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Abstract Recent development of new immune checkpoint inhibitors has been particularly successfully in cancer treatment, but still the majority patients fail to benefit. Converting resistant tumors to immunotherapy sensitive will provide a significant improvement in patient outcome. Here we identify Mi-2β as a key melanoma-intrinsic effector regulating the adaptive anti-tumor immune response. Studies in genetically engineered mouse melanoma models indicate that loss of Mi-2β rescues the immune response to immunotherapy in vivo. Mechanistically, ATAC-seq analysis shows that Mi-2β controls the accessibility of IFN-γ-stimulated genes (ISGs). Mi-2β binds to EZH2 and promotes K510 methylation of EZH2, subsequently activating the trimethylation of H3K27 to inhibit the transcription of ISGs. Finally, we develop an Mi-2β-targeted inhibitor, Z36-MP5, which reduces Mi-2β ATPase activity and reactivates ISG transcription. Consequently, Z36-MP5 induces a response to immune checkpoint inhibitors in otherwise resistant melanoma models. Our work provides a potential therapeutic strategy to convert immunotherapy resistant melanomas to sensitive ones.

AIM: To observe the effect of low oxygen concentration on the neural retina in human induced pluripotent stem cell (hiPSC)-derived retinal organoids (ROs). METHODS: The hiPSC and a three-dimensional culture method were used for the experiments. Generated embryoid bodies (EBs) were randomly and equally divided into hypoxic and normoxic groups. Photographs of the EBs were taken on days 38, 45, and 52, and the corresponding volume of EBs was calculated. Simultaneously, samples were collected at these three timepoints, followed by fixation, sectioning, and immunofluorescence. RESULTS: The proportion of Ki67-positive proliferating cells increased steadily on day 38; this proliferation-promoting effect tended to increase tissue density rather than tissue volume. On days 45 and 52, the two groups had relatively similar ratios of Ki67-positive cells. Further immunofluorescence analysis showed that the ratio of SOX2-positive cells significantly increased within the neural retina on day 52 (P0.05). Moreover, the proportion of PAX6-/TUJ1+ cells within the neural retinas increased considerably (P

The research investigated the potential of heterologous expression of the heat-shock protein PpHSP70 in enhancing high temperature and drought tolerance in rice. After screening the whole genome sequence of Physcomitrium patens in the Phytzome database, 30 members of the HSP70 gene family were obtained. Their expression and the tissue expression patterns under abiotic stressors of high temperature, drought, and salt were analyzed. During the four-leaf stage of rice, overexpressed materials were subjected to a temperature of 45 °C for 20 h and to drought conditions for one week. After processing, 5 overexpression PpHSP70 materials survived against high temperature, and 7 materials survived against drought, while all wild-type materials KY131 died after the treatment. The results demonstrated that overexpression of PpHSP70 significantly improved both high-temperature tolerance and drought. This study provides valuable insights into the utilization of heterologous expression for enhancing crop tolerance to abiotic stressors.

AIM: To compare the postoperative efficacy, safety, predictability, and visual quality of implantable collamer lens (ICL) implantation versus small incision lenticule extraction (SMILE) in myopia eyes. METHODS: PubMed, EMBASE, Web of Science, Cochrane Library and several Chinese databases were searched at May 2021 to select relevant studies in comparison of clinical outcomes between ICL implantation and SMILE for myopia. The primary outcomes were efficacy, safety, and predictability. And the secondary outcomes were postoperative higher-order ocular aberrations (HOAs), modulation transfer function cutoff frequency (MTF), objective scatter index (OSI), contrast sensitivity and a quality of vision (QoV) questionnaire. RESULTS: A total of 1036 eyes from 10 studies, of which 503 eyes underwent ICL implantation and 533 eyes underwent SMILE, were enrolled in this Meta-analysis. Pooled results revealed that ICL group had a better safety index and post-corrected distance visual acuity (CDVA) (P=0.007, 6mo), ICL group had a lower total HOA, coma, and spherical aberration than SMILE group (P=0.003,

