective effects in mice. GAS was also able to survive stomach acid and decomposed in intestinal linings or after absorption to simultaneously release ASA and [6]-gingerol. We further present that GAS inactivates both COX-1 and COX-2 equally. Our results demonstrate the enhanced anticancer properties along with gastroprotective effects of GAS, suggesting that GAS can be a therapeutic equivalent for ASA in inflammatory and proliferative diseases without the deleterious effects on stomach mucosa.

Mounting evidence suggests that whole grain (WG) intake plays an important role in chronic disease prevention. However, numerous human studies have failed to produce clear-cut conclusions on this topic. Here, a combination of non-targeted and targeted metabolomics approaches, together with kinetic studies, was used to investigate biomarkers of WG wheat intake and further explore the diet-disease associations. Via these integrated approaches, forty-one compounds were identified as the most discriminating endogenous metabolites after WG versus refined grain (RG) wheat bread consumption. The corresponding biological assessment of these endogenous changes suggests that, in contrast to RG consumption, WG wheat consumption may facilitate antioxidant defense systems and moderate the risk factors of cancer, cardiovascular diseases, and other chronic diseases. A panel of urinary markers consisting of seven alkylresorcinol metabolites and five benzoxazinoid derivatives as specific biomarkers, as well as five phenolic acid derivatives, was also established to cover multiple time points and longer time periods for correctly and objectively monitoring WG wheat intake. Through these findings, we have established a comprehensive biomarker pool to better assess WG wheat consumption, and to monitor the endogenous changes that are linked to health effects of WG wheat consumption.

Hemolytic anemia intensity has been suggested as a vital factor for the growth of certain clinical complications of sickle cell disease. However, there is no effective and rapid diagnostic method. As a powerful platform for bio-particles testing, biosensors integrated with microfluidics offer great potential for a new generation of portable point of care systems. In this paper, we describe a novel portable microsystem consisting of a multifunctional dielectrophoresis manipulations (MDM) device and a surface stress biosensor to separate and detect red blood cells (RBCs) for diagnosis of hemolytic anemia. The peripheral circuit to power the interdigitated electrode array of the MDM device and the surface stress biosensor test platform were integrated into a portable signal system. The MDM includes a preparing region, a focusing region, and a sorting region. Simulation and experimental results show the RBCs trajectories when they are subjected to the positive DEP force, allowing the successful sorting of living/dead RBCs. Separated RBCs are then transported to the biosensor and the capacitance values resulting from the variation of surface stress were measured. The diagnosis of hemolytic anemia can be realized by detecting RBCs and the portable microsystem provides the assessment to the hemolytic anemia patient.

The application of plasmonics to thermal emitters is generally assisted by absorptive losses in the metal because Kirchhoff's law prescribes that only good absorbers make good thermal emitters. Based on a designed plasmonic crystal and exploiting a slow-wave lattice resonance and spontaneous thermal plasmon emission, we engineer a tungsten-based thermal emitter, fabricated in an industrial CMOS process, and demonstrate its markedly improved practical use in a prototype non-dispersive infrared (NDIR) gas-sensing device. We show that the emission intensity of the thermal emitter at the CO(2) absorption wavelength is enhanced almost 4-fold compared to a standard non-plasmonic emitter, which enables a proportionate increase in the signal-to-noise ratio of the CO(2) gas sensor.

CD4(+)FOXP3(+) regulatory T (Treg) cells are essential for maintaining immunological self-tolerance. Treg cell development and function depend on the transcription factor FOXP3, which is present in several distinct isoforms due to alternative splicing. Despite the importance of FOXP3 in the proper maintenance of Treg cells, the regulation and functional consequences of FOXP3 isoform expression remains poorly understood. Here, we show that in human Treg cells IL-1β promotes excision of FOXP3 exon 7. FOXP3 is not only expressed by Treg cells but is also transiently expressed when naïve T cells differentiate into Th17 cells. Forced splicing of FOXP3 into FOXP3Δ2Δ7 strongly favored Th17 differentiation in vitro. We also found that patients with Crohn's disease express increased levels of FOXP3 transcripts lacking exon 7, which correlate with disease severity and IL-17 production. Our results demonstrate that alternative splicing of FOXP3 modulates T cell differentiation. These results highlight the importance of characterizing FOXP3 expression on an isoform basis and suggest that immune responses may be manipulated by modulating the expression of FOXP3 isoforms, which has broad implications for the treatment of autoimmune diseases.

