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Abstract Radiotherapy has been demonstrated to be one of the most significant treatments for cervical cancer, during which accurate and efficient delineation of target volumes is critical. To alleviate the data demand of deep learning and promote the establishment and promotion of auto-segmentation models in small and medium-sized oncology departments and single centres, we proposed an auto-segmentation algorithm to determine the cervical cancer target volume in small samples based on multi-decoder and semi-supervised learning (MDSSL), and we evaluated the accuracy via an independent test cohort. In this study, we retrospectively collected computed tomography (CT) datasets from 71 pelvic cervical cancer patients, and a 3:4 ratio was used for the training and testing sets. The clinical target volumes (CTVs) of the primary tumour area (CTV1) and pelvic lymph drainage area (CTV2) were delineated. For definitive radiotherapy (dRT), the primary gross target volume (GTVp) was simultaneously delineated. According to the data characteristics for small samples, the MDSSL network structure based on 3D U-Net was established to train the model by combining clinical anatomical information, which was compared with other segmentation methods, including supervised learning (SL) and transfer learning (TL). The dice similarity coefficient (DSC), 95% Hausdorff distance (HD95) and average surface distance (ASD) were used to evaluate the segmentation performance. The ability of the segmentation algorithm to improve the efficiency of online adaptive radiation therapy (ART) was assessed via geometric indicators and a subjective evaluation of radiation oncologists (ROs) in prospective clinical applications. Compared with the SL model and TL model, the proposed MDSSL model displayed the best DSC, HD95 and ASD overall, especially for the GTVp of dRT. We calculated the above geometric indicators in the range of the ground truth (head-foot direction). In the test set, the DSC, HD95 and ASD of the MDSSL model were 0.80/5.85 mm/0.95 mm for CTV1 of post-operative radiotherapy (pRT), 0.84/ 4.88 mm/0.73 mm for CTV2 of pRT, 0.84/6.58 mm/0.89 mm for GTVp of dRT, 0.85/5.36 mm/1.35 mm for CTV1 of dRT, and 0.84/4.09 mm/0.73 mm for CTV2 of dRT, respectively. In a prospective clinical study of online ART, the target volume modification time (MTime) was 3–5 min for dRT and 2–4 min for pRT, and the main duration of CTV1 modification was approximately 2 min. The introduction of the MDSSL method successfully improved the accuracy of auto-segmentation for the cervical cancer target volume in small samples, showed good consistency with RO delineation and satisfied clinical requirements. In this prospective online ART study, the application of the segmentation model was demonstrated to be useful for reducing the target volume delineation time and improving the efficiency of the online ART workflow, which can contribute to the development and promotion of cervical cancer online ART.

For the situation that coal is still capable of oxidative spontaneous combustion under different oxygen conditions, we choose three coals with different metamorphic degrees: lignite, gas coal and fatty coal, selected as experimental samples to carry out programmed temperature gas chromatography(TPGC) experiments and molecular dynamics simulations based on ReaxFF force fields at oxygen concentrations of 3%, 5%, 10%, 14% and 18%, to investigate the characteristics of changes in the oxygen influence of groups under oxygen-poor conditions in coals with different degrees of metamorphosis according to the production patterns and pathways of CO and CO2, etc. The results show that coal is easily affected by temperature and oxygen to produce indicator gases such as CO and CO2, and when the indicator gas tends to increase exponentially, the lower the degree of coal deterioration and the lower the temperature at which the indicator gas is produced at the same oxygen concentration. The simulations show that the reaction of coal with oxygen under oxygen-poor conditions is likely to be an active intermediate fragment reaction between oxygen and coal affected by temperature, rather than a direct attack on the main structure of the coal. The coal structural groups are not directly altered when the coal is subjected to temperature, but undergo structural adjustments for bond twisting, breaking and atomic transformations to produce reactive intermediate fragments suitable for reaction with oxygen. The higher the degree of metamorphosis, the more stable the molecular structure of the coal and the less likely it is to be affected by temperature to produce reactive intermediate fragments, and when oxygen is introduced, the rate of reaction of oxygen with the reactive intermediate is lower than the rate at which the coal is affected by temperature to produce the reactive intermediate, therefore, oxygen under depleted conditions is generally reacted with reactive intermediates to produce indicator gases such as water, CO, rather than with the main structure of the coal among them. A combination of experimental and simulation analysis reveals that the amount of water and oxygen containing gases increases significantly at 3%-5% oxygen concentration for lignite, 10%-14% oxygen concentration for gas coal and 14%-18% oxygen concentration for fat coal compared to the other stages, indicating that these three coals with different degrees of deterioration are more affected by oxygen in this oxygen-poor concentration range and accelerated the process of coal oxidation reaction.

Abstract High‐frequency oscillatory activity in cognition‐related neural circuits during wakefulness consistently induces the growth of dendritic spines and axonal terminals. Although these structural changes are essential for cognitive functions, it is hypothesized that if these newly expanded structures fail to establish functional connections, they may become superfluous. Sleep is believed to facilitate the reduction of such redundant structures to maintain neural homeostasis. However, the mechanisms underlying this pruning process during sleep remain poorly understood. In this study, that melatonin type 3 receptors (MT3Rs) are selectively expressed in the stellate neurons of the medial entorhinal cortex (MEC) is demonstrated, an area where high melatonin levels are detected during sleep. Activation of MT3Rs during sleep initiates the shrinkage of dendritic spines in stellate neurons by downregulating neural network activity and dephosphorylating synaptic proteins in the MEC. This process is disrupted when MT3R expression is knocked down or when MT3Rs are blocked during sleep. Notably, interference with MT3Rs in the MEC during sleep impairs the acquisition of spatial memory but does not affect object memory acquisition following sleep. These findings reveal novel molecular mechanisms involving melatonin and MT3Rs in the regulation of dendritic spine shrinkage during sleep, which is crucial for the acquisition and consolidation of spatial memory.

Antiferromagnetic Weyl semimetal Mn3Sn exhibiting strong magneto-optical Kerr effect (MOKE) due to non-zero Berry curvature is attractive for spintronic and photonic device applications. Despite many reports on the anisotropic anomalous Hall effect (AHE), so far, there have been few studies on its anisotropic optical properties. In this work, we experimentally characterized the anisotropic optical and magneto-optical (MO) properties of Mn3Sn(20)/MgO(110) and Mn3Sn(0001)/Al2O3(0001) epitaxial films using ellipsometry in the wavelength range from 300 to 1690 nm. By measuring the Mueller matrix of magnetized Mn3Sn, the anisotropic permittivity tensor is determined using the 4 × 4 transfer matrix method. Temperature dependent MOKE measurement confirmed the origin of the anisotropic MO effect to the non-zero Berry curvature of the chiral magnetic phase. The measured permittivity also agrees well with first-principles calculations. The anisotropic optical and MO properties determined in this work can be useful for Mn3Sn based spintronic device characterization and photonic device development.