Background and AimThe prognosis and medication response for liver malignancies are both dismal and highly heterogeneous. For this diverse malignancy, multimodality therapies such as drugs, surgical management, and/or l+iver transplantation are available. Biliary complications remain a major problem after liver cancer treatment especially in those patients who undergo liver transplantation for their end stage liver disease. Although, most biliary complications can be successfully managed with endoscopic retrograde cholangiopancreatography. However, biliary complications still considered an important factor influencing long-term results in liver cancer treatment patients. The aim of this study was to evaluate the effect of biliary complications on the overall patient’s survival rate after the endoscopic retrograde cholangiopancreatography.Patients and MethodsWe retrospectively analyzed data of consecutive patients who were treated for liver cancer at our tertiary care hospital from January 2015 to July 2020. We focused on the biliary complications and procedural data, including post-endoscopic retrograde cholangiopancreatography complications, survival rate, and complementary or alternative treatments to endoscopic retrograde cholangiopancreatography.ResultsWe identified 967 cases (mean age 49; range 11-75), 84% men. During the mean follow up of 25 months (range 1 to 66 months), 102 patients developed biliary complications; 68/102 underwent 141 therapeutics endoscopic retrograde cholangiopancreatography procedures. The rest 34/102 patients were managed with percutaneous transhepatic cholangiography, conservative management, and/or surgery. Post- endoscopic retrograde cholangiopancreatography complications occurred in 79.4%, including anastomotic strictures in 25, non-anastomotic strictures in 5, stones in 5, cholangitis in 4, post-sphinctretomy bleeding in 3, pancreatitis in 2, and bile leakage in 1 patient. Seven (13.0%) patients died after ERCP due to multiple organ dysfunction syndrome. Although the survival rate of patients who underwent ERCP and those without ERCP was similar, patients with biliary complications fared significant worse.ConclusionAlthough endoscopic retrograde cholangiopancreatography is useful for the management of post liver cancer treatment biliary complications; the need for multiple rounds of endoscopic retrograde cholangiopancreatography and even post endoscopic retrograde cholangiopancreatography complications is relatively high, and often results in increased mortality. However, the survival following endoscopic or surgical therapy in liver cancer treatment patients is similar.

Gastric cancer is one of the most common cancer types with less than one year prognosis in metastatic disease, which poses a huge disease burden. One of the key players in poor prognosis is human epidermal growth factor receptor 2 (HER2), which also contributes to the pathogenesis of HER2-positive advanced gastric cancer. Trastuzumab is used as first-line chemotherapy that targets the expression of HER2, however, trastuzumab resistance is an inevitable major problem. To overcome this problem, readjustment of the circadian system may play a crucial role, as dysregulation in the expression of circadian clock genes has been observed in tumors. Therefore, pharmacological modulation of clock components can be considered for better efficacy of trastuzumab. In this review, we discuss the association of circadian clock with cancer progression, development, and treatment. Metformin-based chronotherapy can disrupt BMAL1–CLOCK–PER1–HK2 axis, thereby affecting glycolysis oscillation to overcome trastuzumab resistance in HER2-positive advanced gastric cancer.

PurposeThis study aimed to conduct a systematic review of the literature to identify and summarize the existing evidence regarding ERAS failure and related risk factors after hepatic surgery. The objective was to provide physicians with a better understanding of these factors so that they can take appropriate action to minimize ERAS failure and improve patient outcomes.MethodA literature search of the PubMed MEDLINE, OVID, EMBASE, Cochrane Library, and Web of Science was performed. The search strategy involved terms related to ERAS, failure, and hepatectomy.ResultA meta-analysis was conducted on four studies encompassing a total of 1,535 patients, resulting in the identification of 20 risk factors associated with ERAS failure after hepatic surgery. Four of these risk factors were selected for pooling, including major resection, ASA classification of ≥3, advanced age, and male gender. Major resection and ASA ≥ 3 were identified as statistically significant factors of ERAS failure.ConclusionThe comprehensive literature review results indicated that the frequently identified risk factors for ERAS failure after hepatic surgery are linked to operative and anesthesia factors, including substantial resection and an American Society of Anesthesiologists score of 3 or higher. These insights will assist healthcare practitioners in taking prompt remedial measures. Nevertheless, there is a requirement for future high-quality randomized controlled trials with standardized evaluation frameworks for ERAS programs.

AIM: To compare and modify the accuracy of the Haigis formula calculates for intraocular lens(IOL)refraction after myopic excimer laser surgery.METHODS: The clinical records of 31 patients(31 eyes)who firstly accepted myopic corneal refractive surgery(LASIK/PRK)and then underwent phacomulsification was combined with IOL implantation in Tianjin Eye Hospital between February 2014 and March 2019 were finally enrolled in this study. Postoperative refraction was performed at least 6mo after cataract surgery. To compare the accuracy of equivalent keratometry readings(EKR)of different corneal radius(2.0, 3.0, 4.0, 4.5, 5.0mm)combined with the Haigis formula to calculate the IOL diopter after myopia, obtain the modified Haigis formula, and then compare the modified Haigis formula with the accuracy of Barrett true K, Haigis-L and Shammas-PL formulas for calculating IOL diopter after myopia.RESULTS: The median absolute error(MedAE)and mean absolute error(MAE)of 4.0mm EKR Haigis formula was significantly lower than that of 4.5mm and 5.0mm EKR(all P0.05).CONCLUSION: Haigis formula combined with the 4.0mm EKR can be used to calculate the IOL power in eyes after myopic LASIK/PRK, and its accuracy is comparable to the Barrett true K formula. However, the longer the AL is, the higher the possibility of hyperopic drift postoperatively might occur with the modified Haigis.

