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The switch defective/sucrose non-fermentable (SWI/SNF) multisubunit complex plays an important role in the regulation of gene expression by remodeling chromatin structure. Three SWI/SNF complexes have been identified in Arabidopsis including BAS, SAS, and MAS. Many subunits of these complexes are involved in controlling plant development and stress response. However, the function of these complexes has hardly been studied in other plant species. In this study, we identified the subunits of the SWI/SNF complex in sorghum and analyzed their evolutionary relationships in six grass species. The grass species conserved all the subunits as in Arabidopsis, but gene duplication occurred diversely in different species. Expression pattern analysis in sorghum (Sorghum bicolor) showed that most of the subunit-encoding genes were expressed constitutively, although the expression level was different. Transactivation assays revealed that SbAN3, SbGIF3, and SbSWI3B possessed transactivation activity, which suggests that they may interact with the pre-initiation complex (PIC) to activate transcription. We chose 12 subunits in sorghum to investigate their interaction relationship by yeast two-hybrid assay. We found that these subunits displayed distinct interaction patterns compared to their homologs in Arabidopsis and rice. This suggests that different SWI/SNF complexes may be formed in sorghum to perform chromatin remodeling functions. Through the integrated analysis of MNase-seq and RNA-seq data, we uncovered a positive relationship between gene expression levels and nucleosome phasing. Furthermore, we found differential global nucleosome enrichments between leaves and roots, as well as in response to PEG treatment, suggesting that dynamics of nucleosome occupancy, which is probably mediated by the SWI/SNF complex, may play important roles in sorghum development and stress response.

Drought stress is the key factor limiting soybean yield potential. Soybean seed formation involves a coordinated “subtending leaf-podshell-seed” process, but little is known about the assimilation and transport of photoassimilates in subtending leaves, podshells and seeds or their relationships with soybean seed formation under drought stress. To address these research gaps, two-year experiments with two soybean cultivars, Wandou 37 (drought tolerant) and Zhonghuang 13 (drought sensitive), were conducted under three soil water content (SWC) conditions in 2020 and 2021 based on the responses of their yield to drought. We analyzed the photosynthetic assimilation and translocation of photoassimilates in subtending leaves, podshells and seeds by stable isotope labeling. Compared with those under 75% SWC, 60% SWC and 45% SWC significantly decreased the Wandou 37 seed weight by 19.4% and 37.5%, respectively, and that of Zhonghuang 13 by 26.9% and 48.6%, respectively. Compared with those under 75% SWC, drought stress decreased the net photosynthetic rate and the activities of sucrose phosphate synthase (SPS) and sucrose synthase (SuSy), which in turn decreased the photosynthetic capacity of the subtending leaves. The podshells ensure the input of photoassimilates by increasing the SuSy activity, but the weakened source–sink relationship between podshells and seeds under drought stress leads to a decrease in the translocation of assimilates from podshells to seeds. The lack of assimilates under drought stress is an important factor restricting the development of soybean seeds. We conclude that the decrease in seed weight was caused by the decrease in the photosynthetic capacity of the subtending leaves and the decrease in the overall availability of photoassimilates; moreover, by a decrease in the translocation of assimilates from podshells to seeds.

Quercetin (QR) is a natural flavonol compound widely distributed in the plant kingdom with extensive pharmacological effects. To find the potential clinical indications of QR, 156 differentially expressed genes (DEGs) regulated by QR were obtained from the Gene Expression Omnibus database, and new potential pharmacological effects and clinical indications of QR were repurposed by integrating compounds with similar gene perturbation signatures and associated-disease signatures to QR based on the Connectivity Map and Coexpedia platforms. The results suggested QR has mainly potential therapeutic effects on multiple sclerosis (MS), osteoarthritis, type 2 diabetes mellitus, and acute leukemia. Then, MS was selected for subsequent animal experiments as a representative potential indication, and it found that QR significantly delays the onset time of classical MS model animal mice and ameliorates the inflammatory infiltration and demyelination in the central nervous system. Combined with network pharmacology technology, the therapeutic mechanism of QR on MS was further demonstrated to be related to the inhibition of the expression of inflammatory cytokines (TNF-α, IL-6, IL-1β, IFN-γ, IL-17A, and IL-2) related to TNF-α/TNFR1 signaling pathway. In conclusion, this study expanded the clinical indications of QR and preliminarily confirmed the therapeutic effect and potential mechanism of QR on MS.

ObjectivesThis study aimed to construct and validate a predictive risk model (PRM) for nosocomial infections with multi-drug resistant organism (MDRO) in neonatal intensive care units (NICUs), in order to provide a scientific and reliable prediction tool, and to provide reference for clinical prevention and control of MDRO infections in NICUs.MethodsThis multicenter observational study was conducted at NICUs of two tertiary children’s hospitals in Hangzhou, Zhejiang Province. Using cluster sampling, eligible neonates admitted to NICUs of research hospitals from January 2018 to December 2020 (modeling group) or from July 2021 to June 2022 (validation group) were included in this study. Univariate analysis and binary logistic regression analysis were used to construct the PRM. H-L tests, calibration curves, ROC curves and decision curve analysis were used to validate the PRM.ResultsFour hundred and thirty-five and one hundred fourteen neonates were enrolled in the modeling group and validation group, including 89 and 17 neonates infected with MDRO, respectively. Four independent risk factors were obtained and the PRM was constructed, namely: P = 1/ (1+ e−X), X = −4.126 + 1.089× (low birth weight) +1.435× (maternal age ≥ 35 years) +1.498× (use of antibiotics >7 days) + 0.790× (MDRO colonization). A nomogram was drawn to visualize the PRM. Through internal and external validation, the PRM had good fitting degree, calibration, discrimination and certain clinical validity. The prediction accuracy of the PRM was 77.19%.ConclusionPrevention and control strategies for each independent risk factor can be developed in NICUs. Moreover, clinical staff can use the PRM to early identification of neonates at high risk, and do targeted prevention to reduce MDRO infections in NICUs.