In order to study the effect of typical transition metal ions on coal spontaneous combustion under low temperature oxidation conditions, the transition metal ions of lignite (HM), gas coal (QM) and fertilizer coal (FM) were determined, and Fe (Ⅲ), Mn (Ⅲ) and Cu (Ⅱ), which are abundant in transition metal ions and have strong oxidation, were selected as the research objects. The charge distribution, frontier orbitals and Laplacian bond levels were analyzed by the quantum chemistry calculation method, and the existence of active sites was proved. Two reaction processes of Ar—CH2—CH3 to Ar—CO—CH3 with or without transition metal ions were investigated, and the thermodynamic parameters were obtained by model optimization, transition state calculation and IRC verification. The calculation results show that the activation energy barrier is 164.18 kJ/mol without transition metal ion and 158.72 kJ/mol with transition metal ion. The effect of transition metal ion on the total reaction rate is not significant. With the participation of Fe (Ⅲ), Mn (Ⅲ) and Cu (Ⅱ), the total heat releases of the reaction are 1535.52, 1834.97 and 365.93 kJ/mol, respectively, which are higher than the heat release from the oxidation of aliphatic hydrocarbons by oxygen molecules (319.93 kJ/mol). The free energy barriers of C—H in oxidized aliphatic hydrocarbons are 42.79, 4.30 and 117.29 kJ/mol, respectively, which are all lower than the activation energies of C—H oxidation by oxygen molecules (146.38 kJ/mol). The order of C—H oxidation capacity of transition metal ions from high to low is Mn (Ⅲ), Fe (Ⅲ) and Cu (Ⅱ). During the reaction process, the formation of ·OH and H+ is accompanied by further reaction with the coal structure to accelerate the spontaneous combustion process of coal. In order to verify the accuracy of the simulation results, the time and concentration of CO gas products in four different coal samples were measured by temperature programmed gas chromatography. It was found that the temperature points of CO gas products in four coal samples were similar. The coal samples with manganese ion added produced CO gas products at 90 ℃, while the other three coal samples produced CO gas products at 100 ℃. The concentration of CO gas products from large to small is Mn (Ⅲ), Fe (Ⅲ), Cu (Ⅱ) and raw coal sample, which is consistent with the calculated results. With the increase of temperature, the effect of Mn (Ⅲ) on increasing the rate of CO production gradually weakens, and the effect of iron and copper ions on catalytic coal spontaneous combustion is gradually significant. The experimental results have a certain correlation with the simulation results. Compared with oxygen molecules, transition metal ions in coal are more likely to oxidize C—H, which not only causes the free radical chain reaction to occur earlier, but also increases the heat release of the reaction and the production of ·OH and H+, thus promoting spontaneous combustion of coal. This has reference significance for the mechanism of spontaneous combustion of transition metal catalyzed coal.

Abstract Surface condensation control strategies are crucial but commonly require relatively tedious, time-consuming, and expensive techniques for surface-chemical and topographical engineering. Here we report a strategy to alter surface condensation behavior without resorting to any molecule-type or topographical transmutations. After ultrafast contact of liquids with and removal from surfaces, the condensation rate and density of water droplets on the surfaces decrease, the extent of which is positively correlated with the polarity of the liquid and the duration of contact. The liquid contact-induced condensation rate/density decrease (LCICD) can be attributed to the decrease of nucleation site density resulted from the liquid contact-induced adaption of surface molecular conformation. Based on this, we find that LCICD is applicable to various surfaces, on condition that there are flexible segments capable of shielding at least part of nucleation sites through changing the conformation under liquid contact induction. Leveraging the LCICD effect, we achieve erasable information storage on diverse substrates. Furthermore, our strategy holds promise for controlling condensation of other substances since LCICD is not specific to the water condensation process.

This paper reports a strategy for more reliably obtaining sputtered thin yttrium–iron–garnet (YIG) films possessing both low magnetic damping (α) and a highly spin transparent surface, which represent two of the most important properties for YIG films applied in spintronic devices. The two key points of this strategy, concluded from our systematical studies, are as follows: oxygen reactive sputtering of a slight Y-rich YIG target to avoid the over-stoichiometry of the Fe component and at the same time minimize oxygen vacancy density; and employing phosphoric acid wet etching to remove the inevitable thin magnetic dead layer formed on the surface. The feasibility of this strategy was proved by the achievement of a high quality 30 nm-thick YIG film. It possesses a ferromagnetic resonance linewidth of only 3.4 Oe at 8 GHz, α of only 4.6 × 10−4, and a very spin-transparent surface, as proved by the measured extremely large spin pumping voltage of 650.1 µV after depositing a 3 nm Pt layer.

Organ development, regeneration and cancer initiation are typically influenced by the proliferation and lineage plasticity of tissue-specific stem cells. Prostate intermediate cells, which exhibit characteristics of both basal and luminal cells, are prevalent in pathological states and during organ development. However, the identity, fate and function of these intermediate cells in prostate development are not well understood. Through single-cell RNA-seq analysis on neonatal urogenital sinus tissue, we identified intermediate cells exhibiting stem cell potential. A notable decline in the population of intermediate cells was observed during prostate development. Prostate intermediate cells were specifically labeled in early and late postnatal development by the enhanced dual-recombinase-mediated genetic tracing systems. Our findings revealed that these cells possess significant stem cell capabilities as demonstrated in organoid formation and cell fate mapping assays. These intermediate cells also exhibited intrinsic bipotential properties, enabling them to differentiate into both basal and luminal cells. Additionally, we discovered a novel transition from intermediate cell expressing neuroendocrine markers to neuroendocrine cell during prostate development. This study highlights intermediate cells as a crucial stem cell population and enhances our understanding of their role in prostate development and the plasticity of prostate cancer lineage.

Virtual reality (VR)-based mindfulness is a promising method to improve the health of older adults. Therefore, many attempts have been made to explore the application of VR-based mindfulness, such as VR meditation and mind–body exercises, in older adults. Generally, current studies indicate the heavy reliance on apparatus for implementing VR-based mindfulness interventions. In VR meditation, the crucial apparatus is VR headsets. In VR mind–body exercises, three essential components are required: motion capture sensors, main consoles, and display screens. In the aspect of health promotion, VR meditation is an effective method for improving mental health, pain, and quality of life in older adults. VR mind–body exercises contribute to increasing the mental health and physical function of older adults. Furthermore, VR mind–body exercises may be combined with other forms of exercise as a mixed method to promote the health of older adults. VR-based mindfulness interventions enhance the meditation and mind–body exercises experience for older adults while improving accessibility. However, their implementation still encounters a series of challenges, such as cost, technical anxiety, and apparatus-related issues. Additionally, we recommend future research to examine the optimal exercise dose for VR mind–body exercises to maximize their health benefits.

Abstract Background Leeches are an integral component of aquatic biocenosis and can be found in a wide range of ecosystems such as freshwater, saltwater, flowing, and still-water ecosystems. It especially plays an important role in the freshwater benthic community and is an important part of the food web. In this study, a leech species was found in the mantle cavity of wild freshwater mussels in Zigong City, Sichuan Province, China, and its identity was determined through morphological analysis and molecular biological analysis. Results The leech is Hemiclepsis khankiana, a new species of Hemiclepsis that has been discovered in Russia in recent years. Through morphological analysis, the current survey observed that the morphological characteristics of Hemiclepsis khankiana eyespots were significantly different from the first reported description. The first pair of eyespots on the leech were separated and clear, while it had been reduced to unclear shadows in the previous report. The phylogenetic tree based on the COI gene showed that the COI gene sequence obtained in this study was in the same evolutionary branch as Hemiclepsis khankiana (MN295420, MN295421). Genetically, it was most closely related to Hemiclepsis kasmiana (mean COI p-distance = 3.98%). Conclusions The current study reported on the new distribution range of Hemiclepsis khankiana, which was initially discovered in China. This study indicates that the distribution range of the leech species has expanded, laying a foundation for further studies in China.