Despite increasing knowledge of the fitness costs of viability and fecundity involved in the herbicide-resistant weeds, relatively little is known about the linkage between herbicide resistance costs and phytochemical cues in weed species and biotypes. This study demonstrated relative fitness and phytochemical responses in six herbicide-resistant weeds and their susceptible counterparts. There were significant differences in the parameters of viability (growth and photosynthesis), fecundity fitness (flowering and seed biomass) and a ubiquitous phytochemical (–)-loliolide levels between herbicide-resistant weeds and their susceptible counterparts. Fitness costs occurred in herbicide-resistant Digitaria sanguinalis and Leptochloa chinensis but they were not observed in herbicide-resistant Alopecurus japonicas, Eleusine indica, Ammannia arenaria, and Echinochloa crus-galli. Correlation analysis indicated that the morphological characteristics of resistant and susceptible weeds were negatively correlated with (–)-loliolide concentration, but positively correlated with lipid peroxidation malondialdehyde and total phenol contents. Principal component analysis showed that the lower the (–)-loliolide concentration, the stronger the adaptability in E. crus-galli and E. indica. Therefore, not all herbicide-resistant weeds have fitness costs, but the findings showed several examples of resistance leading to improved fitness even in the absence of herbicides. In particular, (–)-loliolide may act as a phytochemical cue to explain the fitness cost of herbicide-resistant weeds by regulating vitality and fecundity.

Primary effusion lymphoma (PEL) caused by Kaposi sarcoma-associated herpesvirus (KSHV) is an aggressive malignancy with poor prognosis even under chemotherapy. Currently, there is no specific treatment for PEL therefore requiring new therapies. Both histone deacetylases (HDACs) and bromodomain-containing protein 4 (BRD4) have been found as therapeutic targets for PEL through inducing viral lytic reactivation. However, the strategy of dual targeting with one agent and potential synergistic effects have never been explored. In the current study, we first demonstrated the synergistic effect of concurrently targeting HDACs and BRD4 on KSHV reactivation by using SAHA or entinostat (HDACs inhibitors) and (+)-JQ1 (BRD4 inhibitor), which indicated dual blockage of HDACs/BRD4 is a viable therapeutic approach. We were then able to rationally design and synthesize a series of new small-molecule inhibitors targeting HDACs and BRD4 with a balanced activity profile by generating a hybrid of the key binding motifs between (+)-JQ1 and entinostat or SAHA. Upon two iterative screenings of optimized compounds, a pair of epimers, 009P1 and 009P2, were identified to better inhibit the growth of KSHV positive lymphomas compared to (+)-JQ1 or SAHA alone at low nanomolar concentrations, but not KSHV negative control cells or normal cells. Mechanistic studies of 009P1 and 009P2 demonstrated significantly enhanced viral reactivation, cell cycle arrest and apoptosis in KSHV+ lymphomas through dually targeting HDACs and BRD4 signaling activities. Importantly, in vivo preclinical studies showed that 009P1 and 009P2 dramatically suppressed KSHV+ lymphoma progression with oral bioavailability and minimal visible toxicity. These data together provide a novel strategy for the development of agents for inducing lytic activation-based therapies against these viruses-associated malignancies.

Horizontal gene transfer (HGT) has been proved a major driving force in prokaryotic evolution. However, the molecular functions of these transferred genes in pathogenic bacteria especially plant pathogenic bacteria are still not fully investigated. In this study, the whole-genome in silico analysis was performed and found a syringopeptin synthetase (syp) homolog in Burkholderia glumae, which can cause bacterial panicle blight in rice, was predicted to be horizontally transferred from Pseudomonas ancestor with solid confidence by phylogenetic analysis. The comprehensive molecular experiments were performed to study the potential role of this gene in B. glumae. Inoculation of rice panicles with the syp mutant resulted in 60% lower disease index compared with the wild type (WT) parent strain, suggesting the requirement of syp for the full virulence of B. glumae. Chromatography analysis of exudates from B. glumae showed suppression of synthesis of metabolites analogous to syringopeptin in the mutants. All these data raise the possibility of HGT phenomenon in shaping the virulence and adaptation of B. glumae over evolutionary time.