Hepatocellular carcinoma (HCC) has a high fatality rate and limited therapeutic options with side effects and low efficacy. Here, we proposed a new anti-HCC approach based on cancer-specific post-transcriptional targeting. To this end, trans-splicing ribozymes from Tetrahymena group I intron were developed, which can specifically induce therapeutic gene activity through HCC-specific replacement of telomerase reverse transcriptase (TERT) RNA. To circumvent side effects due to TERT expression in regenerating liver tissue, liver-specific microRNA-regulated ribozymes were constructed by incorporating complementary binding sites for the hepatocyte-selective microRNA-122a (miR-122a), which is down-regulated in HCC. The ribozyme activity in vivo was assessed in mouse models orthotopically implanted with HCC. Systemic administration of adenovirus encoding the developed ribozymes caused efficient anti-cancer effect and the least hepatotoxicity with regulation of ribozyme expression by miR-122a in both xenografted and syngeneic orthotopic murine model of multifocal HCC. Of note, the ribozyme induced local and systemic antitumor immunity, thereby completely suppressing secondary tumor challenge in the syngeneic mouse. The cancer specific trans-splicing ribozyme system, which mediates tissue-specific microRNA-regulated RNA replacement, provides a clinically relevant, safe, and efficient strategy for HCC treatment.

The application of next generation sequencing (NGS) technology in the diagnosis of human pathogens is hindered by the fact that pathogenic sequences, especially viral, are often scarce in human clinical specimens. This known disproportion leads to the requirement of subsequent deep sequencing and extensive bioinformatics analysis. Here we report a method we called "Preferential Amplification of Pathogenic Sequences (PATHseq)" that can be used to greatly enrich pathogenic sequences. Using a computer program, we developed 8-, 9-, and 10-mer oligonucleotides called "non-human primers" that do not match the most abundant human transcripts, but instead selectively match transcripts of human pathogens. Instead of using random primers in the construction of cDNA libraries, the PATHseq method recruits these short non-human primers, which in turn, preferentially amplifies non-human, presumably pathogenic sequences. Using this method, we were able to enrich pathogenic sequences up to 200-fold in the final sequencing library. This method does not require prior knowledge of the pathogen or assumption of the infection; therefore, it provides a fast and sequence-independent approach for detection and identification of human viruses and other pathogens. The PATHseq method, coupled with NGS technology, can be broadly used in identification of known human pathogens and discovery of new pathogens.

Polymer light emitting diodes (PLEDs) using quantum dots (QDs) as emissive materials have received much attention as promising components for next-generation displays. Despite their outstanding properties, toxic and hazardous nature of QDs is a serious impediment to their use in future eco-friendly opto-electronic device applications. Owing to the desires to develop new types of nano-material without health and environmental effects but with strong opto-electrical properties similar to QDs, graphene quantum dots (GQDs) have attracted great interest as promising luminophores. However, the origin of electroluminescence from GQDs incorporated PLEDs is unclear. Herein, we synthesized graphene oxide quantum dots (GOQDs) using a modified hydrothermal deoxidization method and characterized the PLED performance using GOQDs blended poly(N-vinyl carbazole) (PVK) as emissive layer. Simple device structure was used to reveal the origin of EL by excluding the contribution of and contamination from other layers. The energy transfer and interaction between the PVK host and GOQDs guest were investigated using steady-state PL, time-correlated single photon counting (TCSPC) and density functional theory (DFT) calculations. Experiments revealed that white EL emission from the PLED originated from the hybridized GOQD-PVK complex emission with the contributions from the individual GOQDs and PVK emissions.

Dental hypersensitivity due to exposure of dentinal tubules under the enamel layer to saliva is a very popular and highly elusive technology priority in dentistry. Blocking water flow within exposed dentinal tubules is a key principle for curing dental hypersensitivity. Some salts used in "at home" solutions remineralize the tubules inside by concentrating saliva ingredients. An "in-office" option of applying dense resin sealants on the tubule entrance has only localized effects on well-defined sore spots. We report a self-assembled film that was formed by facile, rapid (4 min), and efficient (approximately 0.5 g/L concentration) dip-coating of teeth in an aqueous solution containing a tannic acid-iron(III) complex. It quickly and effectively occluded the dentinal tubules of human teeth. It withstood intense tooth brushing and induced hydroxyapatite remineralisation within the dentinal tubules. This strategy holds great promise for future applications as an effective and user-friendly desensitizer for managing dental hypersensitivity.

We have realized a p-type-like conduction in initially n-type SnO2 nanowires grown using a vapor-liquid-solid method. The transition was achieved by irradiating n-type SnO2 nanowires with a high-energy electron beam, without intentional chemical doping. The nanowires were irradiated at doses of 50 and 150 kGy, and were then used to fabricate NO2 gas sensors, which exhibited n-type and p-type conductivities, respectively. The tuneability of the conduction behavior is assumed to be governed by the formation of tin vacancies (under high-energy electron beam irradiation), because it is the only possible acceptor, excluding all possible defects via density functional theory (DFT) calculations. The effect of external electric fields on the defect stability was studied using DFT calculations. The measured NO2 sensing dynamics, including response and recovery times, were well represented by the electron-hole compensation mechanism from standard electron-hole gas equilibrium statistics. This study elucidates the charge-transport characteristics of bipolar semiconductors that underlie surface chemical reactions. The principles derived will guide the development of future SnO2-based electronic and electrochemical devices.