The application of tumor antigen-based immunotherapy is hindered by the rarity of validated immunogenic peptides. In this study, we aimed to investigate the potential of circular RNAs (circRNAs) as a novel source of tumor antigen peptides in hepatobiliary tumor organoids. Using RNA-sequencing (RNA-seq) with an algorithm-based score tool, 3950 translated tumor-specific circRNAs were predicted to generate 18 971 antigen peptides in 27 organoids. In view of the antigen landscape, 11 amino acid length (mer) peptides and human leukocyte antigen (HLA)-A binding peptides harbored the highest immunogenicity-related scores. In three out of five analyzed organoids, 13 predicted antigen peptides were directly confirmed as HLA-A, -B, and -C (HLA-ABC) binding peptides with mass spectrometry (MS)-based immunopeptidomics. CircRNA-derived tumor-specific peptides presented by the HLA-ABC molecules stimulated cluster of differentiation 8 (CD8) T cells to exhibit increased CD107a interferon γ (IFNγ) co-expressions and IFNγ secretion in flow cytometry and enzyme-linked immunosorbent assay (ELISA). Cytotoxic T cell activity targeting the organoids, induced by the immunogenic circRNA-derived peptides, was verified in a killing assay. Notably, the antigen peptide YGFNEILKK from circTBC1D15 was not only recognized as an HLA-ABC-presented peptide of the organoids but also drastically reduced the tumor organoid survival rate. Our findings highlight a crucial subset for generating tumor antigens, which has implications for targeting tumor-specific circRNAs in cancers.

Abstract In adults, hepatocytes are mainly replenished from the existing progenitor pools of hepatocytes and cholangiocytes during chronic liver injury. However, it is unclear whether other cell types in addition to classical hepatocytes and cholangiocytes contribute to hepatocyte regeneration after chronic liver injuries. Here, we identified a new biphenotypic cell population that contributes to hepatocyte regeneration during chronic liver injuries. We found that a cell population expressed Gli1 and EpCAM (EpCAM+Gli1+), which was further characterized with both epithelial and mesenchymal identities by single-cell RNA sequencing. Genetic lineage tracing using dual recombinases revealed that Gli1+ nonhepatocyte cell population could generate hepatocytes after chronic liver injury. EpCAM+Gli1+ cells exhibited a greater capacity for organoid formation with functional hepatocytes in vitro and liver regeneration upon transplantation in vivo. Collectively, these findings demonstrate that EpCAM+Gli1+ cells can serve as a new source of liver progenitor cells and contribute to liver repair and regeneration.

Spontaneous imbibition behavior of fracturing fluid retained in reservoirs is considered to be one of the important mechanisms of spontaneous oil–water displacement in tight reservoirs. However, the mechanism of imbibition displacement in oil-wet rocks remains unclear. Inspired by the principle of the Marangoni effect, a mathematical model of oil displacement driven by an interfacial tension gradient in an oil-wet capillary tube was established, and the effects of osmotic pressure and hydraulic mechanical dispersion were coupled in the model. The results show that the key component of this mechanism is the breakdown of the initial capillary equilibrium state due to the diffusion of solute, which changes the pressure distribution in the capillary and drives the water to drive oil out of the pores. This can explain the spontaneous imbibition of low-salinity fracturing fluid into the oil-wet tight sample and displace oil without any external force, despite its low permeability. In addition, the related factors were analyzed, including initial concentration, contact angle, solute type, osmotic behavior, and size of the capillary. The results show that for an oil wet reservoir with high salinity, the connate water interfacial tension gradient plays an important role in oil displacement, and the coupling effect of osmotic pressure and hydromechanical dispersion considerably improves recovery. This can provide new insight into the mechanism of spontaneous imbibition of fracturing fluid.

Microencapsulated linseed oil (MLO) has been used in diets to enhance the omega-3 fatty acid concentration of meat in beef cattle without negatively affecting ruminal microbials and digestion; however, the growth performance, meat quality, intramuscular fatty acid profile, and rumen characteristics in response to MLO have not been examined in sheep. Thus, the aim of the present study was to evaluate the effects of microencapsulated or conventional linseed oil supplement on growth performance, meat quality, intramuscular fatty acid profile, rumen characteristics and serum parameters in Small-tailed Han sheep. Eighteen 5-months-old male sheep (25.31 ± 1.31 kg) were allocated to three groups. After seven days of adaptation to a basal diet, fed for 80 days, the treatments allocated were (1) basal diet (CON); (2) basal diet with added 2% linseed oil (LO); (3) basal diet with added 4% MLO. The results showed that treatments had no effects on growth performance (P ≥ 0.10). Compared to CON and MLO group, the pH24 h of the longissimus dorsi (LD) muscle in LO group was lower (P = 0.07), while the shear force was higher (P = 0.01). Compared to CON group, the addition of linseed oil increased proportions of C17:1, C18:2 n-6c, total polyunsaturated fatty acids (PUFA), PUFA/saturated fatty acids and total n-6, while it decreased the proportion of C17:0, C16:1 and C18:1 c-9 in LD muscle (P < 0.10). The lambs in LO and MLO group had higher proportions of C20:1, C18:3 n-3 and total n-3 in LD muscle than those in CON group (P < 0.10). Compared to CON group, the ruminal pH value of MLO group and the ruminal NH3-N content of LO group were lower (P < 0.10). The total volatile fatty acid, proportion of acetate, and acetate/propionate were deceased in LO and MLO groups (P < 0.05). Furthermore, the two supplements significantly increased the proportions of propionate, butyrate and isovalerate (P < 0.05). Circulating cholesterol and high-density lipoprotein cholesterol concentrations were increased by linseed oil supplementation (P = 0.04). In conclusion, these results indicate that microencapsulated linseed oil did not exhibit any superior effects on muscle fatty acid composition and rumen fermentation of lambs.

Summary: In castration-resistant prostate cancer (CRPC), clinical response to androgen receptor (AR) antagonists is limited mainly due to AR-variants expression and restored AR signaling. The metabolite spermine is most abundant in prostate and it decreases as prostate cancer progresses, but its functions remain poorly understood. Here, we show spermine inhibits full-length androgen receptor (AR-FL) and androgen receptor splice variant 7 (AR-V7) signaling and suppresses CRPC cell proliferation by directly binding and inhibiting protein arginine methyltransferase PRMT1. Spermine reduces H4R3me2a modification at the AR locus and suppresses AR binding as well as H3K27ac modification levels at AR target genes. Spermine supplementation restrains CRPC growth in vivo. PRMT1 inhibition also suppresses AR-FL and AR-V7 signaling and reduces CRPC growth. Collectively, we demonstrate spermine as an anticancer metabolite by inhibiting PRMT1 to transcriptionally inhibit AR-FL and AR-V7 signaling in CRPC, and we indicate spermine and PRMT1 inhibition as powerful strategies overcoming limitations of current AR-based therapies in CRPC.