Lipotoxicity has been implicated in the pathogenesis of obesity-related kidney damage and propagates chronic kidney injury like diabetic kidney disease; however, the underlying mechanisms have not yet been fully elucidated. To date, reduction of lipid acquisition and enhancement of lipid metabolism are the major, albeit non-specific, approaches to improve lipotoxic kidney damage. In the kidneys of high-fat diet (HFD)-fed mice and tubule cells cultured with palmitic acid (PA), we observed a dramatic upregulation of the long intergenic non-coding RNA-p21 (LincRNA-p21) through a p53-dependent mechanism. Kidney tubule cell-specific deletion of LincRNA-p21 attenuated oxidative stress, inflammation, apoptosis, and endoplasmic reticulum stress, leading to reduction of histological and functional kidney injury despite persistent obesity and hyperlipidemia. Mechanistically, HFD- or PA-initiated lipotoxicity suppressed the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR)/murine double minute 2 homolog (MDM2) signaling cascade to activate p53 and enhance the transcriptional activity of LincRNA-p21. Collectively, our findings suggest that the p53/LincRNA-p21 axis is the downstream effector in lipotoxic kidney injury and that targeting this axis particularly in the kidney tubule could be a novel therapeutic strategy.

Abstract We have recently described Pz-1, a benzimidazole-based type-2 RET and VEGFR2 inhibitor. Based on a kinome scan, here we show that Pz-1 is also a potent (IC50

Summary: Metabolites are not only substrates in metabolic reactions, but they also serve as signaling molecules to regulate diverse biological functions. Identification of the binding proteins for the metabolites helps in the understanding of their functions beyond the classic metabolic pathways in which they are involved. We provide the protocol for synthesizing the biotin-labeled myo-inositol, which is used to identify its binding proteins by using biotin pull-down assay, given there is no available tool for the rapid screening of inositol-binding proteins in cells and in vitro systems. Biotin-labeled inositol probe therefore provides a tool to identify inositol’s sensors.For complete details on the use and execution of this protocol, please refer to Hsu et al. (2021). : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Despite increasing evidence of kin recognition in natural and crop plants, there is a lack of knowledge of kin recognition in herbicide-resistant weeds that are escalating in cropping systems. Here, we identified a penoxsulam-resistant barnyardgrass biotype with the ability for kin recognition from two biotypes of penoxsulam-susceptible barnyardgrass and normal barnyardgrass at different levels of relatedness. When grown with closely related penoxsulam-susceptible barnyardgrass, penoxsulam-resistant barnyardgrass reduced root growth and distribution, lowering belowground competition, and advanced flowering and increased seed production, enhancing reproductive effectiveness. However, such kin recognition responses were not occurred in the presence of distantly related normal barnyardgrass. Root segregation, soil activated carbon amendment, and root exudates incubation indicated chemically-mediated kin recognition among barnyardgrass biotypes. Interestingly, penoxsulam-resistant barnyardgrass significantly reduced a putative signaling (–)-loliolide production in the presence of closely related biotype but increased production when growing with distantly related biotype and more distantly related interspecific allelopathic rice cultivar. Importantly, genetically identical penoxsulam-resistant and -susceptible barnyardgrass biotypes synergistically interact to influence the action of allelopathic rice cultivar. Therefore, kin recognition in plants could also occur at the herbicide-resistant barnyardgrass biotype level, and intraspecific kin recognition may facilitate cooperation between genetically related biotypes to compete with interspecific rice, offering many potential implications and applications in paddy systems.