Objective: Oculocutaneous albinism (OCA) is an autosomal recessive disorder caused by a variety of genomic variations. Our aim is to identify the molecular basis of OCA in two families and lay the foundation for prenatal diagnosis.Methods: Four types of OCA-causing mutations in the TYR, p, TYRP1, or SLC45A2 genes were screened. Linkage analysis was performed because the mutations found in the p gene violated the laws of classical Mendelian heredity. Primer-walking sequencing combined with microsatellite and single-nucleotide polymorphism analysis was used to ascertain deletion ranges. Bioinformatics methods were used to assess the pathogenicity of the new mutations.Results: Proband 1 was diagnosed as OCA2 with Prader–Willi syndrome (PWS) due to a novel atypical paternal deletion (chromosome 15: 22330347–26089649) and a pathogenic mutation, c.1327G>A (Val443Ile), in the p gene of the maternal chromosome. The prenatal diagnosis results for family 1 indicated the fetus was a heterozygous carrier (c.1327G>A in the p gene) with a normal phenotype. Proband 2 was diagnosed as OCA2 with Angelman syndrome (AS) due to a typical maternal deletion of chromosome 15q11-q13 and a novel mutation, c.1514T>C (Phe505Ser), in the p gene of the paternal chromosome. This novel mutation c.1514T>C (Phe505Ser) in the p gene was predicted as a pathogenic mutation.Conclusion: Our study has shown clear genotype–phenotype correlations in patients affected by distinct deletions of the PWS or AS region and missense mutations in the p gene. Our results have enriched the mutation spectrum of albinism diseases and provided insights for more accurate diagnosis and genetic counseling.

Meiotic recombination starts with the programmed formation of double-strand breaks (DSB) in DNA, which are catalyzed by SPO11, a type II topoisomerase that is evolutionarily conserved, and several other accessary proteins. Homologs of MEIOSIS INHIBITOR 4 (MEI4/REC24/PRD2) are proteins that are also essential for the generation of meiotic DSBs in budding yeast, mice and Arabidopsis thaliana. In Arabidopsis, the protein ARABIDOPSIS THALIANA PUTATIVE RECOMBINATION INITIATION DEFECTS 2/MULTIPOLAR SPINDLE 1 (AtPRD2/MPS1) has been shown to have additional roles in spindle assembly, indicating a functional diversification. Here we characterize the role of the rice MEI4/PRD2 homolog in meiosis. The osprd2 mutant was completely male and female sterile. In male meiocytes of osprd2, no γH2AX foci were detected and twenty-four univalents were produced at diakinesis, suggesting that OsPRD2 is essential for DSB generation. OsPRD2 showed a dynamic localization during meiosis. For instance, OsPRD2 foci first appeared as discrete signals across chromosome at leptotene, and then became confined to the centromeres during zygotene, suggesting that they might be involved in assembly of the spindle. However we did not observe any obvious aberrant morphologies in neither the organization of the bipolar spindle nor in the orientation of the kinetochore in the mutant. These findings suggest that in rice PRD2 might not be required for spindle assembly and organization, as it does in Arabidopsis. Taken together our results indicate that plant MEI4/PRD2 homologs do play a conserved role in the formation of meiotic DSBs in DNA, but that their involvement in bipolar spindle assembly is rather species-specific.

Deep seismic sounding (DSS) profiles are one of the most powerful tools for detecting crustal structures, and they have been deployed worldwide. Generally, the analysis of DSS data mainly focuses on body waves, while the surface waves are considered noise. We suggest that the surface waves in DSS data can be used to constrain subsurface structures. In this study, we use a DSS profile in the Piedmont and Atlantic Coastal Plain as an example to present the usage of the DSS surface wave. Multimodal dispersion curves were extracted from the DSS data with the Frequency-Bessel transform method, and were used in Monte Carlo joint inversions with body wave refraction traveltimes to constrain the shallow structures. Through the inversion, a horizontal stratum on the surface was identified in the Piedmont, and a two-layer sedimentary structure was identified in the Atlantic Coastal Plain. Comparisons with existing studies verified the accuracy of the shallow structures obtained in this study, demonstrating that the shallow velocity structure could be well constrained with the additional constraints provided by the multimodal dispersion curves. Thus, we believe that further research on the surface waves recorded in DSS surveys is warranted.

Purpose: The aim of the study was to investigate microcirculation changes in the macula evaluated by optical coherence tomography angiography (OCTA)in patients receiving anatomical repair after surgery for rhegmatogenous retinal detachment (RRD).Methods: A literature search was conducted in PubMed, EMBASE, Web of Science and the Cochrane Library. Studies including patients with macula-on or macula-off RRD and repaired successfully through primary surgery were selected. Foveal avascular zone (FAZ) area and macular vascular density (VD) in both the superficial capillary plexus (SCP) and deep capillary plexus (DCP) were analyzed using RevMan 5.4 software.Results: Twelve studies including 430 RRD eyes and 430 control eyes were selected. In eyes with macula-on RRD, FAZ area, VD in the foveal SCP and DCP, and VD in the parafoveal SCP and DCP were not altered compared with control eyes, after the retina was reattached. In eyes with macula-off RRD that was repaired successfully through surgery, FAZ area in the DCP (0.13 mm2, 95% CI: 0.02 to 0.25, p = 0.02) remained enlarged compared with control eyes. Meanwhile, VD in the foveal DCP was also significantly reduced (−3.12%, 95% CI: −6.15 to −0.09%, p = 0.04), even though retinal reattachment was achieved by surgery in eyes with macula-off RRD.Conclusion: In patients with macula-off rhegmatogenous retinal detachment, foveal avascular zone area in the deep capillary plexuses was enlarged and vascular density in the foveal deep capillary plexus was reduced, even after the retina was successfully reattached through a primary surgery.

