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Abstract Plenty of circRNAs have been reported to play an important role in colorectal cancer (CRC), while the reason of abnormal circRNA expression in cancer still keep elusive. Here, we found that m7G RNA modifications were enriched in some circRNAs, these m7G modifications in circRNAs were catalyzed by METTL1, and the GG motif was the main site preference for m7G modifications in circRNAs. We further confirmed that METTL1 played a cancer-promoting role in CRC. We then screened a highly expressed circRNA, called circKDM1A, and found that METTL1 prevented the degradation of circKDM1A by m7G modification. CircKDM1A was further verified to promote proliferation, invasion and migration of CRC in vivo and in vitro. Its cancer-promoting ability was weakened after the m7G site mutation. CircKDM1A was verified to activate AKT pathway by upregulating PDK1, consequently promoting CRC progression. These results suggest that m7G-modified circRNA promotes CRC progression via activating AKT pathway. Our study uncovers an essential physiological function and mechanism of METTL1-mediated m7G modification in the regulation of circRNA stability and cancer progression.

The effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection persist months and years after recovery. We conducted an online survey to assess the health condition of convalescents approximately 5 months following the primary infection of SARS-CoV-2. The study recruited 5,510 individuals who were primary infected, 626 participants who had experienced reinfection, and 521 participants who were without infective history. The most common disorders after the primary infection group were fatigue (15.18 %), memory issue (13.13 %), post-exertional malaise (PEM, 11.68 %), and brain fog (11.29 %) at the time of survey. In addition, SARS-CoV-2 infection had an impact on the reproductive systems. In stepwise logistic regression analysis, smoking currently, with background diseases, and outpatient visits in the acute phase could be associated with moderate / severe disorders. Further analysis of different background diseases showed that allergic rhinitis, hyperlipidemia, cardiovascular disease, autoimmune diseases, neurological diseases, and asthma likely increased the risk of moderate/severe disorders. The probability of developing disorders of individuals with SARS-CoV-2 reinfection was higher before the secondary infection than uninfected people. Fatigue, PEM, muscle pain/spasms, chills, joint pain, excessive sweating at rest, headache / dizziness, sore throat or foreign body sensation in the throat, cough, expectoration, dry / painful / watery eyes, loss of appetite and constipation were associated with an increased risk of reinfection. It was essential to undertake further research with enhanced randomization in a larger sample in the community, and to strengthen the validation of the research conclusions. The findings of this study contribute to a deeper understanding of the health recovery process among coronavirus disease 2019 (COVID-19) convalescents. Moreover, the findings help identify characteristic health risk factors associated with convalescents and highlight the risk of moderate / severe disorders and reinfection. Furthermore, the findings also provide valuable guidance and reference for SARS-CoV-2 rehabilitation strategies and the prevention of reinfection, offering insights for scientific recommendations.

Abstract TFE3 and TFEB, as the master regulators of lysosome biogenesis and autophagy, are well characterized to enhance the synaptic protein α-synuclein degradation in protecting against Parkinson’s disease (PD) and their levels are significantly decreased in the brain of PD patients. However, how TFE3 and TFEB are regulated during PD pathogenesis remains largely vague. Herein, we identified that programmed cell death 4 (PDCD4) promoted pathologic α-synuclein accumulation to facilitate PD development via suppressing both TFE3 and TFEB translation. Conversely, PDCD4 deficiency significantly augmented global and nuclear TFE3 and TFEB distributions to alleviate neurodegeneration in a mouse model of PD with overexpressing α-synuclein in the striatum. Mechanistically, like TFEB as we reported before, PDCD4 also suppressed TFE3 translation, rather than influencing its transcription and protein stability, to restrain its nuclear translocation and lysosomal functions, eventually leading to α-synuclein aggregation. We proved that the two MA3 domains of PDCD4 mediated the translational suppression of TFE3 through binding to its 5’-UTR of mRNA in an eIF-4A dependent manner. Based on this, we developed a blood-brain barrier penetrating RVG polypeptide modified small RNA drug against pdcd4 to efficiently prevent α-synuclein neurodegeneration in improving PD symptoms by intraperitoneal injections. Together, we suggest PDCD4 as a PD-risk protein to facilitate α-synuclein neurodegeneration via suppressing TFE3 and TFEB translation and further provide a potential small RNA drug against pdcd4 to treat PD by intraperitoneal injections.