Soil salinity and alkalinity can inhibit crop growth and reduce yield, and this has become a global environmental concern. Combined changes in nitrogen (N) application and hill density can improve rice yields in sodic saline–alkaline paddy fields and protect the environment. We investigated the interactive effects of N application rate and hill density on rice yield and N accumulation, translocation and utilization in two field experiments during 2018 and 2019 in sodic saline–alkaline paddy fields. Five N application rates (0 (control), 90, 120, 150, and 180 kg N ha–1 (N0–N4), respectively) and three hill densities (achieved by altering the distance between hills, in rows spaced 30 cm apart: 16.5 cm (D1), 13.3 cm (D2) and 10 cm (D3)) were utilized in a split-plot design with three replicates. Nitrogen application rate and hill density significantly affected grain yield. The mathematical model of quadratic saturated D-optimal design showed that with an N application rate in the range of 0–180 kg N ha–1, the highest yield was obtained at 142.61 kg N ha–1 which matched with a planting density of 33.3×104 ha–1. Higher grain yield was mainly attributed to the increase in panicles m–2. Nitrogen application rate and hill density significantly affected N accumulation in the aboveground parts of rice plants and showed a highly significant positive correlation with grain yield at maturity. From full heading to maturity, the average N loss rate of the aboveground parts of rice plants in N4 was 70.21% higher than that of N3. This is one of the reasons why the yield of N4 treatment is lower than that of the N3 treatment. Nitrogen accumulation rates in the aboveground parts under treatment N3 (150 kg N ha–1) were 81.68 and 106.07% higher in 2018 and 2019, respectively, than those in the control. The N translocation and N translocation contribution rates increased with the increase in the N application rate and hill density, whereas N productivity of dry matter and grain first increased and then decreased with the increase in N application rate and hill density. Agronomic N-use efficiency decreased with an increase in N application rate, whereas hill density did not significantly affect it. Nitrogen productivity of dry matter and grain, and agronomic N-use efficiency, were negatively correlated with grain yield. Thus, rice yield in sodic saline–alkaline paddy fields can be improved by combined changes in the N application rate and hill density to promote aboveground N accumulation. Our study provides novel evidence regarding optimal N application rates and hill densities for sodic saline–alkaline rice paddies.

In this work, silicon photonics structures for the optical addressing of trapped ion is developed for quantum computing applications. Grating-waveguide-grating structures of various designs are designed, and fabricated for various radius curvatures of 12, 15, 25 and 30 µm, respectively. From the optical measurements, gratings with radius of curvature of 25 and 30 µm exhibit lower power loss of 36.5 and 33.9 dB with better-focused beam profiles as compared to those with radius of curvature of 12 and 15 µm. The beam width from these gratings ranges between 17.31 to 41.54 µm, which provides the feasibility to perform optical addressing on 2 to 4 Sr+ ions trapped along the ground electrode of the ion trap.

As a key approach to augment Moore's Law scaling, 3D integration technologies have enabled small form factor, low cost, diverse, modular and flexible assembly of integrated circuits in the semiconductor industry. It is therefore essential to adopt these technologies to the quantum computing devices which are at the nascent stage and generally require large scale integration to be practical. In this review, we focus on four popular quantum bit (qubit) candidates (trapped ion, superconducting circuit, silicon spin and photon) which are encoded by distinct physical systems but all intrinsically compatible with advanced CMOS fabrication process. We introduce the specific scalability bottlenecks of each qubit type and present the current solutions using 3D integration technologies. We evaluate and classify these technologies into three main categories based on the hierarchy. A brief discussion regarding the thermal management is also provided. We believe this review serves to provide some useful insights on the contributions of interconnect, integration and packaging to the field of quantum computing where rapid development is ongoing.

Bloodstream infections (BSIs) caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) are potentially life-threatening and an urgent threat to public health. The present study aims to clarify the characteristics of carbapenemase-encoding and virulent plasmids, and their interactions with the host bacterium. A total of 425 Kp isolates were collected from the blood of BSI patients from nine Chinese hospitals, between 2005 and 2019. Integrated epidemiological and genomic data showed that ST11 and ST307 Kp isolates were associated with nosocomial outbreak and transmission. Comparative analysis of 147 Kp genomes and 39 completely assembled chromosomes revealed extensive interruption of acrR by ISKpn26 in all Kp carbapenemase-2 (KPC-2)-producing ST11 Kp isolates, leading to activation of the AcrAB-Tolc multidrug efflux pump and a subsequent reduction in susceptibility to the last-resort antibiotic tigecycline and six other antibiotics. We described 29 KPC-2 plasmids showing diverse structures, two virulence plasmids in two KPC-2-producing Kp, and two novel multidrug-resistant (MDR)-virulent plasmids. This study revealed a multifactorial impact of KPC-2 plasmid on Kp, which may be associated with nosocomial dissemination of MDR isolates.