Background: Renshen-Fuzi herb pair (RS-FZ) is often used in the clinical treatment of heart failure (HF) and has a remarkable therapeutic effect. However, the mechanism of RS-FZ for treating HF remains unclear. In our study, we explored the mechanism of RS-FZ for treating HF.Methods: Evaluation of RS-FZ efficacy by cardiovascular pharmacology. Moreover, Global metabolomics profiling of the serum was detected by UPLC-QTOF/MS. Multivariate statistics analyzed the specific serum metabolites and corresponding metabolic pathways. Combining serum metabolomics with network pharmacology, animal experiments screened and validated the critical targets of RS-FZ intervention in HF.Results: RS-FZ significantly ameliorated myocardial fibrosis, enhanced cardiac function, and reduced the serum HF marker (brain natriuretic peptide) level in rats with HF. Through topological analysis of the “Metabolite-Target-Component” interaction network, we found that 79 compounds of RS-FZ directly regulated the downstream specific serum metabolites by acting on four critical target proteins (CYP2D6, EPHX2, MAOB, and ENPP2). The immunohistochemistry results showed that RS-FZ observably improved the expression of CYP2D6 and ENPP2 proteins while decreasing the expression of EPHX2 and MAOB proteins dramatically.Conclusion: The integrated cardiovascular pharmacological assessment with serum metabolomics revealed that RS-FZ plays a crucial role in the treatment of HF by intervening in CYP2D6, EPHX2, MAOB, and ENPP2 target proteins. It provides a theoretical basis for RS-FZ for treating HF.

In this paper, an adaptive finite-time fan-coil outlet wind temperature control scheme is proposed for the air-source heat pump air-conditioning system. First, a correction module is introduced to compensate the first-order damp elements in the temperature sensor to capture the temperature in real-time. Then, a simple neural network is employed to approximate the unknown and nonlinear functions of the system. On this basis, an adaptive finite-time neural controller is developed, and the finite-time convergence of temperature regulation error is ensured. The stability of the studied fan-coil control is guaranteed by rigorous Lyapunov proof. Finally, two simulation examples are carried out to verify the effectiveness of the proposed control scheme.

The crustal low-velocity zone (LVZ), an important anomaly found in some regional structures of Iceland, is still absent in the Icelandic average velocity structure due to limitations of tomography methods. Using stations from the HOTSPOT experiment and other supplemental stations throughout Iceland, we apply the frequency-Bessel transform method (F-J method) to extract the first two mode dispersion curves from ambient noise data. We obtain an average S-wave velocity (Vs) model of Iceland down to 120 km depth, where two LVZs at depths of 12–22 km and below 55 km are found. The shallow LVZ, whose rationalities are justified using theoretical dispersion curves of certain models to recover themselves, may improve the understanding of the Icelandic average crust. Furthermore, our model shows better representativeness by comparing travel time residuals of the primary wave between observed and synthetic data predicted using different average velocity models. Based on the variations of the Vs gradient, the Icelandic crust with an average thickness of 32 km is divided into the upper crust (0–10 km), middle crust (10–22 km), and lower crust (22–32 km). The asthenosphere starts from the deeper LVZ at 55 km depth, potentially indicating the relatively concentrated melt in this depth range. In this study, crustal LVZs are revealed both in a volcanic active zone and a non-volcanic zone, which may also suggest the LVZ in the average model has more complex origins than the high-temperature zone beneath the central volcanoes. The prevalent thick-cold crustal model of Iceland, considered to rule out the existence of a broad region of partial melt in the crust, also strengthens the possibility of diverse origins. The variations in petrology may also contribute to the crustal LVZ in the average model.

Electrochemical carbon nanotube (CNT) and carboxylated carbon nanotube (CNT-COOH) membranes were prepared by vacuum filtration for the removal of antibiotics and antibiotic resistance genes (ARGs) from water. Scanning electron microscopy and energy-dispersive spectroscopy were used to analyze the performances of the two electrochemical membranes in the removal of antibiotics and ARGs, to determine the effects of different factors on removal rates, and to explore the mechanisms of the removal of antibiotics and ARGs. The results showed that CNT-COOH formed a porous mesh structure on the surface of polytetrafluoroethylene membrane and contained more oxygen than CNT. The electrochemical CNT-COOH membrane showed higher antibiotic and ARG removal rates than the electrochemical CNT membrane, with an antibiotics removal rate of 82% after 60 min of reaction and an ARGs concentration decrease by 1.85 log. The removal rate of antibiotics and ARGs increased with the increase in electrolyte concentration and anode voltage but decreased with the increase in the influent flow rate. The removal rate of antibiotics decreased with the increase in pH, while the best removal rates of ARGs were observed in a neutral environment. The degradation mechanism of antibiotics on the electrochemical CNT-COOH membrane was analyzed, and possible antibiotic degradation pathways were proposed. The removal of antibiotics and ARGs mainly occurred through electrochemical degradation, where hydroxyl radicals (-OH) played a dominant role.