Abstract Background Cerebral spinal fluid (CSF) leak remains an important issue in endoscopic endonasal surgery (EES). A standard protocol for skull base closure has not yet been established, and the application of rigid buttress has not been given sufficient attention. To emphasize the functions of support and fixation from rigid buttress in reconstruction, we introduced the cruciate embedding fascia-bone flap (CEFB) technique using autologous bone graft to buttress the fascia lata attachment to the partially sutured skull base dural defect and evaluated its efficacy in a consecutive case series of grade II–III CSF leaks in EES. Methods Data from consecutive patients diagnosed with sellar region lesions with grade II–III CSF leaks during EES were collected from May 2015 to May 2020. Skull base reconstructions were performed with the CEFB or the conventional pedicle vascularized nasoseptal flap (PNSF). Related clinical data were analysed. The combined use of the CEFB and PNSF was applied to an additional supplemental case series of patients with grade III leak and multiple high-risk factors. Results There were 110 and 65 patients included in the CEFB and PNSF groups, respectively. The CEFB demonstrated similar effects on the incidence of postoperative CSF leak (2.7%), intracranial infection (4.5%), and lumbar drainage (LD) placement (5.5%) as PNSF (3.1%, 3.1%, and 6.2%), but with less epistaxis (CEFB: 0%, PNSF: 6.2%) and nasal discomforts (CEFB: 0%, PNSF: 7.7%). The LD duration (CEFB: 6.67 ± 2.16 days, PNSF: 10.50 ± 2.38 days), bed-stay time (CEFB: 5.74 ± 1.58 days, PNSF: 8.83 ± 3.78 days) and hospitalization time (CEFB: 10.49 ± 5.51 days, PNSF: 13.58 ± 5.50 days) were shortened in the CEFB group. The combined use of CEFB and PNSF resulted in 0 postoperative CSF leaks in the supplemental case series of 23 highly susceptible patients. Conclusion This study suggested that the new CEFB technique has the potential to prevent postoperative CSF leak in EES. The results indicated that it can be used effectively without PNSF in suitable cases or applied in addition to a PNSF with high compatibility when necessary. Its effectiveness should be further verified with a larger cohort and better design in the next step. Trial Registration Current Controlled Trials ChiCTR2100044764 (Chinese Clinical Trial Registry); date of registration: 27 March 2020. Retrospectively registered

BackgroundThe relationship between anxiety, depression, and metabolic parameters and the incidence of breast nodules is unclear. This study aims to investigate the association between female breast nodules and anxiety, depression and metabolic factors.MethodsThis cross-sectional study recruited 857 individuals with biological indicators and breast ultrasound data from the Daping hospital from April 2021 to February 2022. Serum samples were used to measure fasting blood glucose, uric acid, triglycerides, total cholesterol, urea nitrogen, alanine transaminase, aspartate transaminase, albumin, high-density lipoprotein, low-density lipoprotein. Self-rating anxiety scale (SAS) and self-rating depression scale (SDS) were used to assess the level of anxiety and depression.ResultThe positive rate of breast nodules in women aged 40 to 49 years old was significantly higher than that of other age women. The proportion of participants aged 40–49 years old in the group with breast nodules was significantly higher than that in the group without breast nodules (34.6% vs. 16.9%, p

Abstract Background The yellow catfish, Pelteobagrus fulvidraco, is a commercially important fish species. It is widely distributed in the fresh water areas of China, including rivers, lakes, and reservoirs. Like many other aquaculture fish species, people have observed significant size dimorphism between male and female yellow catfish and it shows a growth advantage in males. Results Here, at the first time, the time-course transcriptome was used to explore the various expression profiles of genes in different gonad developmental stages and genders. A total of 2696 different expression genes (DEGs) were identified from different stages. Based on these DEGs, 13 gonad development related genes were identified which showed time-specific or sex biased expression patterns. Conclusion This study will provide the crucial information on the molecular mechanism of gonad development of female and male yellow catfish. Especially, during the different gonad development stages, these 13 gonad development related genes exhibit various expression patterns in female and male individual respectively. These results could inspire and facilitate us to understanding the various roles of these genes play in different gonad development stages and genders.

The chromatin accessibility landscape and gene regulatory network of pancreatic cancer has not been fully characterised. Here, the authors perform multi-omics analysis of 84 pancreatic cancer organoid lines and reveal gene regulatory networks and distinct molecular subtypes.

Sensitive detection of ochratoxin A (OTA) is significant and essential because OTA may pose risks to human and animal health. Here, we developed an electrochemical aptasensor for OTA analysis using polyamidoamine (PAMAM) dendrimers as a signal amplifier. As a carrier, PAMAM has numerous primary amino groups that can be coupled with thiolated complementary strand DNA (cDNA), allowing it to recognize aptamers bound to the surface of horseradish peroxidase (HRP)-modified gold nanoparticles (AuNPs), thereby improving the sensitivity of the aptasensor. When monitoring the positive samples, OTA was captured by the aptamer fixed on the HRP-conjugated AuNP surface by specific recognition, after which the formed OTA-aptamer conjugates were detached from the electrode surface, ultimately decreasing the electrochemical signal monitored by differential pulse voltammetry. The novel aptasensor achieved a broad linear detection range from 5 to 105 ng L−1 with a low detection limit of 0.31 ng L−1. The proposed aptasensor was successfully applied for OTA analysis in red wine, with recovery rates ranging from 94.15 to 106%. Furthermore, the aptasensor also exhibited good specificity and storage stability. Therefore, the devised aptasensor represents a sensitive, practical and reliable tool for monitoring OTA in agricultural products, which can also be adapted to other mycotoxins.

Ion binding proteins (IBPs) can selectively and non-covalently interact with ions. IBPs in phages also play an important role in biological processes. Therefore, accurate identification of IBPs is necessary for understanding their biological functions and molecular mechanisms that involve binding to ions. Since molecular biology experimental methods are still labor-intensive and cost-ineffective in identifying IBPs, it is helpful to develop computational methods to identify IBPs quickly and efficiently. In this work, a random forest (RF)-based model was constructed to quickly identify IBPs. Based on the protein sequence information and residues’ physicochemical properties, the dipeptide composition combined with the physicochemical correlation between two residues were proposed for the extraction of features. A feature selection technique called analysis of variance (ANOVA) was used to exclude redundant information. By comparing with other classified methods, we demonstrated that our method could identify IBPs accurately. Based on the model, a Python package named IBPred was built with the source code which can be accessed at https://github.com/ShishiYuan/IBPred.

The generation of ectoderm, mesoderm, and endoderm layers is the most critical biological process during the gastrulation of embryo development. Such a differentiation process in human embryonic stem cells (hESCs) is an inherently nonlinear multi-stage dynamical process which contain multiple tipping points playing crucial roles in the cell-fate decision. However, the tipping points of the process are largely unknown, letting alone the understanding of the molecular regulation on these critical events. Here by designing a module-based dynamic network biomarker (M-DNB) model, we quantitatively pinpointed two tipping points of the differentiation of hESCs toward definitive endoderm, which leads to the identification of M-DNB factors (FOS, HSF1, MYCN, TP53, and MYC) of this process. We demonstrate that before the tipping points, M-DNB factors are able to maintain the cell states and orchestrate cell-fate determination during hESC (ES)-to-ME and ME-to-DE differentiation processes, which not only leads to better understanding of endodermal specification of hESCs but also reveals the power of the M-DNB model to identify critical transition points with their key factors in diverse biological processes, including cell differentiation and transdifferentiation dynamics.