Cognitive reserve is the ability to sustain cognitive function even with a certain amount of brain damages. Here we investigate the neural compensation mechanism of cognitive reserve from the perspective of structural brain connectivity. Our goal was to show that normal people with high education levels (i.e., cognitive reserve) maintain abundant pathways connecting any two brain regions, providing better compensation or resilience after brain damage. Accordingly, patients with high education levels show more deterioration in structural brain connectivity than those with low education levels before symptoms of Alzheimer's disease (AD) become apparent. To test this hypothesis, we use network flow measuring the number of alternative paths between two brain regions in the brain network. The experimental results show that for normal aging, education strengthens network reliability, as measured through flow values, in a subnetwork centered at the supramarginal gyrus. For AD, a subnetwork centered at the left middle frontal gyrus shows a negative correlation between flow and education, which implies more collapse in structural brain connectivity for highly educated patients. We conclude that cognitive reserve may come from the ability of network reorganization to secure the information flow within the brain network, therefore making it more resistant to disease progress.

A stencil lithography technique has been developed to fabricate organic-material-based electronic devices with sub-micron resolution. Suspended polymethylmethacrylate (PMMA) membranes were used as shadow masks for defining organic channels and top electrodes. Arrays of pentacene field effect transistors (FETs) with various channel lengths from 50 μm down to 500 nm were successfully produced from the same batch using this technique. Electrical transport measurements showed that the electrical contacts of all devices were stable and the normalized contact resistances were much lower than previously studied organic FETs. Scaling effects, originating from the bulk space charge current, were investigated by analyzing the channel-length-dependent mobility and hysteresis behaviors. This novel lithography method provides a reliable means for studying the fundamental transport properties of organic materials at the nanoscale as well as enabling potential applications requiring the fabrication of integrated organic nanoelectronic devices.

Pine cones fold their scales when it rains to prevent seeds from short-distance dispersal. Given that the scales of pine cones consist of nothing but dead cells, this folding motion is evidently related to structural changes. In this study, the structural characteristics of pine cones are studied on micro-/macro-scale using various imaging instruments. Raindrops fall along the outer scales to the three layers (bract scales, fibers and innermost lignified structure) of inner pine cones. However, not all the layers but only the bract scales get wet and then, most raindrops move to the inner scales. These systems reduce the amount of water used and minimize the time spent on structural changes. The result shows that the pine cones have structural advantages that could influence the efficient motion of pine cones. This study provides new insights to understand the motion of pine cones and would be used to design a novel water transport system.

Aim: Pirarubicin (THP) is recently found to be effective in treating patients with advanced, relapsed or recurrent high-grade osteosarcoma. In this study, the effects of THP on the multidrug-resistant (MDR) osteosarcoma cells were assessed, and the underlying mechanisms for the disruption of cell cycle kinetics by THP were explored., Methods: Human osteosarcoma cell line MG63 and human MDR osteosarcoma cell line MG63/DOX were tested. The cytotoxicity of drugs was examined using a cell proliferation assay with the Cell Counting Kit-8 (CCK-8). The distribution of cells across the cell cycle was determined with flow cytometry. The expression of cell cycle-regulated genes cyclin B1 and Cdc2 (CDK1), and the phosphorylated Cdc2 and Cdc25C was examined using Western blot analyses., Results: MG63/DOX cells were highly resistant to doxorubicin (ADM) and gemcitabine (GEM), but were sensitive or lowly resistant to THP, methotrexate (MTX) and cisplatin (DDP). Treatment of MG63/DOX cells with THP (200-1000 ng/mL) inhibited the cell proliferation in time- and concentration-dependent manners. THP (50-500 ng/mL) induced MG63/DOX cell cycle arrest at the G(2)/M phase in time- and concentration-dependent manners. Furthermore, the treatment of MG63/DOX cells with THP (200-1000 ng/mL) downregulated cyclin B1 expression, and decreased the phosphorylated Cdc2 at Thr(161). Conversely, the treatment increased the phosphorylated Cdc2 at Thr(14)/Tyr(15) and Cdc25C at Ser(216), which led to a decrease in Cdc2-cyclin B1 activity., Conclusion: The cytotoxicity of THP to MG63/DOX cells may be in part due to its ability to arrest cell cycle progression at the G(2)/M phase, which supports the use of THP for managing patients with MDR osteosarcoma.