Source apportionment of surface water is essential for effective pollution control and sustainable water management. Physical mechanism models usually need so much data and parameters for calibration that their application for complex hydrologic condition watershed becomes difficult. However, reverse source tracing methods only based on water quality parameters present a certain subjectivity and uncertainty. In this research, additional land-use parameters were applied as an auxiliary in principal component analysis (PCA) for accurate identification of pollution sources. Thirteen water quality parameters and two meteorology parameters were used in the PCA and absolute principal component score–multiple linear regression (APCS–MLR) model to quantitatively identify potential pollution sources and their contributions to surface water pollution of the Poyang Lake Basin, in which frequent flow and sediment flux exchange with Yangtze River make the river–lake relationship complex. The results showed that urban wastewater with 34% contribution and agricultural non-point sources with 16% contribution, were the major sources of pollution in water quality. TP and NH3–N, the most serious pollutants, causing agricultural non-point source pollutions with 40% contributions and urban wastewater with 21% contributions were the major sources in the Poyang Lake Basin. Urban wastewater with 60% contributions was the major source of organic contamination. It can be concluded that with associated land-use parameters, the GIS approach with the APCS–MLR model can improve the accuracy and certainty of source apportionment, providing aid decision information for managers on protection of surface water quality.

Translational RelevanceEvaluation of targeted therapies is urgently needed for the majority of patients with metastatic/recurrent head and neck squamous cell carcinoma (HNSCC) who progress after immunochemotherapy. Erlotinib, a targeted inhibitor of epidermal growth factor receptor pathway, lacks FDA approval in HNSCC due to inadequate tumor response. This study identifies two potential avenues to improve tumor response to erlotinib among patients with HNSCC. For the first time, this study shows that an increased erlotinib dose of 300 mg in smokers is well-tolerated and produces similar plasma drug concentration as the regular dose of 150 mg in non-smokers, with increased study-specific defined tumor response. The study also highlights the opportunity for improved patient selection for erlotinib treatment by demonstrating that early in-treatment [18]FDG PET/CT is a potential predictor of tumor response, with robust statistical correlations between metabolic changes on early in-treatment PET (4-7 days through treatment) and anatomic response measured by end-of-treatment CT.PurposePatients with advanced HNSCC failing immunochemotherapy have no standard treatment options. Accelerating the investigation of targeted drug therapies is imperative. Treatment with erlotinib produced low response rates in HNSCC. This study investigates the possibility of improved treatment response through patient smoking status-based erlotinib dose optimization, and through early in-treatment [18]FDG PET evaluation to differentiate responders from non-responders.Experimental designIn this window-of-opportunity study, patients with operable HNSCC received neoadjuvant erlotinib with dose determined by smoking status: 150 mg (E150) for non-smokers and 300 mg (E300) for active smokers. Plasma erlotinib levels were measured using mass spectrometry. Patients underwent PET/CT before treatment, between days 4-7 of treatment, and before surgery (post-treatment). Response was measured by diagnostic CT and was defined as decrease in maximum tumor diameter by ≥ 20% (responders), 10-19% (minimum-responders), and < 10% (non-responders).ResultsNineteen patients completed treatment, ten of whom were smokers. There were eleven responders, five minimum-responders, and three non-responders. Tumor response and plasma erlotinib levels were similar between the E150 and E300 patient groups. The percentage change on early PET/CT and post-treatment PET/CT compared to pre-treatment PET/CT were significantly correlated with the radiologic response on post-treatment CTs: R=0.63, p=0.0041 and R=0.71, p=0.00094, respectively.ConclusionThis pilot study suggests that early in-treatment PET/CT can predict response to erlotinib, and treatment with erlotinib dose adjusted according to smoking status is well-tolerated and may improve treatment response in HNSCC. These findings could help optimize erlotinib treatment in HNSCC and should be further investigated.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT00601913, identifier NCT00601913.

BackgroundDevelopment of severe immune-related adverse events (irAEs) is a major predicament to stop treatment with immune checkpoint inhibitors, even though tumor progression is suppressed. However, no effective early phase biomarker has been established to predict irAE until now.MethodThis study retrospectively used the data of four international, multi-center clinical trials to investigate the application of blood test biomarkers to predict irAEs in atezolizumab-treated advanced non-small cell lung cancer (NSCLC) patients. Seven machine learning methods were exploited to dissect the importance score of 21 blood test biomarkers after 1,000 simulations by the training cohort consisting of 80%, 70%, and 60% of the combined cohort with 1,320 eligible patients.ResultsXGBoost and LASSO exhibited the best performance in this study with relatively higher consistency between the training and test cohorts. The best area under the curve (AUC) was obtained by a 10-biomarker panel using the XGBoost method for the 8:2 training:test cohort ratio (training cohort AUC = 0.692, test cohort AUC = 0.681). This panel could be further narrowed down to a three-biomarker panel consisting of C-reactive protein (CRP), platelet-to-lymphocyte ratio (PLR), and thyroid-stimulating hormone (TSH) with a small median AUC difference using the XGBoost method [for the 8:2 training:test cohort ratio, training cohort AUC difference = −0.035 (p < 0.0001), and test cohort AUC difference = 0.001 (p=0.965)].ConclusionBlood test biomarkers currently do not have sufficient predictive power to predict irAE development in atezolizumab-treated advanced NSCLC patients. Nevertheless, biomarkers related to adaptive immunity and liver or thyroid dysfunction warrant further investigation.

