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Abstract Background Inositol‐requiring enzyme 1 (IRE1) is an endoplasmic reticulum (ER)‐resident transmembrane protein that senses ER stress and mediates an essential arm of the unfolded protein response (UPR). IRE1 reduces ER stress by upregulating the expression of multiple ER chaperones through activation of X‐box‐binding protein 1 (XBP1). Emerging lines of evidence have revealed that IRE1‐XBP1 axis serves as a multipurpose signal transducer during oncogenic transformation and cancer development. In this study, we explore how IRE1‐XBP1 signaling promotes chemoresistance in lung cancer. Methods The expression patterns of UPR components and MRP1 were examined by Western blot. qRT‐PCR was employed to determine RNA expression. The promoter activity was determined by luciferase reporter assay. Chemoresistant cancer cells were analyzed by viability, apoptosis. CUT & Tag (Cleavage under targets and tagmentation)‐qPCR analysis was used for analysis of DNA‐protein interaction. Results Here we show that activation of IRE1α‐XBP1 pathway leads to an increase in MDR‐related protein 1 (MRP1) expression, which facilitates drug extrusion and confers resistance to cytotoxic chemotherapy. At the molecular level, XBP1‐induced c‐Myc is necessary for SREBP1 expression, and SREBP1 binds to the MRP1 promoter to directly regulate its transcription. Conclusions We conclude that IRE1α‐XBP1 had important role in chemoresistance and appears to be a novel prognostic marker for lung cancer.

Abstract Bacterial ClpB is an ATP-dependent disaggregate that belongs to the Hsp100/Clp family and facilitates bacterial survival under hostile environmental conditions. Streptococcus agalactiae, which is regarded as the major bacterial pathogen of farmed Nile tilapia (Oreochromis niloticus), is known to cause high mortality and large economic losses. Here, we report a ClpB homologue of S. agalactiae and explore its functionality. S. agalactiae with a clpB deletion mutant (∆clpB) exhibited defective tolerance against heat and acidic stress, without affecting growth or morphology under optimal conditions. Moreover, the ΔclpB mutant exhibited reduced intracellular survival in RAW264.7 cells, diminished adherence to the brain cells of tilapia, increased sensitivity to leukocytes from the head kidney of tilapia and whole blood killing, and reduced mortality and bacterial loads in a tilapia infection assay. Furthermore, the reduced virulence of the ∆clpB mutant was investigated by transcriptome analysis, which revealed that deletion of clpB altered the expression levels of multiple genes that contribute to the stress response as well as certain metabolic pathways. Collectively, our findings demonstrated that ClpB, a molecular chaperone, plays critical roles in heat and acid stress resistance and virulence in S. agalactiae. This finding provides an enhanced understanding of the functionality of this ClpB homologue in gram-positive bacteria and the survival strategy of S. agalactiae against immune clearance during infection.

Abstract Translational control exerts immediate effect on the composition, abundance, and integrity of the proteome. Ribosome-associated quality control (RQC) handles ribosomes stalled at the elongation and termination steps of translation, with ZNF598 in mammals and Hel2 in yeast serving as key sensors of translation stalling and coordinators of downstream resolution of collided ribosomes, termination of stalled translation, and removal of faulty translation products. The physiological regulation of RQC in general and ZNF598 in particular in multicellular settings is underexplored. Here we show that ZNF598 undergoes regulatory K63-linked ubiquitination in a CNOT4-dependent manner and is upregulated upon mitochondrial stresses in mammalian cells and Drosophila. ZNF598 promotes resolution of stalled ribosomes and protects against mitochondrial stress in a ubiquitination-dependent fashion. In Drosophila models of neurodegenerative diseases and patient cells, ZNF598 overexpression aborts stalled translation of mitochondrial outer membrane-associated mRNAs, removes faulty translation products causal of disease, and improves mitochondrial and tissue health. These results shed lights on the regulation of ZNF598 and its functional role in mitochondrial and tissue homeostasis.

ABSTRACTThis study utilizes micro-level farm panel data from 2007 to 2012 to measure the technical efficiency of grain production among farms using a stochastic frontier analysis model. Additionally, it employs a two-way fixed effects model to empirically investigate the impact of fiscal support for agriculture on grain production technical efficiency and its underlying mechanisms. The results reveal significant room for improvement in the technical efficiency of grain production among Chinese farms, with increased fiscal support for agriculture demonstrating a substantial enhancement of their efficiency. This promoting effect only exists in the major grain-producing areas and increases with the increase of farm size. The augmentation of fiscal support for agriculture achieves this goal by augmenting modern agricultural input factors, alleviating financing constraints faced by farms, and optimizing agricultural production infrastructure. Our findings provide guidance for optimizing fiscal policy to support agriculture, promoting agricultural modernization, and achieving food security.

Summary: ER-phagy, a selective autophagy targeting the endoplasmic reticulum (ER) for lysosomal degradation through cargo receptors, plays a critical role in ER quality control and is linked to various diseases. However, its physiological and pathological roles remain largely unclear due to a lack of animal model studies. This study establishes Drosophila as an in vivo ER-phagy model. Starvation triggers ER-phagy across multiple fly tissues. Disturbing ER-phagy by either globally upregulating or downregulating ER-phagy receptors, Atl or Rtnl1, harms the fly. Notably, moderate upregulation of ER-phagy in fly brains by overexpressing Atl or Rtnl1 significantly attenuates age-associated neurodegenerations. Furthermore, in a Drosophila model of Alzheimer’s disease expressing human amyloid precursor protein (APP), impaired ER-phagy is observed. Enhancing ER-phagy in the APP-expressing fly brain facilitates APP degradation, significantly alleviating disease symptoms. Therefore, our findings suggest that modulating ER-phagy may offer a therapeutic strategy to treat aging and diseases associated with ER protein aggregation.

Abstract Therapeutic cancer vaccines fail to produce satisfactory outcomes against solid tumors since vaccine‐induced anti‐tumor immunity is significantly hampered by immunosuppression. Generating an in situ cancer vaccine targeting immunological cold tumor microenvironment (TME) appears attractive. Here, a type of free‐field based whole‐body ultrasound (US)‐driven nanovaccines are constructed, named G5‐CHC‐R, by conjugating the sonosensitizer, Chenghai chlorin (CHC) and the immunomodulator, resiquimod (R848) on top of a super small‐sized dendrimeric nanoscaffold. Once entering tumors, R848 can be cleaved from a hypoxia‐sensitive linker, thus modifying the TME via converting macrophage phenotypes. The animals bearing orthotopic pancreatic cancer with intestinal metastasis and breast cancer with lung metastasis are treated with G5‐CHC‐R under a free‐field based whole‐body US system. Benefit from the deep penetration capacity and highly spatiotemporal selectiveness, G5‐CHC‐R triggered by US represented a superior alternative for noninvasive irradiation of deep‐seated tumors and magnification of local immune responses via driving mass release of tumor antigens and “cold‐warm‐hot” three‐state transformation of TME. In addition to irradiating primary tumors, a robust adaptive anti‐tumor immunity is potentiated, leading to successful induction of systemic tumor suppression. The sono‐nanovaccines with good biocompatibility posed wide applicability to a broad spectrum of tumors, revealing immeasurable potential for translational research in oncology.