Abstract Tuberous sclerosis complex 2 (TSC2) crucially suppresses Rheb activity to prevent mTORC1 activation. However, mutations in TSC genes lead to mTORC1 overactivation, thereby causing various developmental disorders and cancer. Therefore, the discovery of novel Rheb inhibitors is vital to prevent mTOR overactivation. Here, we reveals that the anti-inflammatory cytokine IL-37d can bind to lysosomal Rheb and suppress its activity independent of TSC2, thereby preventing mTORC1 activation. The binding of IL-37d to Rheb switch-II subregion destabilizes the Rheb-mTOR and mTOR-S6K interactions, further halting mTORC1 signaling. Unlike TSC2, IL-37d is reduced under ethanol stimulation, which results in mitigating the suppression of lysosomal Rheb-mTORC1 activity. Consequently, the recombinant human IL-37d protein (rh-IL-37d) with a TAT peptide greatly improves alcohol-induced liver disorders by hindering Rheb-mTORC1 axis overactivation in a TSC2- independent manner. Together, IL-37d emerges as a novel Rheb suppressor independent of TSC2 to terminate mTORC1 activation and improve abnormal lipid metabolism in the liver.

Understanding how human leukocyte antigen (HLA) polymorphism affects both the susceptibility and severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection will help to identify individuals at higher risk to better manage and prioritize vaccination at the clinical level and explain the differences in epidemic trends in different regions at the epidemiological level. This study compared the frequencies of HLA class I alleles (HLA-A, B) in 214 coronavirus disease 2019 (COVID-19) patients with different disease severity and 35 healthy controls and analyzed the correlations between specific HLA alleles and disease severity and T cell memory. The results showed no significant difference in HLA allele frequencies between COVID-19 patients and healthy controls (P > 0.05). The allele HLA-B*13:02 was significantly correlated with the disease severity of COVID-19 patients (P = 0.006). After adjustment for age and disease severity, the T cell responses of COVID-19 convalescents with the allele HLA-B*40:01 may be lower at six months (P = 0.044) and 12 months (P = 0.069). Moreover, these results may be due to their rare peptide anchors by analyzing the binding peptide motifs of these HLA alleles. The study may be valuable for investigating the potential association of specific HLA alleles with SARS-CoV-2 infection.

Abstract The potentiation of synaptic plasticity and serotonin generation by brain-derived neurotrophic factor (BDNF) and tryptophan hydroxylase 2 (TPH2) is well characterized to facilitate rapid and long-lasting antidepressant actions. Therefore, the identification of the key protein that simultaneously controls both BDNF and TPH2 is important for the treatment of depression. We show here that a lack of acetyl-CoA synthetase short-chain family member 2 (ACSS2) causes impairments in BDNF-dependent synaptic plasticity and tryptophan hydroxylase 2 (TPH2)-mediated serotonin generation, thereby contributing to spontaneous and chronic restraint stress (CRS)-induced depressive-like behavior in mice. Conversely, D-mannose is identified as a rapid ACSS2 inducer and thus mediates rapid and long-lasting antidepressant-like effects. Mechanistically, acute and chronic D-mannose administration inhibits the phosphorylation of EF2 to increase BDNF levels and reverse the reduction of TPH2 histone acetylation and transcription. We reveal that ACSS2 promotes TPH2 histone acetylation and transcription with the requirement of AMPK activation. To elevate nuclear ACSS2 levels, D-mannose can rapidly and persistently activate AMPK via Ca2+-CAMKK2 and the lysosomal AXIN-LKB1 pathway to facilitate its fast-acting and persistent antidepressant responses. Taken together, the results presented here reveal that ACSS2 functions as a novel target to link rapid and persistent antidepressant actions and further suggest that D-mannose is a potential therapeutic agent to resist depression through its augmentation of the ACSS2 dependent BDNF and TPH2 pathways.