Electrolytic aluminum operation accidents have caused great losses to countries and people. Therefore, taking two typical accidents of explosion and leakage in electrolytic aluminum production as the research object, the form of accident risk characterization was explored and a risk characterization visualization system was designed. Based on the methods of risk assessment and characterization, the likelihood and consequence of accidents were studied. The influencing factors of likelihood and a type of Euclidean distance formula were used to characterize the likelihood. The consequence portion was characterized by two components, with one being the failure degree determined by the accident and the other being the exposure degree of people and equipment. The intensity of event was used to characterize the failure degree and the spatial search model was used to characterize the exposure degree. Finally, the visual system of electrolytic aluminum operation accidents was established based on the risk characterization model.

Abstract Downstream processing of mAb charge variants is difficult owing to their similar molecular structures and surface charge properties. This study aimed to apply a novel twin‐column continuous chromatography (called N‐rich mode) to separate and enrich acidic variants of an IgG1 mAb. Besides, a comparison study with traditional scaled‐up batch‐mode cation exchange (CEX) chromatography was conducted. For the N‐rich process, two 3.93 mL columns were used, and the buffer system, flow rate and elution gradient slope were optimized. The results showed that 1.33 mg acidic variants with nearly 100% purity could be attained after a 22‐cycle accumulation. The yield was 86.21% with the productivity of 7.82 mg/L/h. On the other hand, for the batch CEX process, 4.15 mL column was first used to optimize the separation conditions, and then a scaled‐up column of 88.20 mL was used to separate 1.19 mg acidic variants with the purity of nearly 100%. The yield was 59.18% with the productivity of 7.78 mg/L/h. By comparing between the N‐rich and scaled‐up CEX processes, the results indicated that the N‐rich method displays a remarkable advantage on the product yield, i.e. 1.46‐fold increment without the loss of productivity and purity. Generally, twin‐column N‐rich continuous chromatography displays a high potential to enrich minor compounds with a higher yield, more flexibility and lower resin cost.

Background: Gastric cancer (GC) has a high mortality rate and is particularly prevalent in China. The extracellular matrix protein, prolyl 4-hydroxylase subunit alpha 3 (P4HA3), has been implicated in various cancers. We aimed to assess the diagnostic and prognostic value of P4HA3 in GC and investigate its correlation with immune cell infiltration.Methods: The present study used microarray data from the Cancer Genome Atlas (TCGA) to analyze the association of P4HA3 expression with clinicopathological features. Data from the Gene Expression Omnibus (GEO) were used for validation. Receiver operating characteristic (ROC) and Kaplan–Meier curves were constructed to determine the diagnostic and prognostic value of P4HA3 in GC. Univariate and multivariate regression analyses were performed to assess the impact of P4HA3 on overall survival (OS) rates. A protein–protein interaction (PPI) network was generated and functional enrichment evaluated. Single-sample gene set enrichment analysis (ssGSEA) was conducted to correlate P4HA3 expression with immune cell infiltration. The correlation between P4HA3 and immune check point genes was studied.Results: P4HA3 was over-expressed in GC, along with 15 other types of cancer, including breast invasive carcinoma and cholangiocarcinoma. P4HA3 showed high diagnostic and prognostic value in GC and was an independent prognostic factor. P4HA3, TNM (tumor, node, metastases) stage, pathological stage and age all correlated with OS rates. Genes related to P4HA3 were enriched in the lumen of the endoplasmic reticulum and included procollagen-proline 3-dioxygenase activity. P4HA3 expression correlated with numbers of macrophages, natural killer (NK) cells, immature dendritic cells (iDC), mast cells, eosinophils, effective memory T cells (Tem), T-helper 1 (Th1) cells and dendritic cells (DC). P4HA3 was positively correlated with hepatitis A virus cellular receptor 2 (HAVCR2) and programmed cell death 1 ligand 2 (PDCD1LG2).Conclusion: P4HA3 is a potential independent biomarker for prognosis of GC and may be an immunotherapy target in the treatment of GC.

Summary: The exploitation of biocompatible ice-control materials especially the small molecules for non-vitreous cryopreservation remains challenging. Here, we report a small molecule of fulvic acid (FA) with strong hydration ability, which enables non-vitreous cellular cryopreservation by reducing ice growth during freezing and reducing ice recrystallization/promoting ice melting during thawing. Without adding any other cryoprotectants, FA can enhance the recovery of sheep red blood cells (RBCs) by three times as compared with a commercial cryoprotectant (hydroxyethyl starch) under a stringent test condition. Investigation of water mobility reveals that the ice-control properties of FA can be ascribed to its strong bondage to water molecules. Furthermore, we found that FA can be absorbed by RBCs and mainly locates on membranes, suggesting the possible contribution of FA to cell protection through stabilizing membranes. This work bespeaks a bright future for small-molecule cryoprotectants in non-vitreous cryopreservation application.

Enzalutamide, an approved drug for prostate cancer, acts on TMPRSS2 expression, a key mediator for SARS-CoV-2 infection. Here, the authors characterize the anti-SARS-CoV-2 effects of Enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and in hACE2-transduced Tmprss2 knockout mice and show lack antiviral action in human lung cells and human lung organoids, likely due to the AR-independent TMPRSS2 expression in mouse and human lung epithelial cells.

Ovarian surface epithelium (OSE) undergoes recurring ovulatory rupture and OSE stem cells rapidly generate new cells for the repair. How the stem cell activation is triggered by the rupture and promptly turns on proliferation is unclear. Our previous study has identified that Protein C Receptor (Procr) marks OSE progenitors. In this study, we observed decreased adherent junction and selective activation of YAP signaling in Procr progenitors at OSE rupture site. OSE repair is impeded upon deletion of Yap1 in these progenitors. Interestingly, Procr+ progenitors show lower expression of Vgll4, an antagonist of YAP signaling. Overexpression of Vgll4 in Procr+ cells hampers OSE repair and progenitor proliferation, indicating that selective low Vgll4 expression in Procr+ progenitors is critical for OSE repair. In addition, YAP activation promotes transcription of the OSE stemness gene Procr. The combination of increased cell division and Procr expression leads to expansion of Procr+ progenitors surrounding the rupture site. These results illustrate a YAP-dependent mechanism by which the stem/progenitor cells recognize the murine ovulatory rupture, and rapidly multiply their numbers, highlighting a YAP-induced stem cell expansion strategy.

Abstract Molecular heterogeneity of hepatobiliary tumor including intertumoral and intratumoral disparity always leads to drug resistance. Here, seven hepatobiliary tumor organoids are generated to explore heterogeneity and evolution via single‐cell RNA sequencing. HCC272 with high status of epithelia‐mesenchymal transition proves broad‐spectrum drug resistance. By examining the expression pattern of cancer stem cells markers (e.g., PROM1, CD44, and EPCAM), it is found that CD44 positive population may render drug resistance in HCC272. UMAP and pseudo‐time analysis identify the intratumoral heterogeneity and distinct evolutionary trajectories, of which catenin beta‐1 (CTNNB1), glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH), and nuclear paraspeckle assembly transcript 1 (NEAT1) advantage expression clusters are commonly shared across hepatobiliary organoids. CellphoneDB analysis further implies that metabolism advantage organoids with enrichment of hypoxia signal upregulate NEAT1 expression in CD44 subgroup and mediate drug resistance that relies on Jak‐STAT pathway. Moreover, metabolism advantage clusters shared in several organoids have similar characteristic genes (GAPDH, NDRG1 (N‐Myc downstream regulated 1), ALDOA, and CA9). The combination of GAPDH and NDRG1 is an independent risk factor and predictor for patient survival. This study delineates heterogeneity of hepatobiliary tumor organoids and proposes that the collaboration of intratumoral heterogenic subpopulations renders malignant phenotypes and drug resistance.