Asiatic acid (AA) is a pentacyclic triterpene derived from the traditional medicine Centella asiatica. It is known for its anti-inflammatory, antioxidant, and lipid-regulating properties. Though previous studies have suggested its potential therapeutic benefits for atherosclerosis, its pharmacological mechanism is unclear. The objective of this study was to investigate the molecular mechanism of AA in the treatment of atherosclerosis. Therefore, network pharmacology was employed to uncover the mechanism by which AA acts as an anti-atherosclerotic agent. Furthermore, molecular docking, molecular dynamics (MD) simulation, and in vitro experiments were performed to elucidate the mechanism of AA’s anti-atherosclerotic effects. Molecular docking analysis demonstrated a strong affinity between AA and PPARγ. Further MD simulations demonstrated the favorable stability of AA-PPARγ protein complexes. In vitro experiments demonstrated that AA can dose-dependently inhibit the expression of inflammatory factors induced by lipopolysaccharide (LPS) in RAW264.7 cells. This effect may be mediated through the PPARγ/NF-κB signaling pathway. This research underscores anti-inflammation as a crucial biological process in AA treatments for atherosclerosis, with PPARγ potentially serving as a key target.

Manganese oxide-cerium oxide supported on titanate nanotubes (i.e., MnCe/TiNTs) were prepared and their catalytic activities towards NH3-SCR of NO were tested. The results indicated that the MnCe/TiNT catalyst can achieve a high NO removal efficiency above 95% within the temperature range of 150–350 °C. Even after exposure to a HCl-containing atmosphere for 2 h, the NO removal efficiency of the MnCe/TiNT catalyst maintains at approximately 90% at 150 °C. This is attributed to the large specific surface area as well as the unique hollow tubular structure of TiNTs that exposes more Ce atoms, which preferentially react with HCl and thus protect the active Mn atoms. Moreover, the abundant OH groups on TiNTs serve as Brønsted acid sites and provide H protons to expel Cl atom from the catalyst surface. The irreversible deactivation caused by HCl can be alleviated by H2O. That is because the dissociated adsorption of H2O on TiNTs forms additional OH groups and relieves HCl poisoning.

Abstract Ferroptosis is a newly defined non-apoptotic programmed cell death resulting from the accumulation of lipid peroxides. Whether ferroptosis plays any role in chemotherapy remains to be established. Here, we reported that ferroptosis represents a part of the chemotherapeutic drug etoposide-induced cell death response in Small Cell Lung Cancer (SCLC) cells and adaptive signaling molecule lactate protects Non-Small Cell Lung Cancer (NSCLC) from etoposide-induced ferroptosis. Lactate derived from metabolic reprogramming increases the expression of glutathione peroxidase 4 (GPX4) to promote ferroptosis resistance in NSCLC. Furthermore, we identified E3-ubiquitin ligase NEDD4L as a major regulator of GPX4 stability. Mechanistically, Lactate increases mitochondrial ROS generation and drives activation of the p38-SGK1 pathway, which attenuates the interaction of NEDD4L with GPX4 and subsequent ubiquitination and degradation of GPX4. Our data implicated the role of ferroptosis in chemotherapeutic resistance and identified a novel post-translational regulatory mechanism for the key Ferroptosis mediator GPX4.

The iron-modified coal gasification slag (Fe-CGS) material has excellent performance in purifying heavy-metal-contaminated water due to its good surface properties and adsorption capacities. However, it is unclear whether it can provide long-term simultaneous stabilization of Cd and As in composite-contaminated soils in extreme environments. This study investigated the long-term stabilization of Cd and As in acidic (JLG) and alkaline (QD) soils by simulating prolonged heavy rainfall with the addition of Fe-CGS. Multiple extraction methods were used to analyze the immobilization mechanisms of Cd and As in soil and their effects on bioavailability. The results indicate that the stabilization efficiency was related to the dosage of Fe-CGS. The concentrations of Cd and As in the JLG soil leachate were reduced by 77.6% (2.0 wt%) and 87.8% (1.0 wt%), respectively. Additionally, the availability of Cd and As decreased by 46.7% (2.0 wt%) and 53.0% (1.0 wt%), respectively. In the QD soil leachate, the concentration of Cd did not significantly change, while the concentration of As decreased by 92.3% (2.0 wt%). Furthermore, the availability of Cd and As decreased by 22.1% (2.0 wt%) and 40.2% (1.0 wt%), respectively. Continuous extraction revealed that Fe-CGS facilitated the conversion of unstable, acid-soluble Cd into oxidizable Cd and acid-soluble Cd. Additionally, it promoted the transformation of both non-specifically and specifically adsorbed As into amorphous iron oxide-bound and residual As. Fe-CGS effectively improved the soil pH, reduced the bioavailability of Cd and As, and blocked the migration of Cd and As under extreme rainfall leaching conditions. It also promoted the transformation of Cd and As into more stable forms, exhibiting satisfactory long-term stabilization performance for Cd and As.

Light spectrum is an important environmental factor affecting fish activities. However, the existing studies on spectrum are usually conducted under monochromatic light, which are multiple variables compared to the natural light conditions and increase uncertainty. The results may be caused by the absence of all other chromatic lights. The tiger puffer Takifugu rubripes is an important commercial marine fish in China, Japan, and Korea. In this study, the effects of red light on the eyes and brain of T. rubripes brooder, including histological changes in retina and optic tectum, the levels of oxidative stress indicators in serum, and changes in gene expression at transcriptome level were examined, after the treatment of full spectrum LED (Fs) and red light filtered LED (Rf) for 52 days. The results showed that the growth and histological structure of retina and optic tectum were not significantly altered. While, Rf significantly decreased the activity of superoxide dismutase and catalase, and increased the content of cortisol (P

Aeromonas hydrophila is an emerging foodborne pathogen causing human gastroenteritis. Aeromonas species isolated from food such as seafood presented multidrug-resistance (MDR), raising serious concerns regarding food safety and public health. The use of phages to infect bacteria is a defense against drug-resistant pathogens. In this study, phage ZPAH34 isolated from the lake sample exerted lytic activity against MDR A. hydrophila strain ZYAH75 and inhibited the biofilm on different food-contacting surfaces. ZPAH34 has a large dsDNA genome of 234 kb which belongs to a novel jumbo phage. However, its particle size is the smallest of known jumbo phages so far. Based on phylogenetic analysis, ZPAH34 was used to establish a new genus Chaoshanvirus. Biological characterization revealed that ZPAH34 exhibited wide environmental tolerance, and a high rapid adsorb and reproductive capacity. Food biocontrol experiments demonstrated that ZPAH34 reduces the viable count of A. hydrophila on fish fillets (2.31 log) and lettuce (3.28 log) with potential bactericidal effects. This study isolated and characterized jumbo phage ZPAH34 not only enriched the understanding of phage biological entity diversity and evolution because of its minimal virion size with large genome but also was the first usage of jumbo phage in food safety to eliminate A. hydrophila.