CREB-regulated transcription coactivator 1 (CRTC1), a pivotal synaptonuclear messenger, regulates synaptic plasticity and transmission to prevent depression. Despite exhaustive investigations into CRTC1 mRNA reductions in the depressed mice, the regulatory mechanisms governing its transcription remain elusive. Consequently, exploring rapid but non-toxic CRTC1 inducers at the transcriptional level is important for resisting depression. Here, we demonstrate the potential of D-arabinose, a unique monosaccharide prevalent in edible-medicinal plants, to rapidly enter the brain and induce CRTC1 expression, thereby eliciting rapid-acting and persistent antidepressant responses in chronic restrain stress (CRS)-induced depressed mice. Mechanistically, D-arabinose induces the expressions of peroxisome proliferator-activated receptor gamma (PPARγ) and transcription factor EB (TFEB), thereby activating CRTC1 transcription. Notably, we elucidate the pivotal role of the acetyl-CoA synthetase short-chain family member 2 (ACSS2) as an obligatory mediator for PPARγ and TFEB to potentiate CRTC1 transcription. Furthermore, D-arabinose augments ACSS2-dependent CRTC1 transcription by activating AMPK through lysosomal AXIN-LKB1 pathway. Correspondingly, the hippocampal down-regulations of ACSS2, PPARγ or TFEB alone failed to reverse CRTC1 reductions in CRS-exposure mice, ultimately abolishing the anti-depressant efficacy of D-arabinose. In summary, our study unveils a previously unexplored role of D-arabinose in activating the ACSS2-PPARγ/TFEB-CRTC1 axis, presenting it as a promising avenue for the prevention and treatment of depression.

ObjectiveTo investigate the value of predicting axillary lymph node (ALN) metastasis based on intratumoral and peritumoral dynamic contrast-enhanced MRI (DCE-MRI) radiomics and clinico-radiological characteristics in breast cancer.MethodsA total of 473 breast cancer patients who underwent preoperative DCE-MRI from Jan 2017 to Dec 2020 were enrolled. These patients were randomly divided into training (n=378) and testing sets (n=95) at 8:2 ratio. Intratumoral regions (ITRs) of interest were manually delineated, and peritumoral regions of 3 mm (3 mmPTRs) were automatically obtained by morphologically dilating the ITR. Radiomics features were extracted, and ALN metastasis-related radiomics features were selected by the Mann-Whitney U test, Z score normalization, variance thresholding, K-best algorithm and least absolute shrinkage and selection operator (LASSO) algorithm. Clinico-radiological risk factors were selected by logistic regression and were also used to construct predictive models combined with radiomics features. Then, 5 models were constructed, including ITR, 3 mmPTR, ITR+3 mmPTR, clinico-radiological and combined (ITR+3 mmPTR+ clinico-radiological) models. The performance of models was assessed by sensitivity, specificity, accuracy, F1 score and area under the curve (AUC) of receiver operating characteristic (ROC), calibration curves and decision curve analysis (DCA).ResultsA total of 2264 radiomics features were extracted from each region of interest (ROI), 3 and 10 radiomics features were selected for the ITR and 3 mmPTR, respectively. 5 clinico-radiological risk factors were selected, including lesion size, human epidermal growth factor receptor 2 (HER2) expression, vascular cancer thrombus status, MR-reported ALN status, and time-signal intensity curve (TIC) type. In the testing set, the combined model showed the highest AUC (0.839), specificity (74.2%), accuracy (75.8%) and F1 Score (69.3%) among the 5 models. DCA showed that it had the greatest net clinical benefit compared to the other models.ConclusionThe intra- and peritumoral radiomics models based on DCE-MRI could be used to predict ALN metastasis in breast cancer, especially for the combined model with clinico-radiological characteristics showing promising clinical application value.

Summary: The spontaneous migration of bone marrow neutrophils (BMNs) is typically induced by distant tumor cells during the early stage of the tumor and critically controls tumor progression and metastases. Therefore, identifying the key molecule that prevents this process is extremely important for suppressing tumors. Interleukin-37 (IL-37) can suppress pro-inflammatory cytokine generation via an IL-1R8- or Smad3-mediated pathway. Here, we demonstrate that human neutrophil IL-37 is responsively reduced by tumor cells and the recombinant IL-37 isoform d (IL-37d) significantly inhibits spontaneous BMN migration and tumor lesion formation in the lung by negatively modulating CCAAT/enhancer binding protein beta (C/EBPβ) in a Lewis lung carcinoma (LLC)-inducing lung cancer mouse model. Mechanistically, IL-37d promotes C/EBPβ ubiquitination degradation by facilitating ubiquitin ligase COP1 recruitment and disrupts C/EBPβ DNA binding abilities, thereby reducing neutrophil ATP generation and migration. Our work reveals an anti-tumor mechanism for IL-37 via destabilization of C/EBPβ to prevent spontaneous BMN migration and tumor progression.