Seed germination is the sensitive period to salt stress. Calcium chloride (CaCl2) has been proved as an effective priming agent which can promote the sorghum germination under salt stress. However, there are few reports on CaCl2 priming to improve the salt tolerance during seed germination. The present study investigated the effects of CaCl2 priming on sorghum germination, antioxidant metabolism, osmotic regulation and ion balance under salt stress (150 mM NaCl). The results revealed that the salt stress inhibited the elongation of mesocotyl and root and reduced the germination rate of sorghum. While CaCl2 priming significantly promoted the elongation of mesocotyl and root, and increased the germination rate of sorghum under salt stress. CaCl2 priming notably increased the content of osmotic substances in mesocotyl and root of sorghum under salt stress, and increased the relative water content in these tissues. CaCl2 priming decreased Na+ content and increased K+, Ca2+ contents and the K+/ Na+ in mesocotyl and root, such effects might be induced by up-regulating the expression of NHX2, NHX4, SOS1, AKT1, AKT2, HKT1, HAK1, and KUP. CaCl2 priming reduced the antioxidant enzymes activities and related gene expression compared with untreated sorghum seeds under salt stress. In short, CaCl2 priming improved sorghum germination by enhancing osmotic regulation and ion balance instead of antioxidant enzyme activity. However, the molecular mechanisms of Ca2+ signaling induced by CaCl2 priming in association with the enhanced germination in primed sorghum seeds under salt stress need to be addressed in future studies.

AimThis study aimed to explore how different dimensions of caregivers' reaction shape their caring experience, and the factors associated with different reaction patterns.DesignA second analysis of a multisite cross-sectional study were conducted. Caregivers of children with imperforate anus (IA) were enrolled in three tertiary children's hospitals in Eastern China between November 2018 and February 2019.MethodsThe caregiver's experience, stigma feeling, social support level and perception of uncertainty were assessed by Caregiver Reaction Assessment, Parent Stigma Scale, Social Support Scale and Parent's Perception of Uncertainty Scale accordingly. The demographic information of caregivers as well as the children's clinical data were collected. Latent profile analysis was conducted to determine different patterns of caregiver's reaction, and logistics analysis was used to explore the associated factors of the reaction pattern.FindingsA total number of 229 caregivers (median age = 30, quartiles: 28, 36) were included. Three distinguishable caregiving reaction types were identified (Class 1: low burden and high benefit, 4.8%; Class 2: moderate burden and benefit, 48.9%; Class 3: high burden and low benefit, 46.3%). In logistics analysis, the Class 1 and Class 2 were combined as one group due to the low population in Class 1. The marital status of caregiver (OR = 0.067, 95% CI: 0.006, 0.700, P = 0.024), IA type (OR = 1.745, 95% CI: 1.198, 2.541, P = 0.004), children aged > 2 years (OR = 3.219, 95% CI: 1.364, 7.597, P = 0.008), social support (OR = 0.907, 95% CI: 0.865, 0.951, P < 0.001) and perception of uncertainty (OR = 1.054, 95% CI: 1.026, 1.083, P < 0.001) were associated with different caregiver reaction patterns.ConclusionNearly half of the caregivers of children with IA experience reaction of high burden and low benefit, but considerable proportion of caregivers could benefit from the caregiving rather than burden from. Married caregivers may have more negative reaction, especially when children > 2 years and diagnosed with intermediate or high type of IA. However, increasing caregiver's social support and reducing perception of uncertainty may have the potential to modify their reaction pattern.

The northwestern Bohemian Massif and adjacent areas are a tectonically active region associated with complex geodynamic activities, that manifest as Quaternary volcanism, earthquake swarms in the upper and middle crust, degassing of CO2, and crustal fluid migration. The intricate tectonic evolution and activities of this region reflect the complexity of the crustal structure therein. However, the crustal models derived from previous studies in this area offer different, even contradictory information regarding the existence of a mid-crustal low-velocity zone (LVZ). In this study, we apply the frequency-Bessel transform (F-J) method to extract the fundamental-mode and up to five higher-mode Rayleigh wave dispersion curves from ambient seismic noise data recorded in the study area and perform multimodal ambient noise dispersion curves inversion. The addition of higher-mode dispersion curves enhances the vertical resolution of the velocity structure inversion results. Our models support the view that the general S-wave velocity level of the crust is high within the study area. We detect two S-wave LVZs beneath the study area that are distributed mainly in the middle crust rather than the lower crust, and these LVZs are separated by a high-velocity zone. Considering the results of previous studies in the area, we infer that these S-wave LVZs may be the consequence of crustal fluids, plastic deformation and even partial melting of the felsic middle crust at relatively high crustal temperatures. Furthermore, these S-wave LVZs could be responsible for the origin and foci depth distribution of earthquake swarms. S-wave low-velocity anomalies are also observed in the uppermost mantle beneath the study area. These S-wave models based on the joint inversion of multimodal dispersion curves can provide new references for understanding the tectonic activity and geodynamic evolution of the northwestern Bohemian Massif and adjacent areas.