Ferroptosis is a newly defined form of programmed cell death. It possesses unique processes of cell demise, cytopathological changes, and independent signal regulation pathways. Ferroptosis is considered to be deeply involved in the development of many diseases, including cancer, cardiovascular diseases, and neurodegeneration. Intriguingly, why cells in certain tissues and organs (such as the central nervous system, CNS) are more sensitive to changes in ferroptosis remains a question that has not been carefully discussed. In this Holmesian review, we discuss lipid composition as a potential but often overlooked determining factor in ferroptosis sensitivity and the role of polyunsaturated fatty acids (PUFAs) in the pathogenesis of several common human neurodegenerative diseases. In subsequent studies of ferroptosis, lipid composition needs to be given special attention, as it may significantly affect the susceptibility of the cell model used (or the tissue studied).

Stimulator of IFN genes type I (STING-Type I) IFN signaling in myeloid cells plays a critical role in effective antitumor immune responses, but STING agonists as monotherapy have shown limited efficacy in clinical trials. The mechanisms that downregulate STING signaling are not fully understood. Here, we report that protein phosphatase 2A (PP2A), with its specific B regulatory subunit Striatin 4 (STRN4), negatively regulated STING-Type I IFN in macrophages. Mice with macrophage PP2A deficiency exhibited reduced tumor progression. The tumor microenvironment showed decreased immunosuppressive and increased IFN-activated macrophages and CD8+ T cells. Mechanistically, we demonstrated that Hippo kinase MST1/2 was required for STING activation. STING agonists induced dissociation of PP2A from MST1/2 in normal macrophages, but not in tumor conditioned macrophages. Furthermore, our data showed that STRN4 mediated PP2A binding to and dephosphorylation of Hippo kinase MST1/2, resulting in stabilization of YAP/TAZ to antagonize STING activation. In human patients with glioblastoma (GBM), YAP/TAZ was highly expressed in tumor-associated macrophages but not in nontumor macrophages. We also demonstrated that PP2A/STRN4 deficiency in macrophages reduced YAP/TAZ expression and sensitized tumor-conditioned macrophages to STING stimulation. In summary, we demonstrated that PP2A/STRN4-YAP/TAZ has, in our opinion, been an unappreciated mechanism that mediates immunosuppression in tumor-associated macrophages, and targeting the PP2A/STRN4-YAP/TAZ axis can sensitize tumors to immunotherapy.

Sweet potato (Ipomoea batatas (L.) Lam.) is one of the most widely cultivated crops in the world, with outstanding stress tolerance, but drought stress can lead to a significant decrease in its yield. To reveal the response mechanism of sweet potato to drought stress, an integrated physiological, transcriptome and metabolome investigations were conducted in the leaves of two sweet potato varieties, drought-tolerant zhenghong23 (Z23) and a more sensitive variety, jinong432 (J432). The results for the physiological indexes of drought showed that the peroxidase (POD) and superoxide dismutase (SOD) activities of Z23 were 3.68 and 1.21 times higher than those of J432 under severe drought, while Z23 had a higher antioxidant capacity. Transcriptome and metabolome analysis showed the importance of the amino acid metabolism, respiratory metabolism, and antioxidant systems in drought tolerance. In Z23, amino acids such as asparagine participated in energy production during drought by providing substrates for the citrate cycle (TCA cycle) and glycolysis (EMP). A stronger respiratory metabolism ability could better maintain the energy supply level under drought stress. Drought stress also activated the expression of the genes encoding to antioxidant enzymes and the biosynthesis of flavonoids such as rutin, resulting in improved tolerance to drought. This study provides new insights into the molecular mechanisms of drought tolerance in sweet potato.

The interplay of the enteric nervous system (ENS) and SIP syncytium (smooth muscle cells–interstitial cells of Cajal–PDGFRα+ cells) plays an important role in the regulation of gastrointestinal (GI) motility. This study aimed to investigate the dynamic regulatory mechanisms of the ENS-SIP system on colon motility during postnatal development. Colonic samples of postnatal 1-week-old (PW1), 3-week-old (PW3), and 5-week-old (PW5) mice were characterized by RNA sequencing, qPCR, Western blotting, isometric force recordings (IFR), and colonic motor complex (CMC) force measurements. Our study showed that the transcriptional expression of Pdgfrα, c-Kit, P2ry1, Nos1, and Slc18a3, and the protein expression of nNOS, c-Kit, and ANO1 significantly increased with age from PW1 to PW5. In PW1 and PW3 mice, colonic migrating movement was not fully developed. In PW5 mice, rhythmic CMCs were recorded, similar to the CMC pattern described previously in adult mice. The inhibition of nNOS revealed excitatory and non-propulsive responses which are normally suppressed due to ongoing nitrergic inhibition. During postnatal development, molecular data demonstrated the establishment and expansion of ICC and PDGFRα+ cells, along with nitrergic and cholinergic nerves and purinergic receptors. Our findings are important for understanding the role of the SIP syncytium in generating and establishing CMCs in postnatal, developing murine colons.

PKAN and PD are two distinct diseases with overlapping pathophysiology. Here, authors show that their pathogenic genes PANK2 and PINK1 interact. PANK2 regulates mitophagy via CoA metabolism, while PINK1 supervises PANK2 translation on mitochondria.

Abstract Prostate cancer remains the second‐most common cancer diagnosed in men, despite the increasingly widespread use of serum prostate‐specific antigen (PSA) screening. The controversial clinical implications and cost benefits of PSA screening have been highlighted due to its poor specificity, resulting in a high rate of overdiagnosis and underdiagnosis. Thus, the development of novel biomarkers for prostate cancer detection remains an intriguing challenge. Urine is emerging as a source for prostate cancer biomarker discovery. Currently, new urine biomarkers already outperform serum PSA in clinical diagnosis. Meanwhile, the advances in nanotechnology have provided a suite of diagnostic tools to study prostate cancer in more detail, sparking a new era of biomarker discoveries. In this review, we envision that future prostate cancer diagnosis will probably integrate multiplex nano‐diagnostic approaches to detect novel urinary biomarkers. However, challenges remain in differentiating indolent from aggressive cancers to better inform treatment decisions, and clinical translation still needs to be overcome.

Aeromonas hydrophila, a ubiquitous bacterium in aquatic habitats with broad host ranges, has earned the nickname of a ‘Jack-of-all-trades’. However, there is still a limited understanding of the mechanism of how this bacterium fit the competition with other species in dynamic surroundings. The type VI secretion system (T6SS) is macromolecular machinery found in Gram-negative bacteria’s cell envelope that is responsible for bacterial killing and/or pathogenicity toward different host cells. In this study, the depression of A. hydrophila T6SS under iron-limiting conditions was detected. The ferric uptake regulator (Fur) was then found to act as an activator of T6SS by directly binding to the Fur box region in vipA promoter in the T6SS gene cluster. The transcription of vipA was repressed in Δfur. Moreover, the inactivation of Fur resulted in considerable defects in the interbacterial competition activity and pathogenicity of A. hydrophila in vitro and in vivo. These findings provide the first direct evidence that Fur positively regulates the expression and functional activity of T6SS in Gram-negative bacteria and will help to understand the fascinating mechanism of competitive advantage for A. hydrophila in different ecological niches.