Abstract As the manufacturing industry is facing increasingly serious environmental problems, because of which carbon tax policies are being implemented, choosing the optimum cutting parameters during the machining process is crucial for automobile panel dies in order to achieve synergistic minimization of the environment impact, product quality, and processing efficiency. This paper presents a processing task-based evaluation method to optimize the cutting parameters, considering the trade-off among carbon emissions, surface roughness, and processing time. Three objective models and their relationships with the cutting parameters were obtained through input–output, response surface, and theoretical analyses, respectively. Examples of cylindrical turning were applied to achieve a central composite design (CCD), and relative validation experiments were applied to evaluate the proposed method. The experiments were conducted on the CAK50135di lathe cutting of AISI 1045 steel, and NSGA-II was used to obtain the Pareto fronts of the three objectives. Based on the TOPSIS method, the Pareto solution set was ranked to find the optimal solution to evaluate and select the optimal cutting parameters. An S/N ratio analysis and contour plots were applied to analyze the influence of each decision variable on the optimization objective. Finally, the changing rules of a single factor for each objective were analyzed. The results demonstrate that the proposed method is effective in finding the trade-off among the three objectives and obtaining reasonable application ranges of the cutting parameters from Pareto fronts.

Alloy magic-size clusters (MSCs) are difficult to synthesize, in part because so little is known about how they form. Here, the authors produce single-ensemble alloy CdTeSe MSCs at room temperature by mixing prenucleation-stage solutions of CdTe and CdSe, uncovering a formation pathway that may extend to the synthesis of other alloy MSCs.

Tebuconazole is widely applied for controlling pathogenic fungi of crops and proved hazardous to human being. To better measure tebuconazole residues, an enzyme-linked immunosorbent assay for screening tebuconazole residues in aqueous samples was established using an innovative hapten (hapten1) designed via molecular model. The work concentration of calibration standard curves based on aqueous matrices ranged from 0.51 to 10.71 ng mL–1. The cross-reactivities of other analogs were less than 6%. The detection limits of the assay were in the range of 0.197–0.297 ng mL–1 for tebuconazole in water samples. The average recoveries of tebuconazole in the spiked water samples varied from 76.76% to 107.52% with the variation coefficient scope of 4.54–13.26%. The obtained immunoassay was verified by gas chromatography coupled to mass spectrometry with high correlation coefficients (r > 0.9868). Herein, the proposed immunoassay offers a cost-effective, convenient, reliable tool for the determination of tebuconazole residues in aqueous samples.

A large component flexible manufacturing system provides more application scenarios for industrial robots, and, in turn, these robots exhibit competitive advantages in machining applications. However, the structural characteristic of low stiffness is the main obstacle for the industrial robot. Aiming at obtaining sufficient stiffness in the whole machining process, this paper focuses on robot placement optimization in the flexible manufacturing of large components. The geometric center of the machined feature is selected as, firstly, the base point, and the center-reachable placement space of the robot base is obtained by establishing the kinematic model considering a variety of motion constraints. Then, according to the reachability of the machining feature contour, the global placement space meeting all machining boundaries is further extracted. The mapping relationship between joint force and posture is established, and the most suitable robot placement is selected based on the criterion of global stiffness optimization. A series of numerical and finite element simulations verify the correctness and effectiveness of the proposed optimization strategy. The developed stiffness-oriented placement planning algorithm can provide beneficial references for robotic machining applications.

Yellowfin seabream (Acanthopagrus latus), a protandrous hermaphroditic fish, is a good model for studying the mechanism of sex reversal. However, limited knowledge is known about the genetic information related to reproduction and sex differentiation in this species. Here, we performed de novo transcriptome sequencing analysis of the testis, ovotestis, and ovary to identify sex-related genes in yellowfin seabream. The results assembled 71,765 unigenes in which 16,126 and 17,560 unigenes were differentially expressed in the ovotestis and ovary compared to the testis, respectively. The most differentially expressed gene (DEG)-enriched Kyoto Encyclopedia of Genes and Genomes and GO pathways were closely associated with the synthesis of sex steroid hormones. Functional analyses identified 55 important sex-related DEGs, including 32 testis-biased DEGs (dmrt1, amh, and sox9, etc.), 20 ovary-biased DEGs (cyp19a, foxl2, and wnt4, etc.), and 3 ovotestis-biased DEGs (lhb, dmrt2, and foxh1). Furthermore, the testis-specific expression of dmrt1 and the brain-pituitary-ovary axis expression of foxl2 were characterized, suggesting that they might play important roles in sex differentiation in yellowfin seabream. Our present work provided an important molecular basis for elucidating the mechanisms underlying sexual transition and reproductional regulation in yellowfin seabream.

The objective of this paper is to study the variation in the physical and mechanical properties of expanded perlite mortar with environmental factors and analyze its deterioration mechanism. In this paper, the influence of the heat-rain cyclic and natural aging on the physical and mechanical properties of expanded perlite mortar has been studied. The expanded perlite mortar specimens were subjected to 80 heat-rain cycles (the maximum temperature rises to 70 °C, and the spray volume reaches 1 l/(m ^2 min)) and 60-day natural aging tests (the daily average temperature is 23 °C, with the maximum temperature reaching 36 °C). The corresponding mass loss rate, water absorption, and compressive strength of the specimens at every 10 heat-rain cycles and 10 days were determined. The results show that the mass loss rate gradually increases with the increase in heat-rain cycles and the natural aging days. The variation range was found as about 0.2%∼0.7% and −0.4%∼0.2%, respectively. The water absorption rate gradually decreases with the number of heat-rain cycles and natural aging days; however, the decay rate of the water absorption rate differs by orders of magnitude in the two weathering conditions. The compressive strength does not have an obvious change with the number of heat rain cycles, but it first increases and then decreases with the number of natural aging days. Under artificial and natural aging, the deterioration mechanism and aging speed of expanded perlite mortar are much different. The comparative analysis of the physical and mechanical properties of expanded perlite mortar under artificially accelerated and natural aging conditions can further reveal its evolution model and the corresponding relationships under the two conditions and provide a theoretical basis for establishing a more scientific and reasonable aging system.