Background: Formaldehyde (FA) is ubiquitous in the environment and can be transferred to the fetus through placental circulation, causing miscarriage and congenital heart disease (CHD). Studies have shown that βII spectrin is necessary for cardiomyocyte survival and differentiation, and its loss leads to heart development defects and cardiomyocyte apoptosis. Additionally, previous studies have demonstrated that miRNA is essential in heart development and remodeling. However, whether miRNA regulates FA-induced CHD and cardiomyocyte apoptosis remains unclear.Methods: Using commercially available rat embryonic cardiomyocytes and a rat model of fetal cardiomyocyte apoptosis. Real-time quantitative PCR (RT-qPCR) and Western blot were performed to examine the level of miR-153-3p, βII spectrin, caspase 7, cleaved caspase7, Bax, Bcl-2 expression in embryonic cardiomyocytes and a rat model of fetal cardiomyocyte apoptosis. Apoptotic cell populations were evaluated by flow cytometry and Tunel. Luciferase activity assay and RNA pull-down assay were used to detect the interaction between miR-153-3p and βII spectrin. Masson's trichrome staining detects the degree of tissue fibrosis. Fluorescence in situ hybridization (FISH) and Immunohistochemistry were used to detect the expression of miR-153-3p and βII spectrin in tissues.Results: Using commercially available rat embryonic cardiomyocytes and a rat model of fetal cardiomyocyte apoptosis, our studies indicate that miR-153-3p plays a regulatory role by directly targeting βII spectrin to promote cardiomyocyte apoptosis. miR-153-3p mainly regulates cardiomyocyte apoptosis by regulating the expression of caspase7, further elucidating the importance of apoptosis in heart development. Finally, the results with our animal model revealed that targeting the miR-153-3p/βII spectrin pathway effectively regulated FA-induced damage during heart development. Recovery experiments with miR-153-3p antagomir resulted in the reversal of FA-induced cardiomyocyte apoptosis and fetal cardiac fibrosis.Conclusion: This study investigated the molecular mechanism underpinning the role of βII spectrin in FA-induced CHD and the associated upstream miRNA pathway. The study findings suggest that miR-153-3p may provide a potential target for the clinical diagnosis and treatment of CHD.

Demand response (DR) is a powerful tool to maintain the stability of the power system and maximize the profit of the electricity market, where the customers engage in the pricing scheme and adjust their electricity demand proactively based on the price. In DR programs, most existing works are based on the assumption that the prediction of the electricity demand from customers is always accurate and trustworthy, which will lead to high cost and fluctuation of the electricity market once the prediction is obeyed. In this paper, we design a reward and punishment mechanism to constrain customers’ dishonest behaviors and propose a novel pricing algorithm based on the reward and punishment mechanism to relax the assumption, which guarantees the total electricity demands of all customers are within a secure range and obtain the maximum profit of the supplier. Meanwhile, we obtain the optimal demand and provide a upper and lower bound of the proposed price for the electricity market. In addition to a single type of customer, we also consider multiple types of customers, each of whom has different characteristics to prices. Extensive simulation results are constructed to demonstrate the effectiveness of the proposed algorithm compared with other pricing algorithms. It also shows that the average electricity consumption of a whole community is mostly affected by the residents’ electricity consumption and the balance of the supply and all types of customers is achieved under the proposed pricing algorithm.

Our previous study showed that hypidone hydrochloride (YL-0919), a partial serotonin 1A (5-HT1A) receptor agonist and 5-HT reuptake inhibitor, exerts a significant antidepressant effect in various animal models. The aim of the present study was to further investigate the underlying mechanisms and whether it could act as a fast-onset antidepressant. In the current study, depressive-like behavior was induced in rats by a chronic unpredictable stress (CUS) model and assessed with the Sucrose Preference Test (SPT). Treatment with YL-0919 (2.5 mg/kg, i.g.), but not with fluoxetine (Flx; 10 mg/kg, i.g.), caused a fast improvement in the SPT scores. In CUS-exposed rats, YL-0919 treatment for 5 days decreased the immobility time in a forced swimming test (FST), and a 10-day treatment decreased the latency to feed in a Novelty-Suppressed Feeding Test (NSFT). In addition to the behavioral tests, the effects of YL-0919 on synaptic protein expression were also evaluated. Western blotting showed that YL-0919 significantly enhanced the expression levels of synaptic proteins such as synapsin I, postsynaptic density protein 95 (PSD95), phosphorylated mammalian targeting of rapamycin (pmTOR) and brain-derived neurotrophic factor (BDNF) in the hippocampus. To determine how the mTOR signaling is involved in the fast-onset antidepressant-like effects of YL-0919, the mTOR-specific inhibitor rapamycin was administered intracerebroventricularly (i.c.v.) together with the YL-0919 treatment. The observed changes in behavioral tests and protein expression could be reversed by rapamycin treatment. This suggests that the fast-onset antidepressant effects of YL-0919 were partially caused by changes in synaptogenesis mediated by activation of mTOR pathways. Our data suggest that YL-0919 may be a powerful/effective antidepressant with fast-onset.

BackgroundMechanical failure following total spondylectomy is a surgical challenge. The cervicothoracic junction region is a special anatomical site with complex biomechanics, and few studies have reported a detailed surgical management strategy for cases where the mesh cage subsides and compresses the spinal cord in the cervicothoracic junction region after total spondylectomy.Case presentationA 56-year-old male patient experienced screw and rod fracture and mesh cage retropulsion into the spinal canal 5 years after total spondylectomy for osteochondroma in the first to third thoracic vertebrae. The patient complained of numbness and discomfort in both lower extremities, accompanied by unstable walking for 8 months prior to admission at our hospital. We concluded that uncorrected local kyphosis in the cervicothoracic junction after the first surgery resulted in current mesh cage subsidence and rod/screw fracture. Considering the difficulty and risks of removing the mesh cage from the anterior approach, we initially freed the superior end of the mesh cage without removing the mesh from the anterior approach by resecting the C6/7 intervertebral disc and the destroyed C7 vertebral body. We then removed the original screws and rods and performed long segment fixation from C4 to T6 via a posterior approach after recovering sagittal alignment by skull traction. Finally, the iliac bone was harvested and transplanted between the superior end of the mesh cage and the inferior end plate of C6 to fill the defect caused by kyphosis correction and C7 vertebral resection. After surgery, the patient experienced sagittal alignment reconstruction and symptom relief, and he was asked to wear a cast for at least 6 months until bone fusion was achieved. At the 3-year follow-up, there was fusion between the mesh cage and the C6 vertebra with successful instrument reconstruction and no mesh cage subsidence were observed.ConclusionsWhen a subsided and migrated titanium mesh cage is difficult to remove after mechanical failure following total spondylectomy, recovering sagittal alignment to achieve indirect decompression based on unique anterior and middle column reconstruction, solid instrument construction, and bone fusion is an alternative solution.