BackgroundTo investigate the effect of the distribution and expression of interstitial cells of Cajal (ICCs) and platelet-derived growth factor receptor-α positive (PDGFRα+) cells in different colon segments on colonic motility in children with Hirschsprung disease (HSCR).MethodsSmooth muscles of the narrow and dilated segments of the colon were obtained from 16 pediatric patients with HSCR. The proximal margin was set as the control section. The mRNA and protein expressions of c-Kit, PDGFRα, ANO1, and SK3 channels were examined. Circular smooth muscle strips of the colon were prepared for performing electrophysiology experiments using electric field stimulation (EFS) and intervention from different drugs (TTX, NPPB, Apamin, L-NAME, and CyPPA).ResultsThe mRNA and protein expressions of c-Kit, ANO1, PDGFRα, and SK3 were much lower in the narrow segment than those in the dilated and proximal segments of the colon. The narrow segment showed a considerably spontaneous contraction of the muscle strip. After the EFS, the relaxation response decreased from the proximal to the narrow segment, whereas the contraction response increased. TTX blocking did not cause any significant changes in the narrow segment. In contrast, when NPPB, Apamin, L-NAME, and CyPPA were used to intervene in the muscle strips, the proximal segment showed a more sensitive inhibitory or excitatory response than the narrow segment.ConclusionsDownregulation of the ICCs and PDGFRα+ cells from the proximal to narrow segment may be responsible for the dysmotility of the colon in pediatric HSCR.

In the setting of coronary heart diseases (CHDs) on treatment with clopidogrel, ADP-induced platelet aggregation has been demonstrated with ischemic events. However, there were very limited data for predicting ischemic events by platelet function test via dynamic platelet aggregation counting (DPAC). The present study aimed to evaluate the relationship between adenosine diphosphate (ADP)-induced whole blood platelet aggregation rates (PARs) and clinical outcomes in patients with CHDs on treatment with clopidogrel. We have retrospectively analyzed the clinical data of consecutive patients with CHDs based on the electronic medical records between May 2016 and December 2018. The primary endpoint was a composite endpoint events (CEEs) of ischemic cardiovascular events (including acute coronary syndrome, heart failure, transient ischemic attack, and cerebral infarction) and all-cause death. A total of 490 patients (mean age 66.6 years, 71% man) were received ADP-induced PARs via DPAC. On follow-up (mean 374 days), 107 subjects (21.8%) developed CEEs. Cox regression analysis indicated that the risk of CEEs was independently associated with ADP-induced whole blood PARs [HR: 1.023, 95% CI: 1.005–1.041, P = .011]. The distribution of CYP2C19 loss of function gene was higher in patients with on-treatment platelet hyperresponsiveness (10/12 vs 38/75, P = .042). In conclusion, ADP-induced whole blood PARs via DPAC is feasible, which can predict the incidence of 1-year CEEs in patients with CHDs on treatment with clopidogrel. CYP2C19 gene polymorphism was associated with clopidogrel on-treatment platelet hyperresponsiveness.

Abstract Background Erythropoiesis and iron homeostasis are closely related; anemia due to lower-risk myelodysplastic syndromes (MDS) remains difficult to treat. In the last decade, we have been committed to improving the regulation of iron metabolism using traditional Chinese medicine (TCM). Previous studies have found that the TCM Yi Gong San (YGS) can reduce the expression of transferrin by inhibiting hepcidin overexpression caused by inflammation, promote the outward transfer of intracellular iron, and improve the symptoms of anemia. Here, our study aimed to compare the efficacy of a conventional drug with YGS with that of conventional medicine with placebo to provide a scientific basis for making clinical decisions. Methods A prospective, multicenter, double-blinded, randomized controlled clinical trial will be conducted to evaluate the therapeutic efficacy of conventional medicine combined with YGS with that of conventional medicine alone in the treatment of MDS. A total of 60 patients would be enrolled in this study, with each treatment group (conventional medicine + YGS and conventional medicine + placebo) comprising 30 patients. Oral medication would be administered twice daily for 3 months. All patients would be followed up throughout the 3-month period. The primary outcome was measured by assessing blood hemoglobin level. The secondary outcome was measured by assessing TCM symptom score, iron metabolism, hepcidin levels, and inflammatory factors. Discussion This trial would aim to demonstrate the effectiveness and feasibility of YGS in the treatment of lower-risk MDS anemia, as well as its impact on inflammatory factors and iron metabolism in patients with lower-risk MDS. Trial registration Chinese Clinical Trials Registry ( http://www.chictr.org.cn/ ) ChiCTR1900026774 . Registered on October 21, 2019.

Abstract Objective Dual antiplatelet therapy can reduce coronary thrombosis and improve the prognosis in patients with acute coronary syndrome (ACS). However, there was limited prognostic information about fibrinolytic dysregulation in patients with ACS. This study is aimed to evaluated the prevalence and impact of fibrinolytic dysregulation in patients with acute coronary syndrome (ACS). Methods We retrospectively analyzed coagulation and fibrinolysis related indexes of ACS in hospitalized adults with rapid thrombelastography between May 2016 and December 2018. All of the follow-up visits were ended by December 2019. The primary outcome was the occurrence of major adverse cardiovascular events (MACEs), which included unstable angina pectoris, non-fatal myocardial infarction, non-fatal cerebral infarction, heart failure and all-cause death. Results Three hundred thirty-eight patients were finally included with an average age of 62.5 ± 12.8 years old, 273 (80.5%) were males, 137(40.5%) patients were with ST-elevation myocardial infraction. Fibrinolysis shutdown (LY303.0%) were observed among 163 (48.2%) and 76(22.5%) patients, respectively. During a total of 603.2 person·years of follow-up period, 77 MACEs occurred (22.8%). Multivariate Cox regression analysis indicated that LY30 [HR: 1.101, 95% CI: 1.010–1.200, P = 0.028] was independently correlated with the occurrence of MACEs. The hazard ratios pertaining to MACEs in patients with fibrinolysis shutdown and hyperfibrinolysis compared with those in the physiologic range (LY30: 0.8–3.0%) were 1.196 [HR: 1.196, 95% CI: 0.679–2.109,P = 0.535] and 2.275 [HR: 2.275, 95% CI: 1.241–4.172, P = 0.003], respectively. Conclusions Fibrinolytic dysregulation is very common in selected patients with ACS, and hyperfibrinolysis (LY30 > 3%) is associated with poor outcomes in patients with ACS.

For the remote sensing of turbid waters, the atmospheric correction (AC) is a key issue. The “black pixel” assumption helps to solve the AC for turbid waters. It has proved to be inaccurate to regard all water pixels in the SWIR (Short Wave Infrared) band as black pixels. It is necessary to perform atmospheric correction in the visible bands after removing the radiation contributions of water in the SWIR band. Here, the modified ACZI (m-ACZI) algorithm was developed. The m-ACZI assumes the spatial homogeneity of aerosol types and employs the BPI (Black Pixel Index) and PIFs (Pseudo-Invariant Features) to identify the “black pixel”. Then, the radiation contributions of waters in the SWIR band are removed to complete the atmospheric correction for turbid waters. The results showed that the m-ACZI had better performance than the SeaDAS (SeaWiFS Data Analysis System) -SWIR and the EXP (exponential extrapolation) algorithm in the visible band (sMAPE < 30.71%, RMSE < 0.0111 sr−1) and is similar to the DSF (Dark Spectrum Fitting) algorithm in floating algae waters. The m-ACZI algorithm is suitable for turbid inland waters.