Abstract Background Pyropia yezoensis is an important marine crop which, due to its high protein content, is widely used as a seafood in China. Unfortunately, red rot disease, caused by Pythium porphyrae, seriously damages P. yezoensis farms every year in China, Japan, and Korea. Proteomic methods are often used to study the interactions between hosts and pathogens. Therefore, an iTRAQ-based proteomic analysis was used to identify pathogen-responsive proteins following the artificial infection of P. yezoensis with P. porphyrae spores. Results A total of 762 differentially expressed proteins were identified, of which 378 were up-regulated and 384 were down-regulated following infection. A large amount of these proteins were involved in disease stress, carbohydrate metabolism, cell signaling, chaperone activity, photosynthesis, and energy metabolism, as annotated in the KEGG database. Overall, the data showed that P. yezoensis resists infection by inhibiting photosynthesis, and energy and carbohydrate metabolism pathways, as supported by changes in the expression levels of related proteins. The expression data are available via ProteomeXchange with the identifier PXD009363. Conclusions The current data provide an overall summary of the red algae responses to pathogen infection. This study improves our understanding of infection resistance in P. yezoensis, and may help in increasing the breeding of P. porphyrae-infection tolerant macroalgae.

Abstract Purpose: Myocardial ischemia/reperfusion (Ml/R) injury is a leading cause of damage in cardiac tissues, with high rates of mortality and disability. Biochanin A (BCA) is a main constituent of Trifolium pratense L. This study was intended to explore the effect of BCA on Ml/R injury and explore the potential mechanism. Methods: In vivo MI/R injury was established by transient coronary ligation in Sprague-Dawley rats. Triphenyltetrazolium chloride staining (TTC) was used to measure myocardial infarct size. ELISA assay was employed to evaluate the levels of myocardial enzyme and inflammatory cytokines. Western blot assay was conducted to detect related protein levels in myocardial tissues. Results: BCA significantly ameliorated myocardial infarction area, reduced the release of myocardial enzyme levels including aspartate transaminase (AST), creatine kinase (CK-MB) and lactic dehydrogenase (LDH). It also decreased the production of inflammatory cytokines (IL-1β, IL-18, IL-6 and TNF-α) in serum of Ml/R rats. Further mechanism studies demonstrated that BCA inhibited inflammatory reaction through blocking TLR4/NF-kB/NLRP3 signaling pathway. Conclusion: The present study is the first evidence demonstrating that BCA attenuated Ml/R injury through suppressing TLR4/NF-kB/NLRP3 signaling pathway-mediated anti-inflammation pathway.

There are few available models to study neuroendocrine prostate cancer. Here they develop and characterize patient derived organoids from metastatic lesions, use these models to show the role of EZH2 in driving neuroendocrine phenotype, and perform high throughput organoid screening to identify therapeutic drug combinations.

Abstract Background Pyropia yezoensis, a marine red alga, is an ideal research model for studying the mechanisms of abiotic stress tolerance in intertidal seaweed. Real-time quantitative polymerase chain reaction (RT-qPCR) is the most commonly used method to analyze gene expression levels. To accurately quantify gene expression, selection and validation of stable reference genes is required. Results We used transcriptome profiling data from different abiotic stress treatments to identify six genes with relatively stable expression levels: MAP, ATPase, CGS1, PPK, DPE2, and FHP. These six genes and three conventional reference genes, UBC, EF1-α, and eif4A, were chosen as candidates for optimal reference gene selection. Five common statistical approaches (geNorm, ΔCt method, NormFinder, BestKeeper, and ReFinder) were used to identify the stability of each reference gene. Our results show that: MAP, UBC, and FHP are stably expressed in all analyzed conditions; CGS1 and UBC are stably expressed under conditions of dehydration stress; and MAP, UBC, and CGS1 are stably expressed under conditions of temperature stress. Conclusion We have identified appropriate reference genes for RT-qPCR in P. yezoensis under different abiotic stress conditions which will facilitate studies of gene expression under these conditions.

HAZOP (Hazard and Operability Analysis) is a method of safety analysis, which is widely used in chemical processes. The conventional methods for safety analysis consist of human based safety analysis and computer aid safety analysis. All of them are off-line and qualitative and it is difficult to carry out on-line safety analysis. On-line safety analysis based on scenario object model was proposed for chemical processes. The scenario object model was built using ontology, by which the safety information can be transferred, reused and shared effectively. Deviation degree and qualitative trend were added to the model. Based on the model and new inference algorithm, on-line safety analysis can be implemented for chemical processes. Once a fault or abnormal event occurs, the causes can be traced and the consequences can be predicted. At the same time, semi-quantitative safety analysis is carried out. The resolution can be improved and it can help the operators handle the problems in time and effectively. The method was used for safety analysis of a reactor process and the effectiveness of the method was proved.

It is widely appreciated that reactive stroma or carcinoma-associated fibroblasts can influence epithelial tumor progression. In prostate cancer (PCa), the second most common male malignancy worldwide, the amount of reactive stroma is variable and has predictive value for tumor recurrence. By analyzing human PCa protein and RNA expression databases, we found smooth muscle cells (SMCs) are decreased in advanced tumors, whereas fibroblasts are maintained. In three mouse models of PCa, PB-MYC, ERG/PTEN and TRAMP, we found the composition of the stroma is distinct. SMCs are greatly depleted in advanced PB-MYC tumors and locally reduced in ERG/PTEN prostates, whereas in TRAMP tumors the SMC layers are increased. In addition, interductal fibroblast-like cells expand in PB-MYC and ERG/PTEN tumors, whereas in TRAMP PCa they expand little and stromal cells invade into intraductal adenomas. Fate mapping of SMCs showed that in PB-MYC tumors the cells are depleted, whereas they expand in TRAMP tumors and interestingly contribute to the stromal cells in intraductal adenomas. Hedgehog (HH) ligands secreted by epithelial cells are known to regulate prostate mesenchyme expansion differentially during development and regeneration. Any possible role of HH signaling in stromal cells during PCa progression is poorly understood. We found that HH signaling is high in SMCs and fibroblasts near tumor cells in all models, and epithelial Shh expression is decreased whereas Ihh and Dhh are increased. In human primary PCa, expression of IHH is the highest of the three HH genes, and elevated HH signaling correlates with high stromal gene expression. Moreover, increasing HH signaling in the stroma of PB-MYC PCa resulted in more intact SMC layers and decreased tumor progression (micro-invasive carcinoma). Thus, we propose HH signaling restrains tumor progression by maintaining the smooth muscle and preventing invasion by tumor cells. Our studies highlight the importance of understanding how HH signaling and stromal composition impact on PCa to optimize drug treatments.

For the medical industry, there are problems such as poor sharing of medical data, tampering, and leakage of private data. In view of these problems, a blockchain-based electronic medical record access control research scheme based on the role-based access control model is proposed in this article. First, the appropriate access control strategy is adopted to solve the leakage problem of the user’s medical privacy information during the access process. Then, the information entropy technology is used to quantify the medical data, so that the medical data can be effectively and maximally utilized. Using the distributed general ledger characteristics of blockchain and its inherent security attributes, data islands can be eliminated, data sharing among medical systems can be promoted, access records can be prevented from being tampered with, and medical research and precise medical treatment can be better supported. Through this research, not only can user’s medical privacy information protection be realized during the service process but also patients can manage their own medical data autonomously, which is beneficial to privacy protection under the medical data sharing.