Abstract The emergence and transmission of the mobile colistin resistance gene (mcr-1) threatened the extensive use of polymyxin antimicrobials. Accumulated evidence showed that the banning of colistin additive in livestock feed efficiently reduce mcr-1 prevalence, not only in animals but also in humans and environments. However, our previous study has revealed that a small proportion of Escherichia coli could continually carry chromosomally-encoded mcr-1. The chromosomally-encoded events, indicated the existence of stabilized heritage of mcr-1 and revealed a potential threat in the antimicrobial stewardship interventions, are yet to be investigated. In this study, we systematically investigated the genetic basis of chromosomally-encoded mcr-1 in prevalence and potential mechanisms of lineage, plasmid, insertion sequence, and phage. Our results demonstrated that the emergence of chromosomally-encoded mcr-1 could originate from multiple mechanisms, but mainly derived through the recombination of ISApl1/Tn6330. We reported a specific transmission mechanism, which is a phage-like region without lysogenic components, could associate with the emergence and stabilization of chromosomally-encoded mcr-1. These results highlighted the potential origin and risks of chromosomally-encoded mcr-1, which could be a heritable repository and thrive again when confronted with new selective pressures. To the best of our knowledge, this is the first study to systematically reveal the genomic basis of chromosomally-encoded mcr-1, and report a specific transmission pattern involved in phage-like region. Overall, we demonstrate the origin mechanisms and risks of chromosomally-encoded mcr-1. It highlights the need of public attention on chromosome-encoded mcr-1 to prevent from its reemergence.

A facile microwave-assisted method for the synthesis of tetramic acid derivatives has been developed through an Ugi/Dieckmann cyclization strategy with DBU. This two-step one-pot procedure afforded the targeted tetramic acid analogues in good yields. With commercially available Ugi starting materials, microwave irradiation, a simple operation, excellent yields, and a broad scope, this reaction has the potential to produce a large number of tetramic acid analogues, which cannot be easily accessed by the classic synthetic methods.

Calculating the intraocular lens(IOL)power in eyes with prior corneal refractive surgery(LASIK/PRK)is still a challenging task for all cataract ophthalmologists. The accuracy of the IOL power calculating is lower than virgin eyes, because the three generation formulae and traditional corneal instruments which measure central corneal radius of curvature in the paracentral 2.5-3.2mm zone are incorrect after myopic refractive surgery. There are three main sources of error in IOL calculation after refractive surgery: the radius measurement error, the keratometer index error and the IOL formula error. The purpose of the present paper is to describe the different available techniques to improve the accuracy of the IOL power calculation after refractive procedures.

Abstract DNA‐binding proteins, including transcription factors (TFs), play essential roles in various cellular processes and pathogenesis of diseases, deeming to be potential therapeutic targets. However, these proteins are generally considered undruggable as they lack an enzymatic catalytic site or a ligand‐binding pocket. Proteolysis‐targeting chimera (PROTAC) technology has been developed by engineering a bifunctional molecule chimera to bring a protein of interest (POI) to the proximity of an E3 ubiquitin ligase, thus inducing the ubiquitination of POI and further degradation through the proteasome pathway. Here, the development of oligonucleotide‐based PROTAC (O'PROTACs), a class of noncanonical PROTACs in which a TF‐recognizing double‐stranded oligonucleotide is incorporated as a binding moiety of POI is reported. It is demonstrated that O'PROTACs of lymphoid enhancer‐binding factor 1 (LEF1) and ETS‐related gene (ERG), two highly cancer‐related transcription factors, successfully promote degradation of these proteins, impede their transcriptional activity, and inhibit cancer cell growth in vitro and in vivo. The programmable nature of O'PROTACs indicates that this approach is also applicable to destruct other TFs. O'PROTACs not only can serve as a research tool but also can be harnessed as a therapeutic arsenal to target DNA binding proteins for effective treatment of diseases such as cancer.

Cell cycle progression and lipid metabolism are well-coordinated processes required for proper cell proliferation. In liver diseases that arise from dysregulated lipid metabolism, hepatocyte proliferation is diminished. To study the outcome of CDK1 loss and blocked hepatocyte proliferation on lipid metabolism and the consequent impact on whole-body physiology, we performed lipidomics, metabolomics, and RNA-seq analyses on a mouse model. We observed reduced triacylglycerides in liver of young mice, caused by oxidative stress that activated FOXO1 to promote the expression of Pnpla2/ATGL. Additionally, we discovered that hepatocytes displayed malfunctioning β-oxidation, reflected by increased acylcarnitines (ACs) and reduced β-hydroxybutyrate. This led to elevated plasma free fatty acids (FFAs), which were transported to the adipose tissue for storage and triggered greater insulin secretion. Upon aging, chronic hyperinsulinemia resulted in insulin resistance and hepatic steatosis through activation of LXR. Here, we demonstrate that loss of hepatocyte proliferation is not only an outcome but also possibly a causative factor for liver pathology.