The increase in agricultural machinery input contribution rate has been the most significant structural change in the input factors of grain production in recent years. In this study, we constructed a threshold regression model and a spatial Durbin model to investigate the threshold effects and the spatial spillovers of agricultural mechanization level on grain production, using panel data of 13 prefecture-level cities in Jiangsu, China, from 2000 to 2016. The results reveal that agricultural mechanization has a single threshold effect on grain yield, and that there is a significant spatial spillover effect of agricultural mechanization on grain yield. This means that the improvement of the mechanization level in one region, will significantly promote the increase in the grain yield in its surrounding regions, due to the cross-regional operation of agricultural machinery.

Fat greenling Hexagrammos otakii, belonging to Scorpaeniformes, is an important commercial marine fish species distributed in coast waters of China, Japan, and Korea. Artificial gynogenesis induction is one of the important techniques of chromosome manipulation and genetic breeding. The eggs are fertilized with genetic inactivated sperm, and genome information of the offspring is totally contributed by maternal genome. Until now, no gynogenesis induction was reported in H. otakii and other Scorpaeniformes species. The present study developed an effective gynogenesis induction method in H. otakii by applying hydrostatic pressure to the eggs activated with UV-irradiated homologous sperm. The optimal inducing conditions were 36,000 erg mm−2 for UV-irradiated and pressure of 65 MPa for 6 min at 20 min post fertilization. The relative hatching rates could reach 92%. The early development and growth before 6 month post hatching showed no difference between the gynogenetic and control diploid. The all-maternal inheritance was confirmed with 4 microsatellite loci. The genetic diversity of the control and gynogenetic diploid revealed with 20 microsatellite loci showed that the homozygosity of the gynogenetic diploid stocks was 0.84 in average, which was nearly double the value of the control diploid stocks (0.45 in average). Under scanning electron microscope, the egg envelop had a gelatinous-honeycomb before 0.5 h post fertilization (hpf). Then all or part of the gelatinous-honeycomb layer disappeared before 24 hpf. The uniform pores distributed to hexagonal pattern on the egg envelop were found in the control diploid and haploid groups. However, no pore on the egg envelop was found in the gynogenetic diploid from fertilization to hatching. These results would provide a valuable reference for gynogenesis induction in fish with viscous ovarian fluid coated eggs, although special incubation process to increase the survival rate should be further developed based on the characteristics of gynogenetic H. otakii.

Abstract Background Metabolic reprogramming contributes significantly to tumor development and is tightly linked to drug resistance. The chemotherapeutic agent etoposide (VP-16) has been used clinically in the treatment of lung cancer but possess different sensitivity and efficacy towards SCLC and NSCLC. Here, we assessed the impact of etoposide on glycolytic metabolism in SCLC and NSCLC cell lines and investigated the role of metabolic rewiring in mediating etoposide resistance. Methods glycolytic differences of drug-treated cancer cells were determined by extracellular acidification rate (ECAR), glucose consumption, lactate production and western blot. DNA damage was evaluated by the comet assay and western blot. Chemoresistant cancer cells were analyzed by viability, apoptosis and western blot. Chromatin immunoprecipitation (ChIP) was used for analysis of DNA-protein interaction. Results Here we showed that exposure to chemotherapeutic drug etoposide induces an exacerbation of ROS production which activates HIF-1α-mediated the metabolic reprogramming toward increased glycolysis and lactate production in non-small cell lung cancer (NSCLC). We identified lactic acidosis as the key that confers multidrug resistance through upregulation of multidrug resistance-associated protein 1 (MRP1, encoded by ABCC1), a member of ATP-binding cassette (ABC) transporter family. Mechanistically, lactic acid coordinates TGF-β1/Snail and TAZ/AP-1 pathway to induce formation of Snail/TAZ/AP-1 complex at the MRP1/ABCC1 promoter. Induction of MRP1 expression inhibits genotoxic and apoptotic effects of chemotherapeutic drugs by increasing drug efflux. Furthermore, titration of lactic acid with NaHCO3 was sufficient to overcome resistance. Conclusions The chemotherapeutic drug etoposide induces the shift toward aerobic glycolysis in the NSCLC rather than SCLC cell lines. The increased lactic acid in extracellular environment plays important role in etoposide resistance through upregulation of MRP expression. These data provide first evidence for the increased lactate production, upon drug treatment, contributes to adaptive resistance in NSCLC and reveal potential vulnerabilities of lactate metabolism and/or pathway suitable for therapeutic targeting. Video Abstract Graphical abstract The chemotherapeutic drug etoposide induces metabolic reprogramming towards glycolysis in the NSCLC cells. The secreted lactic acid coordinates TGF-β1/Snail and TAZ/AP-1 pathway to activate the expression of MRP1/ABCC1 protein, thus contributing to chemoresistance in NSCLC.

Sequential recommendation has become a research trending that exploits user’s recent behaviors for recommendation. The user-item interactions contain a sequential dependency that we need to capture to better recommend. Item-item Product (IIP), which models item co-occurrence, has shown good potential by characterizing the pairwise item relationships. Generally, recent behaviors have a greater impact on the current than long-term historical behaviors. And the decaying rate of influence around infrequent behaviors is fast. However, IIP ignores such a phenomenon when considering item-item relevance and leads to suboptimal performance. In this paper, we propose an attenuated IIP mechanism which is position-aware and decays the influence of historical items at an exponential rate. Besides, In order to make up for scenarios where the influence is not in a monotonous decline trend, we add another normalized IIP mechanism to complement the attenuated IIP mechanism. It also strengthen the model’s ability in discriminating favorite items under the sparse data condition by enlarging the gap of matching degree between items. Experiments conducted on five real-world datasets demonstrate that our proposed model achieves better performance than a set of state-of-the-art sequential recommendation models.

Item co-occurrence is an important pattern in recommendation. Due to the difference in correlation, the matching degrees between the target and historical items vary. The higher the matching degree, the greater probability they co-occur. Recently, the recommendation performance has been greatly improved by leveraging item relations. As an important bond imposed by relations, these connected items should have a strong correlation in the calculation of certain measures. This kind of correlation can be the biased knowledge that benefits parameter training. Specifically, we focus on tuples containing the target item and latest relational items that have relations such as complement or substitute with the target item in user's behavior sequence. Such close relations mean the matching degrees between relational items and historical items should be highly affected by that of the target item and historical items. For example, given a relational item having relation complement with the target item, if the target item has high matching degrees with some items in user's behavior sequence, this complementary item should behave similarly for the co-occurrence of complementary items. Under guidance of the above thought, in this work, we propose a target-relation regulated mechanism which converts the biased knowledge of high correlation of matching degrees into a regulation. It integrates the target item and relational items in history as a whole to characterize the matching score between the target item and historical items. Experiments conducted on three real-world datasets demonstrate that our model can significantly outperform a set of state-of-the-art models.