In order to study the influence of caved rocks in the goaf on the backfilling body in the backfilling mining, uniaxial compression test are carried out on the backfilling body-cemented granular body combination with different granular heights, discrete element lithology and backfilling body strength. The uniaxial compression failure of the combination body specimen is monitored in real time by using the three-dimensional acoustic emission positioning technology. The deformation and failure corresponding to the AE events in the loading process is characterized by combining the time parameters of AE events with the starting time points of the four stages of the stress-strain curve. Based on this, the failure model for the interface of the combination body is established. The results show that the height of granular is negatively correlated with the strength of the combination body, and the uniaxial compressive strength of the combination body with the backfilling height ratio of 1:4 is only 55.0 % of that of the single backfilling body. The discrete element lithology and the strength of backfilling body are positively correlated with the strength of the combination body. Although high-strength backfilling body can improve the uniaxial compressive strength of the combination body, the higher the strength of filling body in the combination body, the more serious the strength reduction of the combination body. When the particle lithology in cemented bulk is siltstone with low strength, the uniaxial compressive strength of the combination body is only 42.9% of that of single combination body. The siltstone with smaller compressive strength will have a fracture plane due to shear failure during the failure, and the limestone with larger compressive strength can withstand shear load by using the shear strength of the granular particles. When the cementing matrix in the cemented granular fails or the particles in the cemented granular are broken, the interface of the backfilling body and the cemented granular undergoes non-uniform compression deformation, resulting in the stress concentration on the backfilling body on the interface damaged by the cemented granular, resulting in the shear failure of the upper backfilling body locally, and the failure of backfilling body is the contribution of both axial stress and non-uniform deformation of the interface.

Short-chain fatty acids (SCFAs) have been increasingly evidenced to be important bioactive metabolites of the gut microbiota and transducers in controlling diverse psychiatric or neurological disorders via the microbiota–gut–brain axis. However, the precise mechanism by which brain SCFAs extert multiple beneficial effects is not completely understood. Our previous research has demonstrated that the acetyl-coenzyme A synthetase short-chain family member 2 (ACSS2) is a novel target of the rapid and long-lasting antidepressant responses. Here, we show that micromolar SCFAs significantly augment both total cellular and nuclear ACSS2 to trigger tryptophan hydroxylase 2 (TPH2) promoter histone acetylation and its transcription in SH-SY5Y cells. In chronic-restraint-stress-induced depression mice, neuronal ACSS2 knockdown by stereotaxic injection of adeno-associated virus in the hippocampus abolished SCFA-mediated improvements in depressive-like behaviors of mice, supporting that ACSS2 is required for SCFA-mediated antidepressant responses. Mechanistically, the peroxisome-proliferator-activated receptor gamma (PPARγ) is identified as a novel partner of ACSS2 to activate TPH2 transcription. Importantly, PPARγ is also responsible for SCFA-mediated antidepressant-like effects via ACSS2–TPH2 axis. To further support brain SCFAs as a therapeutic target for antidepressant effects, d-mannose, which is a naturally present hexose, can significantly reverse the dysbiosis of gut microbiota in the chronic-restraint-stress-exposure mice and augment brain SCFAs to protect against the depressive-like behaviors via ACSS2–PPARγ–TPH2 axis. In summary, brain SCFAs can activate ACSS2–PPARγ–TPH2 axis to play the antidepressive-like effects, and d-mannose is suggested to be an inducer of brain SCFAs in resisting depression.

With the increasingly widespread application of CMOS image sensors (CIS) in radiation environments, such as aerospace, their radiation effects have gained attention. This paper investigates single-event transient (SET) caused by the proton direct ionization on CIS, combining both experimental and simulation methods. The proton beam energy used in the experiment is 12 MeV, with a flux up to 3.5 × 108 p/(cm2 s). Due to the periodicity of the proton beam, the CIS output displays a phenomenon of alternating brightness and darkness. When the proton beam flux is low, numerous SET bright spots with different outputs are observed. To comprehensively analyze these experimental phenomena, a typical three-dimensional 4T pinned photodiode model is constructed in TCAD, and relevant SET simulation is carried out. The results indicate that incident position, incident time, and the number of incident protons significantly affect the output of SET-generated bright spots, which are key factors contributing to the different bright spots observed in the experiment.