Oligonucleotides have shifted drug discovery into a new paradigm due to their ability to silence the genes and inhibit protein translation. Importantly, they can drug the un-druggable targets from the conventional small-molecule perspective. Unfortunately, poor cellular permeability and susceptibility to nuclease degradation remain as major hurdles for the development of oligonucleotide therapeutic agents. Studies of safe and effective delivery technique with lipid bioconjugates gains attention to resolve these issues. Our review article summarizes the physicochemical effect of well-studied hydrophobic moieties to enhance the cellular entry of oligonucleotides. The structural impacts of fatty acids, cholesterol, tocopherol, and squalene on cellular internalization and membrane penetration in vitro and in vivo were discussed first. The crucial assays for delivery evaluation within this section were analyzed sequentially. Next, we provided a few successful examples of lipid-conjugated oligonucleotides advanced into clinical studies for treating patients with different medical backgrounds. Finally, we pinpointed current limitations and outlooks in this research field along with opportunities to explore new modifications and efficacy studies.

In contrast to the traditional view that economic policy affects investor sentiment and eventually causes stock price fluctuations, we reveal that investor sentiment is a reflection of both economic policy and stock market information. This article first proposes an improved ETE method with a sliding window. We verify that this new method can capture the dynamic orders effectively by validating this method with the linear TE method. Furthermore, using the improved method, we investigate the strength and direction of information flow among economic policy uncertainty (EPU), investor sentiment and stock market by the novel concept of dynamic effective transfer entropy. The EPU and investor sentiment results show that EPU influenced investor sentiment mainly from August 2015 to June 2016. Among different policies, China's exchange rate reform policy and “circuit-breaker” policy in the stock market played an important role. Moreover, the analysis of sentiment and stock price returns shows that investor sentiment is more a reflection of changes in stock price returns with a 1-month lag order and that the stock market has a significant bargainer effect and a weaker bandwagon effect. Finally, there is no significant information flow transmission relationship between EPU and stock market volatility, indicating that stock market fluctuations are essentially not affected by national policy fluctuations. Although investor sentiment is affected by changes, such as exchange rate reform and stock market policies, many investors do not form consensus expectations.

Summary: Background: The global dissemination of colistin resistance encoded by mcr-1 has been attributed to extensive use of colistin in livestock, threatening colistin efficacy in medicine. The emergence of mcr-1 in common pathogens, such as Escherichia coli, is of particular concern. China banned the use of colistin in animal feed from May 1, 2017. We investigated subsequent changes in mcr-1 prevalence in animals, humans, food, and the environment, and the genomic epidemiology of mcr-1-positive E coli (MCRPEC). Methods: Sampling was done before (October to December, 2016) and after (October to December, 2017, and 2018, respectively) the colistin ban. 3675 non-duplicate pig faecal samples were collected from 14 provinces (66 farms) in China to measure intervention-related changes in mcr-1 prevalence. 15 193 samples were collected from pigs, healthy human volunteers, patients colonised or infected with Enterobacteriaceae who were admitted to hospital, food and the environment in Guangzhou, to characterise source-specific mcr-1 prevalence and the wider ecological effect of the ban. From these samples, 688 MCRPEC were analysed with whole genome sequencing, plasmid conjugation, and S1 pulsed-field gel electrophoresis with Southern blots to characterise associated genomic changes. Findings: After the ban, mcr-1 prevalence decreased significantly in national pig farms, from 308 (45%) of 684 samples in 2016 to 274 (19%) of 1416 samples in 2018 (p

Transcranial direct current stimulation (tDCS), which is a safe and noninvasive method for inducing or enhancing neural plasticity, can promote the recovery of post-stroke aphasia (PSA). This paper explores the possible mechanisms of verbal recovery in patients with PSA, and analyzes the role of bilateral hemispheres and cerebellum in speech recovery to review the research progress of application of tDCS in PSA. DOI: 10.3969/j.issn.1672-6731.2018.06.014

HM-3, an integrin antagonist, exhibits anti-tumor biological responses and therefore has potential as a therapeutic polypeptide. However, the clinical applications of HM-3 are limited by its short half-life. In this study, we genetically fused human serum albumin (HSA) to the N or C-terminus of HM-3 to improve HM-3 pharmacokinetics. HM-3/HSA proteins were successfully expressed in Pichia pastoris and displayed improved pharmacokinetic properties and stability. Among them, the half-life of HM-3-HSA was longer than HSA-HM-3. In vitro, the IC50 values of HSA-HM-3 and HM-3-HSA were 0.38 ± 0.14 μM and 0.25 ± 0.08 μM in B16F10 cells, respectively. In vivo, the inhibition rates of B16F10 tumor growth were 36% (HSA-HM-3) and 56% (HM-3-HSA), respectively, indicating antitumor activity of HM-3-HSA was higher than HSA-HM-3. In conclusion, these results suggested that the HM-3/HSA fusion protein might be potential candidate HM-3 agent for treatment of melanoma and when HSA was fused at the C-terminus of HM-3, the fusion protein had a higher stability and activity.