Aeromonas hydrophila is a Gram-negative bacterium that is commonly distributed in aquatic surroundings and has been considered as a pathogen of fish, amphibians, reptiles, and mammals. In this study, a virulent strain A. hydrophila GD18, isolated from grass carp (Ctenopharyngodon idella), was characterized to belong to a new sequence type ST656. Whole-genome sequencing and phylogenetic analysis showed that GD18 was closer to environmental isolates, however distantly away from the epidemic ST251 clonal group. The type VI secretion system (T6SS) was known to target both eukaryotic and prokaryotic cells by delivering various effector proteins in diverse niches by Gram-negative bacteria. Genome-wide searching and hemolysin co-regulated protein (Hcp) expression test showed that GD18 possessed a functional T6SS and is conditionally regulated. Further analysis revealed that VasH, a σ54-transcriptional activator, was strictly required for the functionality of T6SS in A. hydrophila GD18. Mutation of vasH gene by homologous recombination significantly abolished the bactericidal property. Then the virulence contribution of VasH was characterized in both in vitro and in vivo models. The results supported that VasH not only contributed to the bacterial cytotoxicity and resistance against host immune cleaning, but also was required for virulence and systemic dissemination of A. hydrophila GD18. Taken together, these findings provide a perspective for understanding the VasH-mediated regulation mechanism and T6SS-mediated virulence and bactericidal effect of A. hydrophila.

Parkinson’s disease (PD) is a common neurodegenerative disorder without effective disease-modifying therapeutics. Here, we establish a chemogenetic dopamine (DA) neuron ablation model in larval zebrafish with mitochondrial dysfunction and robustness suitable for high-content screening. We use this system to conduct an in vivo DA neuron imaging-based chemical screen and identify the Renin-Angiotensin-Aldosterone System (RAAS) inhibitors as significantly neuroprotective. Knockdown of the angiotensin receptor 1 (agtr1) in DA neurons reveals a cell-autonomous mechanism of neuroprotection. DA neuron-specific RNA-seq identifies mitochondrial pathway gene expression that is significantly restored by RAAS inhibitor treatment. The neuroprotective effect of RAAS inhibitors is further observed in a zebrafish Gaucher disease model and Drosophila pink1-deficient PD model. Finally, examination of clinical data reveals a significant effect of RAAS inhibitors in delaying PD progression. Our findings reveal the therapeutic potential and mechanisms of targeting the RAAS pathway for neuroprotection and demonstrate a salient approach that bridges basic science to translational medicine.

Ice-induced vibration is one of the major risks that face the offshore platform located in cold regions. In this paper, the gated recurrent neural network (GRNN) is utilized to predict and suppress the response of offshore platforms subjected to ice load. First, a simplified model of the offshore platform is derived and validated based on the finite element model (FEM). The time history of the floating ice load is generated using the harmonic superposition method. Gated Recurrent Unit Network (GRU) and the Long-Short-Term Memory Network (LSTM) are composed in MATLAB to predict the behavior of the off-shore platform. Afterward, the linear quadratic regulator (LQR) control algorithm is used to calculate the controlling force for the training of the GRU/LSTM-based prediction controller. Numerical results show that the ice-induced vibration response prediction method based on GRU network design can predict the structural response with satisfying accuracy, and the ice-induced vibration response control method based on the LSTM network and GRU network design can learn the LQR method well and achieve good control effect. Time lag and other problems that the vibration control programs often encountered were solved well.

The high-temperature superconductor (HTS) has been recognised as one of the most up-and-coming materials thanks to its superior electromagnetic performance (e.g., zero resistance). For a high-speed maglev, the HTS magnet can be the most crucial component because it is in charge of both the levitation and the propulsion of the maglev. Therefore, a fundamental study of HTS magnets for maglev is crucial. This article presents the fundamental design and modelling of the superconducting magnet for a high-speed maglev, including mechanics, electromagnetics, and loss analysis during instability. First, the measurements of the superconducting wire were performed. The HTS magnet was primarily designed and modelled to fulfil the basic electromagnetic requirements (e.g., magnetic field) in order to drive the maglev at a high speed. The modelling was verified by experimental tests on a scale-down HTS magnet. A more professional model using the H-formulation based on the finite element method (FEM) was built to further investigate some deeper physical phenomenon of the HTS magnet (e.g., current density and loss behaviours), particularly in situations where the high-speed maglev is in the normal steady state or encountering instability.

A widely used clustering algorithm, density peak clustering (DPC), assigns different attribute values to data points through the distance between data points, and then determines the number and range of clustering by attribute values. However, DPC is inefficient when dealing with scenes with a large amount of data, and the range of parameters is not easy to determine. To fix these problems, we propose a quantum DPC (QDPC) algorithm based on a quantum DistCalc circuit and a Grover circuit. The time complexity is reduced to O(log(N2)+6N+N), whereas that of the traditional algorithm is O(N2). The space complexity is also decreased from O(N·⌈logN⌉) to O(⌈logN⌉).

Summary: Amyotrophic lateral sclerosis (ALS) manifests pathological changes in motor neurons and various other cell types. Compared to motor neurons, the contribution of the other cell types to the ALS phenotypes is understudied. G4C2 repeat expansion in C9ORF72 is the most common genetic cause of ALS along with frontotemporal dementia (C9-ALS/FTD), with increasing evidence supporting repeat-encoded poly(GR) in disease pathogenesis. Here, we show in Drosophila muscle that poly(GR) enters mitochondria and interacts with components of the Mitochondrial Contact Site and Cristae Organizing System (MICOS), altering MICOS dynamics and intra-subunit interactions. This impairs mitochondrial inner membrane structure, ion homeostasis, mitochondrial metabolism, and muscle integrity. Similar mitochondrial defects are observed in patient fibroblasts. Genetic manipulation of MICOS components or pharmacological restoration of ion homeostasis with nigericin effectively rescue the mitochondrial pathology and disease phenotypes in both systems. These results implicate MICOS-regulated ion homeostasis in C9-ALS pathogenesis and suggest potential new therapeutic strategies.

Adenosine-to-inosine (A-to-I) editing and N6-methyladenosine (m6A) are two of the most abundant RNA modifications. Here, we examined the characteristics of the RNA editing and transcriptome-wide m6A modification profile in the gonads of the olive flounder, Paralichthys olivaceus, an important maricultured fish in Asia. The gonadal differentiation and development of the flounder are controlled by genetic as well as environmental factors, and the epigenetic mechanism may play an important role. In total, 742 RNA editing events were identified, 459 of which caused A to I conversion. Most A-to-I sites were located in 3′UTRs, while 61 were detected in coding regions (CDs). The number of editing sites in the testis was higher than that in the ovary. Transcriptome-wide analyses showed that more than one-half of the transcribed genes presented an m6A modification in the flounder gonads, and approximately 60% of the differentially expressed genes (DEGs) between the testis and ovary appeared to be negatively correlated with m6A methylation enrichment. Further analyses revealed that the mRNA expression of some sex-related genes (e.g., dmrt1 and amh) in the gonads may be regulated by changes in mRNA m6A enrichment. Functional enrichment analysis indicated that the RNA editing and m6A modifications were enriched in several canonical pathways (e.g., Wnt and MAPK signaling pathways) in fish gonads and in some pathways whose roles have not been investigated in relation to fish sex differentiation and gonadal development (e.g., PPAR and RNA degradation pathways). There were 125 genes that were modified by both A-to-I editing and m6A, but the two types of modifications mostly occurred at different sites. Our results suggested that the presence of sex-specific RNA modifications may be involved in the regulation of gonadal development and gametogenesis.