Summary: Investigating immune memory to vaccinia virus and pre-existing immunity to mpox virus (MPXV) among the population is crucial for the global response to this ongoing mpox epidemic. Blood was sampled from vaccinees inoculated with vaccinia virus Tiantan (VTT) strain born before 1981 and unvaccinated control subjects born since 1982. After at least 40 years of the inoculation, 60% or 5% VTT vaccinees possess neutralizing antibodies (NAbs) to VTT or MPXV, with at least 50% having T cell memory to VTT protein antigens. Notably, 46.7% vaccinees show pre-existing T cell responses to MPXV. Broad pre-existing CD8+ T cell reactivities to MPXV are detected not only against conserved epitopes but also against variant epitopes between VTT and MPXV. Persistent NAbs and T cell memory to VTT among vaccinees, along with pre-existing T cells to MPXV among both vaccinees and the unvaccinated population, indicate a particular immune barrier to mpox.

Transient γ-radiation and laser-simulated experiments were carried out to investigate the transient dose rate effect (TDRE) in SiGe heterojunction bipolar transistors (HBTs) for the first time. The results indicate that IBM43RF0100 SiGe HBTs experience a significant sensitivity of TDRE. For the laser-simulated experiment, the duration of transient current and charge collection are matched well with that of transient γ-radiation. The amplitude of transient photocurrent induced by the lower energy order of μJ approaches the transient photocurrent induced by transient γ-radiation. It is demonstrated that laser-simulated experiments are a candidate and a convenient method to evaluate the TDRE response of SiGe HBTs, which avoids serious electromagnetic interference in the transient γ-radiation environment.

Abstract Background Previous studies have discussed the pregnancy outcomes of diminished ovarian reserve (DOR) patients. However, data on embryonic development potential, neonatal outcomes, and maternal complications of DOR patients still remained unknown. This is the first study to investigate the risk of DOR on pregnancy and perinatal outcomes among women

BackgroundThe utilization of frozen-thawed embryo transfer (FET) cycles has been linked to heightened risks of adverse perinatal outcomes. However, the potential association between adverse perinatal outcomes and distinct endometrial preparation regimens remains unclear. Therefore, we aim to investigate the maternal and neonatal outcomes after hormone replacement treatment (HRT) cycles, natural cycles (NC) and HRT cycles with pretreatment using GnRHa (HRT + GnRHa) for ovulatory women undergoing FET cycles.MethodsA large sample retrospective cohort study was carried out from 2016 to 2020. The data included a total of 5316 women who had singleton deliveries undergoing FET cycles and which were divided into three groups based on different endometrial preparation protocols: 4399 patients in HRT groups, 621 in GnRHa+HRT groups, 296 in NC groups. The outcomes consisted of maternal outcomes (cesarean section, hypertensive disorders of pregnancy (HDP), placenta previa, gestational diabetes mellitus (GDM));and neonatal outcomes (preterm birth, newborn birthweight, low birthweight, small for gestational age (SGA), macrosomia, large for gestational age (LGA), fetal malformation).ResultsAfter adjusting for a series of confounding variables, we found an increased risk of HDP (aOR=3.362; 95%CI, 1.059-10.675) and cesarean section (aOR=1.838; 95%CI, 1.333-2.535) in HRT cycles compared with NC, especially for ovulatory women under 35 years old. However, in all three groups, newborn birth weight was not significantly different. Meanwhile, perinatal outcomes did not differ significantly in terms of perinatal outcomes in HRT +GnRHa cycles compared with HRT cycles solely.ConclusionDuring FET cycles, singletons from HRT were related to higher risks of HDP and cesarean section, particularly for young women. GnRHa pretreatment didn’t bring any benefit to perinatal outcomes compared with HRT cycles alone. Therefore, the natural cycle may be a more appropriate and safer option for young ovulatory women.