Summary: Drug resistance is a significant hindrance to effective cancer treatment. Although resistance mechanisms of epidermal growth factor receptor (EGFR) mutant cancer cells to lethal EGFR tyrosine kinase inhibitors (TKI) treatment have been investigated intensively, how cancer cells orchestrate adaptive response under sublethal drug challenge remains largely unknown. Here, we find that 2-h sublethal TKI treatment elicits a transient drug-tolerant state in EGFR mutant lung cancer cells. Continuous sublethal treatment reinforces this tolerance and eventually establishes long-term TKI resistance. This adaptive process involves H3K9 demethylation-mediated upregulation of branched-chain amino acid aminotransferase 1 (BCAT1) and subsequent metabolic reprogramming, which promotes TKI resistance through attenuating reactive oxygen species (ROS) accumulation. Combination treatment with TKI- and ROS-inducing reagents overcomes this drug resistance in preclinical mouse models. Clinical information analyses support the correlation of BCAT1 expression with the EGFR TKI response. Our findings reveal the importance of BCAT1-engaged metabolism reprogramming in TKI resistance in lung cancer. : How cancer cells, with strong plasticity, orchestrate their adaptive response under sublethal drug exposure remains largely unknown. Wang et al. show that sublethal tyrosine kinase inhibitor (TKI) treatment elicits drug resistance in EGFR-mutant lung cancer cells through H3K9 demethylation-mediated reprogramming of branched-chain amino acid (BCAA) metabolism. Keywords: lung cancer, EGFR tyrosine kinase inhibitors, drug resistance, metabolic reprogramming, branched-chain amino acids, BCAT1

Background: Ethnic health inequalities for males and females among the elderly have not yet been verified in multicultural societies in developing countries. The aim of this study was to assess the extent of disparities in health expectancy among the elderly from different ethnic groups using quality-adjusted life expectancy. Design: A cross-sectional community-based survey was conducted. A total of 6,511 rural elderly individuals aged ≥60 years were selected from eight different ethnic groups in the Guangxi Zhuang Autonomous Region of China and assessed for health-related quality of life (HRQoL). The HRQoL utility value was combined with life expectancy at age 60 years (LE60) data by using Sullivan's method to estimate quality-adjusted life expectancy at age 60 years (QALE60) and loss in quality-adjusted life years (QALYs) for each group. Results: Overall, LE60 and QALE60 for all ethnic groups were 20.9 and 18.0 years in men, respectively, and 24.2 and 20.3 years in women. The maximum gap in QALE60 between ethnic groups was 3.3 years in males and 4.6 years in females. The average loss in QALY was 2.9 years for men and 3.8 years for women. The correlation coefficient between LE60 and QALY lost was −0.53 in males and 0.12 in females. Conclusion: Women live longer than men, but they suffer more; men have a shorter life expectancy, but those who live longer are healthier. Attempts should be made to reduce suffering in the female elderly and improve longevity for men. Certain ethnic groups had low levels of QALE, needing special attention to improve their lifestyle and access to health care.

The multifunctional photothermal therapy (PTT) platform with the ability to selectively kill bacteria over mammalian cells has received widespread attention recently. Herein, we prepared graphene oxide-amino(polyethyleneglycol) (GO-PEG-NH2) while using the hydrophobic interaction between heptadecyl end groups of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethyleneglycol)] (DSPE-PEG-NH2) and graphene oxide (GO). Based on GO-PEG-NH2, the versatile PTT system was constructed with simultaneous selective recognition, capturing, and photothermal killing of bacteria. When the cells undergo bacterial infection, owing to the poly(ethylene glycol) (PEG) chains and positively charged amino groups, GO-PEG-NH2 can specifically recognize and capture bacteria in the presence of cells. Meanwhile, the stable photothermal performance of GO-PEG-NH2 enables the captured bacteria to be efficiently photothermally ablated upon the irradiation of 808 nm laser. Besides, the GO-PEG-NH2 is highly stable in various biological media and it exhibits low cytotoxicity, suggesting that it holds great promise for biological applications. This work provides new insight into graphene-based materials as a PTT agent for the development of new therapeutic platforms.

Background: Increasing studies have found that high trait anxiety is a key susceptibility phenotype that causes depression. Mindfulness-based interventions can target on dealing with depressogenic vulnerability effectively. Evidence indicates that trait anxiety could affect the trajectory of anti-depressive psychotherapy, and play an important role in the relationship between mindfulness and depression. Furthermore, related studies have found that trait anxiety could involve factors beyond anxiety and be a two-factor construct instead of one-dimensional concept. This viewpoint provides a new prospective for exploring the pathways of the two factors of trait anxiety in the complex relationship and further understand the potential mechanism of vulnerable personality mediated the link of mindfulness and depression.Methods: A cross-sectional survey and a preliminary intervention study were conducted. Thousand two hundred and sixty-two subjects completed a set of self-reported questionnaires that evaluated trait anxiety, mindfulness, and depressive symptoms. Twenty-Three eligible participants with depression were recruited to attend mindfulness-based cognitive training for eight weeks. The same questionnaires were completed 1 week before the training and 6 months after the training. Factor analysis was performed on the 1262-subject sample to explore and confirm the factorial structure of trait anxiety. In addition, mediating effect analysis was conducted in the two studies to test whether two factors of trait anxiety were mediators of the relationship between mindfulness and depression.Results: The exploratory factor analysis extracted two dimensions of trait anxiety, namely, trait anxiety-present factor (TA-P) and trait anxiety-absent factor (TA-A). And confirmatory factor analysis showed that the fit of the two-factor model was acceptable. Both TA-P and TA-A were significantly negatively correlated with mindfulness and positively correlated with depression, and they played a mediating role between mindfulness and depression. The two factors of trait anxiety had multiple mediating effects on the relationship between mindfulness and depression, and the mediating effect of the TA-P factor was stronger than that of the TA-A factor.Conclusion: Our results demonstrated a two-factor model of trait anxiety in the Chinese population. TA-P and TA-A played a multiple mediating role in the relationship between mindfulness and depression. The findings provide new perspectives for psychological interventions to treat depression for people with susceptible personalities. Aiming to reduce negative emotional tendencies (TA-P factor) and enhance positive cognition (TA-A factor) may achieve the early prevention and efficient treatment of depression.

Background: Response inhibition is a hallmark of executive function, which was detected impaired in various psychiatric disorders. However, whether insomnia disorder (ID) impairs response inhibition has caused great controversy.Methods: Using the auditory stop-signal paradigm coupled with event-related potentials (ERPs), we carried out this study to examine whether individuals with ID presented response inhibition deficits and further investigated the neural mechanism correlated to these deficits. Twelve individuals with ID and 13 matched good sleepers (GSs) had participated in this study, and then they performed an auditory stop-signal task (SST) in the laboratory setting with high density EEG recordings.Results: The behavioral results revealed that compared to GSs, patients with ID presented significantly longer stop-signal reaction time (SSRT), suggesting the impairment of motor inhibition among insomniacs. Their reaction time in go trials, however, showed no significant between-group difference. Considering the electrophysiological correlate underlying the longer SSRT, we found reduced P3 amplitude in patients with insomnia in the successful stop trials, which might reflect their poor efficiency of response inhibition. Finally, when we performed exploratory analyses in the failed stop and go trials, patients with ID presented reduced Pe and N1 amplitude in the failed sop trials and go trials respectively.Discussion: Taken together, these findings indicate that individuals with ID would present response inhibition deficits. Moreover, the electrophysiological correlate underlying these deficits mainly revolves around the successful stop P3 component. The present study is the first to investigate the electrophysiological correlate underlying the impaired response inhibition among insomniacs.