The black rockfish Sebastes schlegelii is a commercially important fish species for marine fishery stock enhancement in Asia. This work aimed to evaluate the potential genetic impacts of releasing hatchery-reared juvenile black rockfish on wild stock in Lidao Bay, China. A partial sequence of the mitochondrial DNA (mtDNA) control region and 38 microsatellite DNA loci were used to assess the genetic impact. The haplotype diversity parameter (h) and nucleotide diversity parameter (π) in hatchery-released stock were 0.902 and 0.00483, respectively. The h values in wild stock before stock enhancement and the mixed stock after enhancement were 0.970 and 0.939 (p = 0.025), respectively, and the π values were 0.00581 and 0.00526 (p = 0.150), respectively. The mean effective number of alleles (Ae) in hatchery-released stock was 4.76, the mean polymorphism information content (PIC) was 0.674, the observed heterozygosity (Ho) was 0.668, and the expected heterozygosity (He) was 0.697. In wild stock before stock enhancement and the mixed stock after enhancement, the Ae, PIC, Ho, and He values were 6.01 and 5.82, 0.698 and 0.716, 0.709 and 0.741, and 0.735 and 0.754, respectively. These results indicated no marked decrease in the hatchery-released stock, although it displayed slightly lower levels of genetic diversity and heterozygosity than the wild stock. And the mixed stock after release exhibited similar genetic diversity to that of the wild stock before release. Accordingly, we propose that stock enhancement may not cause genetic diversity reduction on wild S. schlegelii stock in Lidao Bay over the short term. Whereas, discriminant analysis of principal components (DAPC) analysis identified three major clusters. The fixation index (FST) and analysis of molecular variance (AMOVA) also clearly showed low level but significant differentiations between the hatchery-released and wild stocks, and the wild stock before enhancement and the mixed stock after enhancement. Consequently, long-term genetic evaluation might be required.

Abstract: Acute myeloid leukemia (AML), the most common acute leukemia in adults and the second most common cancer in children, is still a lethal disease in the majority of patients, but immunologic approaches have improved outcome. Bispecific antibodies (BsAbs) are novel immunotherapeutics that can redirect immune cells against AML. We now report a tetravalent (2+2) humanized BsAb in the immunoglobulin G light chain single chain fragment variable [IgG(L)-scFv] format to engage polyclonal T cells to kill CD33+ AML targets. In vitro, this BsAb demonstrated strong antigen-specific T-cell–dependent cell-mediated cytotoxicity (TDCC) with an 50% effective concentration (EC50) in the femtomolar range that translated into treatment of established human AML IV xenografts in vivo. Importantly, it could redirect intraperitoneally injected T cells to ablate established and rapidly growing extramedullary subcutaneous AML xenografts in vivo. Furthermore, internalization of CD33 upon BsAb binding was identical to that of a bivalent (1+1) heterodimer, both being substantially less than anti-CD33 IgG. In contrast to the heterodimer, the tetravalent IgG-scFv BsAb was >10-fold more efficient in TDCC of AML cells in vitro and in vivo. This BsAb did not react with and did not kill CD38–CD34+ hematopoietic stem cells from cord blood. We conclude that the novel anti-CD33 IgG(L)-scFv BsAb construct reported here is a potential candidate for clinical development.

Abstract Background The preferential use of aerobic glycolysis by tumor cells lead to high accumulation of lactate in tumor microenvironment. Clinical evidence has linked elevated lactate concentration with cancer outcomes. However, the role and molecular mechanisms of lactate in cellular senescence and tumor progression remain elusive. Methods The function of Snail in lactate-induced EMT in lung cancer cells was explored by wound healing assay and cell invasion assay. The qRT-PCR and dual luciferase reporter assay were performed to investigate how lactate regulates Snail expression. The level of TGF-β1 in culture supernatant of cells was measured by ELISA for its correlation with extracellular levels of lactate. Ras activity assay and SA-β-gal activity assay were established to determine the effect of lactate on oncogene-induced senescence in human lung epithelial cells. ChIP assays were conducted to determine the binding of snail to p16INK4a promoter. Two TCGA data sets (TCGA-LUAD and TCGA-LUSC) were used to explore the correlations between SNAI1 and CDKN2A expression. Results In this study, we showed the invasive and migratory potential of lung cancer cells was significantly enhanced by lactate and was directly linked to snail activity. We also demonstrated that extracellular acidification itself is a direct cause of the increased snail expression and physiologically coupled to LDHA-dependent conversion of pyruvate to lactate. Mechanistically, lactate exerts its central function in induction of snail and EMT by directly remodeling ECM and releasing activated TGF-β1. We also demonstrated that Snail help premalignant cells to escape the oncogene-induced senescence by directly targeting and inhibiting p16INK4a expression. Conclusions Our study extends the understanding of EMT in tumorigenesis by uncovering the role of snail in cellular senescence. This study also reveals lactate may be a potent tumor-promoting factor and provides the basis for the development of lactate-targeted therapy.

Plant tannins have the ability to form stable complexes with metal ions, while microporous membranes have low pressure drop and high flux characteristics. Combining these two materials, a new type of tannin-immobilized membrane (M-TAN) adsorption material has been developed. The PA-BWT, PVDF-BWT, CELL -BWT, and PA-AA-BWT were prepared using different types of microporous membranes as substrates, which maintained the porous structure of the membranes and had the characteristics of high flux and fast filtration rate. The surface contact angle and pure water flux analysis showed that the introduction of tannin with multi-phenolic hydroxyl groups increased the hydrophilicity and water flux of the M-TANs. The adsorption performance shows that the adsorption capacity of four kinds of M-TANs for UO22+ is in the order of PA-BWT > PA-AA-BWT > PVDF-BWT > CELL-BWT, and PA-BWT has the largest adsorption capacity of 0.398 mmol g−1. In addition, the adsorption isothermal and kinetic data of PA-BWT were well fitted by the Langmuir equation and the Elovich model, respectively. The negative values of ΔG for UO22+ adsorption on PA-BWT indicated that adsorption is a spontaneous and favorable process. These facts indicate that PA-BWT can be used as a low-cost adsorbent for effective removal of UO22+ from aqueous solutions.