Summary: Actively controlled nanoliter fluid circuits are an urgently needed technology in electronics, biomedicine, chemical synthesis, and biosensing. The difficulty lies in how to drive the microfluid in an isolated and airtight manner in glass wafer. We used a magnetic oscillator pump to realize the switching of the circulation direction and controlling the flow rate of the 10nL fluid. Results of two-dimensional numerical simulations shows that the flow field can reach a steady state and a stable flow can be obtained. The contribution of each vibration cycle to the flow rate is proportional to the frequency, decays exponentially with the viscosity, is proportional to the 4.2 power of the amplitude, and is proportional to the radius. Compared with the existing fluid technology, this technology realizes the steering and flow control of a fully enclosed magnetic control fluid circuit as small as 10nL in hard materials for the first time.

Abstract Objective To determine the optimal endometrial preparation protocol for a frozen embryo transfer in patients with endometriosis. Design Retrospective cohort study. Setting Tertiary care academic medical center. Patient(s) One thousand four hundred thirteen patients with endometriosis who underwent oocyte aspiration from 2015 to 2020 and frozen embryo transfer from 2016 to 2020 and received natural cycle, hormone replacement treatment with or without GnRHa pretreatment endometrial preparation. Intervention(s) None. Main outcome measure(s) Clinical pregnancy rate, live birth rate, miscarriage rate, multiple pregnancy rate, biochemical pregnancy rate and ectopic pregnancy rate. Singleton live births were assessed for perinatal outcomes and obstetric complications. Result(s) There were no differences in clinical pregnancy outcomes or prenatal outcomes among the three commonly used endometrial preparation protocols for frozen embryo transfer cycles in patients with endometriosis. Results remained after screening variables using univariate logistic regression into multivariate logistic regression. No advantages or disadvantages were found among the three endometrial preparation protocols in patients with endometriosis. Conclusion(s) Natural cycle, hormone replacement cycle, or hormone replacement treatment with GnRHa pretreatment showed no superiority or inferiority in pregnancy and perinatal outcomes in patients with endometriosis.

Abstract Background Utilizing population-based survey data in epidemiological research with a spatial perspective can integrate valuable context into the dynamics of HIV prevalence in West Africa. However, the situation in the Mano River Union (MRU) countries is largely unknown. This research aims to perform an ecological study to determine the HIV prevalence patterns in MRU. Methods We analyzed Demographic and Health Survey (DHS) and AIDS Indicator Survey (AIS) data on HIV prevalence in MRU from 2005 to 2020. We examined the country-specific, regional-specific and sex-specific ratios of respondents to profile the spatial–temporal heterogeneity of HIV prevalence and determine HIV hot spots. We employed Geodetector to measure the spatial stratified heterogeneity (SSH) of HIV prevalence for adult women and men. We assessed the comprehensive correct knowledge (CCK) about HIV/AIDS and HIV testing uptake by employing the Least Absolute Shrinkage and Selection Operator (LASSO) regression to predict which combinations of CCKs can scale up the ratio of HIV testing uptake with sex-specific needs. Results In our analysis, we leveraged data for 158,408 respondents from 11 surveys in the MRU. From 2005–2015, Cote d'Ivoire was the hot spot for HIV prevalence with a Gi_Bin score of 3, Z-Score 8.0–10.1 and P

Inflammasome activation is an essential innate immune defense mechanism against Salmonella infections. Salmonella has developed multiple strategies to avoid or delay inflammasome activation, which may be required for long-term bacterial persistence. However, the mechanisms by which Salmonella evades host immune defenses are still not well understood. In this study, Salmonella Enteritidis (SE) random insertion transposon library was screened to identify the key factors that affect the inflammasome activation. The type I secretion system (T1SS) protein SiiD was demonstrated to repress the NLRP3 inflammasome activation during SE infection and was the first to reveal the antagonistic role of T1SS in the inflammasome pathway. SiiD was translocated into host cells and localized in the membrane fraction in a T1SS-dependent and partially T3SS-1-dependent way during SE infection. Subsequently, SiiD was demonstrated to significantly suppress the generation of mitochondrial reactive oxygen species (mtROS), thus repressing ASC oligomerization to form pyroptosomes, and impairing the NLRP3 dependent Caspase-1 activation and IL-1β secretion. Importantly, SiiD-deficient SE induced stronger gut inflammation in mice and displayed NLRP3-dependent attenuation of the virulence. SiiD-mediated inhibition of NLRP3 inflammasome activation significantly contributed to SE colonization in the infected mice. This study links bacterial T1SS regulation of mtROS-ASC signaling to NLRP3 inflammasome activation and reveals the essential role of T1SS in evading host immune responses.