Translational Relevance: Evaluation of targeted therapies is urgently needed for the majority of patients with metastatic/recurrent head and neck squamous cell carcinoma (HNSCC) who progress after immunochemotherapy. Erlotinib, a targeted inhibitor of epidermal growth factor receptor pathway, lacks FDA approval in HNSCC due to inadequate tumor response. This study identifies two potential avenues to improve tumor response to erlotinib among patients with HNSCC. For the first time, this study shows that an increased erlotinib dose of 300 mg in smokers is well-tolerated and produces similar plasma drug concentration as the regular dose of 150 mg in non-smokers, with increased study-specific defined tumor response. The study also highlights the opportunity for improved patient selection for erlotinib treatment by demonstrating that early in-treatment [18]FDG PET/CT is a potential predictor of tumor response, with robust statistical correlations between metabolic changes on early in-treatment PET (4-7 days through treatment) and anatomic response measured by end-of-treatment CT. Purpose: Patients with advanced HNSCC failing immunochemotherapy have no standard treatment options. Accelerating the investigation of targeted drug therapies is imperative. Treatment with erlotinib produced low response rates in HNSCC. This study investigates the possibility of improved treatment response through patient smoking status-based erlotinib dose optimization, and through early in-treatment [18]FDG PET evaluation to differentiate responders from non-responders. Experimental design: In this window-of-opportunity study, patients with operable HNSCC received neoadjuvant erlotinib with dose determined by smoking status: 150 mg (E150) for non-smokers and 300 mg (E300) for active smokers. Plasma erlotinib levels were measured using mass spectrometry. Patients underwent PET/CT before treatment, between days 4-7 of treatment, and before surgery (post-treatment). Response was measured by diagnostic CT andwas defined as decrease inmaximumtumor diameter by ≥ 20% (responders), 10-19% (minimum-responders), and < 10% (non-responders). Results: Nineteen patients completed treatment, ten of whom were smokers. There were eleven responders, five minimum-responders, and three nonresponders. Tumor response and plasma erlotinib levels were similar between the E150 and E300 patient groups. The percentage change on early PET/CT and post-treatment PET/CT compared to pre-treatment PET/CT were significantly correlated with the radiologic response on post-treatment CTs: R=0.63, p=0.0041 and R=0.71, p=0.00094, respectively. Conclusion: This pilot study suggests that early in-treatment PET/CT can predict response to erlotinib, and treatment with erlotinib dose adjusted according to smoking status is well-tolerated and may improve treatment response in HNSCC. These findings could help optimize erlotinib treatment in HNSCC and should be further investigated. [ABSTRACT FROM AUTHOR]

P1 protein, the most divergent protein of virus members in the genus Potyvirus of the family Potyviridae, is required for robust infection and host adaptation. However, how P1 affects viral proliferation is still largely elusive. In this work, a total number of eight potential P1-interacting Arabidopsis proteins were identified by the yeast-two-hybrid screening using the turnip mosaic virus (TuMV)-encoded P1 protein as the bait. Among which, the stress upregulated NODULIN 19 (NOD19) was selected for further characterization. The bimolecular fluorescent complementation assay confirmed the interaction between TuMV P1 and NOD19. Expression profile, structure, and subcellular localization analyses showed that NOD19 is a membrane-associated protein expressed mainly in plant aerial parts. Viral infectivity assay showed that the infection of turnip mosaic virus and soybean mosaic virus was attenuated in the null mutant of Arabidopsis NOD19 and NOD19-knockdown soybean seedlings, respectively. Together, these data indicate that NOD19 is a P1-interacting host factor required for robust infection.

Low back pain (LBP) caused by intervertebral disc degeneration (IVDD) is accredited to the release of inflammatory cytokines followed by biomechanical and structural deterioration. In our study, we used a plant-derived medicine, curcumenol, to treat IVDD. A cell viability test was carried out to evaluate the possibility of using curcumenol. RNA-seq was used to determine relative pathways involved with curcumenol addition. Using TNFα as a trigger of inflammation, the activation of the NF-κB signaling pathway and expression of the MMP family were determined by qPCR and western blotting. Nucleus pulposus (NP) cells and the rats’ primary NP cells were cultured. The catabolism status was evaluated by an ex vivo model. A lumbar instability mouse model was carried out to show the effects of curcumenol in vivo. In general, RNA-seq revealed that multiple signaling pathways changed with curcumenol addition, especially the TNFα/NF-κB pathway. So, the NP cells and primary NP cells were induced to suffer inflammation with the activated TNFα/NF-κB signaling pathway and increased expression of the MMP family, such as MMP3, MMP9, and MMP13, which would be mitigated by curcumenol. Owing to the protective effects of curcumenol, the height loss and osteophyte formation of the disc could be prevented in the lumbar instability mouse model in vivo.