Artificial tetraploid induction is one of the important techniques of fish chromosome manipulation, and it is the first step for triploid breeding. There are a few reports to artificial induction of tetraploid in marine fish. The induction and survival rates were usually low. We firstly optimized the tetraploid induction conditions in turbot Scophthalmus maximus, one of the most important maricultural fish in China and Europe. For the initiate time of treatment, which is the most important factor in tetraploid induction, the first cleavage index (FCI) was used to reduce the influences of genetic origin and environment factors. Overall, the optimal initiation time for pressure shock was 15 min before the first cleavage at 14.8–15.5°C. The optimal treatment pressure and treatment duration were 67.5 MPa and 6 min. The regression equation prediction model was: The optimal initiation time = 0.982 FCI − 12.182 or the optimal initiation time = 0.85 FCI. Then two tetraploid induction (4n1 and 4n2) populations were obtained under the optimal conditions with diploid controls (2n1 and 2n2). The induction rates in tetraploid induction (4n) populations at hatched larvae stage could reach 100%. The genetic structure of these two 4n populations was also studied. Two to four alleles in each locus were detected in diploid (2n) and 4n populations, respectively. Private alleles were only appeared at locus Sma-USC21, with two alleles lost in 4n populations. Eleven and fourteen loci in 2n and 4n populations respectively showed a negative genetic deviation index. 3D-FCA analysis showed that the two 2n and two 4n populations have obvious differences. The numbers of locus deviating from Hardy–Weinberg equilibrium in 2n1, 4n1, 2n2, and 4n2 populations were 6, 9, 12, and 7, respectively. Overall, 12 loci in either 2n or 4n population deviated from Hardy–Weinberg equilibrium. Tetraploid induction population showed lower heterozygosity and higher heterozygote deletion.

Dinoflagellates have some of the largest genomes, and their liquid-crystalline chromosomes (LCCs) have high degrees of non-nucleosomal superhelicity with cation-mediated DNA condensation. It is currently unknown if condensins, pentameric protein complexes containing structural maintenance of chromosomes 2/4, commonly involved in eukaryotic chromosomes condensation in preparation for M phase, may be involved in the LCC structure. We find that CcSMC4p (dinoflagellate SMC4 homolog) level peaked at S/G2 phase, even though LCCs do not undergo global-decondensation for replication. Despite the differences in the chromosomal packaging system, heterologous CcSMC4p expression suppressed conditional lethality of the corresponding fission yeast mutant, suggesting conservation of some canonical condensin functions. CcSMC4p-knockdown led to sustained expression of the S-phase marker PCNAp, S-phase impediment, and distorted nuclei in the early stage of CcSMC4p depletion. Prolonged CcSMC4p-knockdown resulted in aneuploidal cells and nuclear swelling with increasing LCC decompaction–decondensation. Cumulatively, our data suggested CcSMC4p function was required for dinoflagellate S-phase progression, and we propose that condensin-mediated higher-order compaction provisioning is involved in the provision of local rigidity for the replisome.

Rongcheng Bay is a coastal bay of the Northern Yellow Sea, China. To investigate and monitor the fish resources in Rongcheng Bay, 187 specimens from 41 different species belonging to 28 families in nine orders were DNA-barcoded using the mitochondrial cytochrome c oxidase subunit I gene (COI). Most of the fish species could be discriminated using this COI sequence with the exception of Cynoglossus joyneri and Cynoglossus lighti. The average GC% content of the 41 fish species was 47.3%. The average Kimura 2-parameter genetic distances within the species, genera, families, and orders were 0.21%, 5.28%, 21.30%, and 23.63%, respectively. Our results confirmed that the use of combined morphological and DNA barcoding identification methods facilitated fish species identification in Rongcheng Bay, and also established a reliable DNA barcode reference library for these fish. DNA barcodes will contribute to future efforts to achieve better monitoring, conservation, and management of fisheries in this area.

Background and objective The CpG island aberrant promoter methylation in the tumor suppressor gene region plays an important role in the process of tumorigenesis. Relevant evidence shows that the promoter methylation of RAS association domain family 1A (RASSF1A) gene, a tumor suppressor gene, has a close relationship with non-small cell lung cancer (NSCLC) development; therefore, RASSF1A may be a potential NSCLC biomarker. This paper discussed and summarized the relationship between RASSF1A gene promoter methylation frequency and NSCLC through meta-analysis. Methods By searching Medline, EMBASE, CNKI, and Wanfang database, we selected and collected the published articles regarding RASSF1A gene promoter methylation and NSCLC risk according to the marked inclusion and exclusion criteria. Through meta-analysis, combined odds ratio (OR) and 95% confidence interval (CI) data were used to analyze the RASSF1A gene promoter methylation and NSCLC relationship. Results A total of 23 articles were utilized in this study. Results indicated that the RASSF1A gene promoter methylation rate was 41.50% (95%CI: 34%-49%) in NSCLC tissue and was 5.58% (95%CI: 2%-9%) for the control group. Compared with normal lung tissue, RASSF1A methylation frequency in tumor tissue was significantly higher than that of the control group (OR=8.72, 95%CI: 4.88-15.58, P

Cancer cells exhibit altered glucose metabolism characterized by a preference for aerobic glycolysis even when the oxygen content is normal, a phenomenon termed “Warburg effect”. However the definite molecular mechanisms of Warburg effect remains unclear, recent works indicated that it might be related to the abnormal activity of the oncogene and tumor suppressor genes, also the change of tumor microenvironment, the abnormal expression of glucose metabolic enzyme and so on. Warburg effect has a relationship with tumor progression and provide suitable conditions for tumor metastasis. This review will summarizes the mechanism of Warburg effect and its effect on tumor metastasis.

T-cell-based therapies have emerged as one of the most clinically effective ways to target solid and non-solid tumors. HER2 is responsible for the oncogenesis and treatment resistance of several human solid tumors. As a member of the HER family of tyrosine kinase receptors, its over-activity confers unfavorable clinical outcome. Targeted therapies directed at this receptor have achieved responses, although development of resistance is common. We explored a novel HER2/CD3 bispecific antibody (HER2-BsAb) platform that while preserving the anti-proliferative effects of trastuzumab, it recruits and activates non-specific circulating T-cells, promoting T cell tumor infiltration and ablating HER2(+) tumors, even when these are resistant to standard HER2-targeted therapies. Its in vitro tumor cytotoxicity, when expressed as EC50, correlated with the surface HER2 expression in a large panel of human tumor cell lines, irrespective of lineage or tumor type. HER2-BsAb-mediated cytotoxicity was relatively insensitive to PD-1/PD-L1 immune checkpoint inhibition. In four separate humanized mouse models of human breast cancer and ovarian cancer cell line xenografts, as well as human breast cancer and gastric cancer patient-derived xenografts (PDXs), HER2-BsAb was highly effective in promoting T cell infiltration and suppressing tumor growth when used in the presence of human peripheral blood mononuclear cells (PBMC) or activated T cells (ATC). The in vivo and in vitro antitumor properties of this BsAb support its further clinical development as a cancer immunotherapeutic.

Tau hyperphosphorylation is thought to underlie tauopathy. Working in a Drosophila tauopathy model expressing a human Tau mutant (hTauR406W, or Tau∗), we show that zinc contributes to the development of Tau toxicity through two independent actions: by increasing Tau phosphorylation and, more significantly, by directly binding to Tau. Elimination of zinc binding through amino acid substitution of Cys residues has a minimal effect on phosphorylation levels yet essentially eliminates Tau toxicity. The toxicity of the zinc-binding-deficient mutant Tau∗ (Tau∗C2A) and overexpression of native Drosophila Tau, also lacking the corresponding zinc-binding Cys residues, are largely impervious to zinc concentration. Importantly, restoration of zinc-binding ability to Tau∗ by introduction of a zinc-binding residue (His) into the original Cys positions restores zinc-responsive toxicities in proportion to zinc-binding affinities. These results indicate zinc binding is a substantial contributor to tauopathy and have implications for therapy development.