In host-parasitoid interactions, antagonistic relationship drives parasitoids to vary in virulence in facing different hosts, which makes these systems excellent models for stress-induced evolutionary studies. Venom compositions varied between two strains of Tetrastichus brontispae, Tb-Bl and Tb-On. Tb-Bl targets Brontispa longissima pupae as hosts, and Tb-On is a sub-population of Tb-Bl, which has been experimentally adapted to a new host, Octodonta nipae. Aiming to examine variation in parasitoid virulence of the two strains toward two hosts, we used reciprocal injection experiments to compare effect of venom/ovarian fluids from the two strains on cytotoxicity, inhibition of immunity and fat body lysis of the two hosts. We found that Tb-Onvenom was more virulent towards plasmatocyte spreading, granulocyte function and phenoloxidase activity than Tb-Blvenom. Tb-Blovary was able to suppress encapsulation and phagocytosis in both hosts; however, Tb-Onovary inhibition targeted only B. longissima. Our data suggest that the venom undergoes rapid evolution when facing different hosts, and that the wasp has good evolutionary plasticity.

Objective To explore the arousal of people with high stress-related sleep vulnerability and the effect of music intervention on hyperarousal. Methods A total of 33 healthy subjects from China Rehabilitation Research Center were enrolled in this study. Based on the median value (17 score) of Ford Insomnia Response to Stress Test-Chinese Version (FIRST-C), they were divided into 2 groups: 16 cases of high stress-related sleep vulnerability and 17 cases of low stress-related sleep vulnerability. Multi-parameter physiological indexes monitoring system of Thought Technology Ltd. was used to gather physiological indicators [blood volume pulse (BVP), skin temperature, skin conduction, respiration rate, respiration amplitude and heart rate], and brain wave [δ wave, θ wave, low α wave and high α wave, α wave, sensory - motor rhythm (SMR), low β wave and high β wave]. Results Compared with low vulnerability subjects, high vulnerability subjects had significantly higher skin conduction (P = 0.003, 0.001), amplitude of SMR (P = 0.015, 0.031) and low β wave (P = 0.000, 0.001) before and after treatment, while had significantly increased high β wave after treatment (P = 0.004). After treatment, all subjects had significantly reduced BVP (P = 0.000), increased skin temperature (P = 0.000), increased respiration rate (P = 0.008) and reduced heart rate (P = 0.000). Compared with before treatment, high vulnerability subjects had significantly reduced skin conduction (P = 0.001), respiratory amplitude (P = 0.032), high α wave (P = 0.017) and low β wave (P = 0.013) after treatment. Compared with before treatment, low vulnerability subjects had significantly reduced skin conduction (P = 0.039), low α wave (P = 0.035), high α wave (P = 0.031), α wave (P = 0.044) and low β wave (P = 0.015) after treatment. Conclusions Both physiological and cortical hyperarousal are presented in people with high stress-related sleep vulnerability in resting state. Music intervention can improve the hyperarousal of high vulnerability people, especially their physiological indicators. It can be used as a health management technique to prevent people with high stress-related sleep vulnerability from developing into chronic insomnia. DOI: 10.3969/j.issn.1672-6731.2017.05.005

Objective A rabbit model was used to evaluate the effects of bone-cemented hip arthroplasty on distal femoral blood flow and metabolism relative to that of the non-cemented contralateral leg. Methods The marrow cavity of the right hind femur was filled with bone cement. At each of the following time points, rabbits were randomly selected to receive an injection of one dose of 99m Tc-methylene diphosphonate and then immediately scanned using a gamma camera: immediately postoperatively and at 4 and 8 weeks postoperatively. A BL-410 model biofunction experimental system was used to analyze the acquired images and determine the radioactive counts of each hind leg. Results The X-ray and photographic images of the right femoral bones confirmed successful filling of the marrow cavity with bone cement. The radioactive counts were significantly lower in the experimental than control legs at each time point. The ratio of the radioactive count of the experimental to control leg increased considerably at each time point, but each ratio was