Andersson lesions (ALs) in ankylosing spondylitis (AS) pose a severe risk to the stability of ankylosed spine, which might result in significant deterioration of spinal cord function after traumatic or inflammatory causes. Herein, erosive discovertebral lesions in diffuse idiopathic skeletal hyperostosis (DISH) presented important clinical similarities to AL in AS, but failed to completely recognize unstable spinal lesions. Therefore, we pioneered to identify spinal discovertebral lesions similar to Andersson-like lesions (ALLs) in DISH, followed by the characterization and summarization of the etiology, radiology, laboratory results, clinical symptoms, and treatment strategies for AL in AS with ALL in DISH. By characterizing the ALL in DISH cases, we showed that the ALL was mainly traumatic and established at the junction of focal stress between two adjacent ossified level arms. Erosive discovertebral ALLs were formed after trivial stress of direct impact and could be subdivided into transdiscal, transvertebral, and discovertebral types radiologically. Patients who presented with ALL frequently suffered from consistent back pain clinically and experienced a decrease in motion ability that could reflect skeletal stability, which received treatment effectiveness after conservative external spinal immobilization or further surgical internal fixation, indicating the significance of recognizing ALL in the ankylosed DISH spine to further maintain spinal stability in order to prevent catastrophic neurologic sequelae. Our work highlighted the clinical relevance of ALL in DISH in comparison with AL in AS, which provided broader insight to identify ALL in DISH, thus facilitating early intervention against DISH deterioration.

The HapMap (haplotype map) projects have produced valuable genetic resources in life science research communities, allowing researchers to investigate sequence variations and conduct genome-wide association study (GWAS) analyses. A typical HapMap project may require sequencing hundreds, even thousands, of individual lines or accessions within a species. Due to limitations in current sequencing technology, the genotype values for some accessions cannot be clearly called. Additionally, allelic heterozygosity can be very high in some lines, causing genetic and sometimes phenotypic segregation in their descendants. Genetic and phenotypic segregation degrades the original accession’s specificity and makes it difficult to distinguish one accession from another. Therefore, it is vitally important to determine and validate HapMap accessions before one conducts a GWAS analysis. However, to the best of our knowledge, there are no prior methodologies or tools that can readily distinguish or validate multiple accessions in a HapMap population. We devised a bioinformatics approach to distinguish multiple HapMap accessions using only a minimum number of genetic markers. First, we assign each candidate marker with a distinguishing score (DS), which measures its capability in distinguishing accessions. The DS score prioritizes those markers with higher percentages of homozygous genotypes (allele combinations), as they can be stably passed on to offspring. Next, we apply the “set-partitioning” concept to select optimal markers by recursively partitioning accession sets. Subsequently, we build a hierarchical decision tree in which a specific path represents the selected markers and the homogenous genotypes that can be used to distinguish one accession from others in the HapMap population. Based on these algorithms, we developed a web tool named MAD-HiDTree (Multiple Accession Distinguishment-Hierarchical Decision Tree), designed to analyze a user-input genotype matrix and construct a hierarchical decision tree. Using genetic marker data extracted from the Medicago truncatula HapMap population, we successfully constructed hierarchical decision trees by which the original 262 M. truncatula accessions could be efficiently distinguished. PCR experiments verified our proposed method, confirming that MAD-HiDTree can be used for the identification of a specific accession. MAD-HiDTree was developed in C/C++ in Linux. Both the source code and test data are publicly available at https://bioinfo.noble.org/MAD-HiDTree/.

Transfer (T)-DNA insertions in mutants isolated from forward genetic screens are typically identified through thermal asymmetric interlaced polymerase chain reaction (TAIL-PCR), inverse PCR, or plasmid rescue. Despite the popularity and success of these methods, they have limited capabilities, particularly in situations in which the T-DNA is truncated. Here, we present a next generation sequencing (NGS)-based platform to facilitate the identification of complete and truncated T-DNA insertions. Our method enables the detection of the corresponding T-DNA insertion orientation and zygosity as well as insertion annotation. This method, called TDNAscan, was developed to be an open source software. We expect that TDNAscan will be a valuable addition to forward genetics toolkits because it provides a solution to the problem of causal gene identification, particularly genes disrupted by truncated T-DNA insertions. We present a case study in which TDNAscan was used to determine that the recessive Arabidopsis thaliana hypersensitive to latrunculin B (hlb3) mutant isolated in a forward genetic screen of T-DNA mutagenized plants encodes a class II FORMIN.

Deletion mutagenesis such as fast neutron bombardment (FNB) has been widely used for forward and reverse genetics studies in functional genomics. Traditionally, the time-consuming map-based cloning is used to locate causal deletions in deletion mutants. In recent years, comparative genomic hybridization (CGH) has been used to speed up and scale up the lesion identification process in deletion mutants. However, limitations of low accuracy and sensitivity for small deletions in the CGH approach are apparent. With the next generation sequencing (NGS) becoming affordable for most users, NGS-based bioinformatics tools are more appealing. Although several deletion callers are available, these tools are not efficient in detecting small deletions. Population-scale deletion callers that can identify both small and large deletions are rare. We were motivated to create a population-scale deletion detection tool, called FNBtools, to identify homozygous causal deletions in mutant populations by using NGS data. FNBtools is a tool to call deletions at a population-scale and to achieve high accuracy at different levels of coverage. In addition, FNBtools can detect both small and large deletions with the ability to identify unique deletions in a mutant pool by filtering deletions that exist in a wild-type or control pool. Furthermore, FNBtools is also able to visualize all identified deletions in a genome-wide scope by using Circos. From simulated data analysis, FNBtools outperforms four existing popular deletion callers in detecting small deletions at different coverage levels. To test the usefulness of FNBtools in real biological applications, we used it to analyze a salt-tolerant mutant in Medicago truncatula and identified the unique deletion locus that is tightly linked with this trait. The causal deletion in the mutant was confirmed by PCR amplification, sequencing and genetic linkage analyses. FNBtools can be used for homozygous deletion identification in any species with reference genome sequences. FNBtools is publicly available at: https://github.com/noble-research-institute/fnbtools.