ObjectiveTo investigate the association between different ovarian reserves and reproductive and adverse perinatal outcomes in patients with endometriosis.DesignRetrospective study.SettingReproductive Medicine Center in a hospital.PatientsPatients surgically diagnosed with endometriosis were divided into three groups according to their ovarian reserve: diminished ovarian reserve (DOR) group (n=66), normal ovarian reserve (NOR) group (n=160), and high ovarian reserve (HOR) group (n=141).Intervention(s)None.Main Outcome MeasuresLive birth rate (LBR), cumulative live birth rate (CLBR), and adverse perinatal outcome for singleton live births.ResultsThere were significantly higher live birth and cumulative live birth rates in endometriosis patients with NOR or HOR than in those with DOR. For adverse perinatal outcomes, patients with NOR or HOR had no significant association with preterm birth, gestational hypertension, placenta previa, fetal malformation, abruptio placentae, macrosomia, or low birth weight, except for a decreased risk of gestational diabetes mellitus.ConclusionOur study revealed that although patients with endometriosis with NOR and HOR had increased reproductive outcomes, patients with endometriosis with DOR had still an acceptable live birth rate and a similar cumulative live birth rate with available oocytes. Moreover, patients with NOR and HOR might not exhibit a decreased risk of abnormal perinatal outcomes, except for gestational diabetes mellitus. Multicenter prospective studies are needed to further clarify the relationship.

This research was to summarize the comparative efficacy and safety of red yeast rice (RYR) preparations and analyze the treatment ranking of lipid-lowering agents including RYR. Thirty-one systematic reviews (SRs) involving 165 randomized trials with 14,987 dyslipidemia participants were included. All the SRs showed a high overall risk of bias. A Bayesian network meta-analysis was performed. Only five trials reported major adverse cardiovascular events (MACE) and three trials reported lipoprotein(a)[Lp(a)]. Compared to placebo or other lipid-lowering drugs, RYR preparations showed some regulating action on lipids and glucose metabolism, with fewer side effects (P

This paper introduces a new finding regarding single event upsets (SEUs) in configuration memory, and their potential impact on enhancing the performance of deep neural networks (DNNs) on the multiprocessor system on chip (MPSoC) platform. Traditionally, SEUs are considered to have negative effects on electronic systems or designs, but the current study demonstrates that they can also have positive contributions to the DNN on the MPSoC. The assertion that SEUs can have positive contributions to electronic system design was supported by conducting fault injections through dynamic reconfiguration on DNNs implemented on a 16nm FinFET technology Zynq UltraScale+ MPSoC. The results of the current study were highly significant, indicating that an SEU in configuration memory could result in an impressive 8.72% enhancement in DNN recognition on the MPSoC. One possible cause is that SEU in the configuration memory leads to slight changes in weight or bias values, resulting in improved activation levels of neurons and enhanced final recognition accuracy. This discovery offers a flexible and effective solution for boosting DNN performance on the MPSoC platform.

Compared to linear accelerators, pulsed lasers have the characteristics of high efficiency, low cost, stable pulse output, and low environment interference for researching the transient dose rate effect (TDRE) on semiconductor devices. In this paper, pulsed laser radiation experiments are performed on a level-shifting transceiver. The experimental results are consistent with the results of the transient γ-ray radiation experiment, demonstrating the feasibility of using the pulsed laser in TDRE research on the level-shifting transceiver. This paper obtains theoretical and experimental conversion factors (CFs) through theoretical analysis and equivalency of the peak photocurrents, which are measured in pulsed laser and transient γ-ray radiation experiments. The CF results from the two approaches are within 7% of each other. In pulsed laser radiation experiments, an uncommon phenomenon is found. At the I/O (Input/Output) ports of the level-shifting transceiver, a trend of a positive photocurrent followed by a negative pulse is observed. A hypothesis is proposed that this photocurrent is produced by the turn-on and turn-off of the parasitic PNP (Positive-Negative-Positive) transistors in electrostatic discharge circuits at the level-shifting transceiver I/O ports. In addition, this hypothesis is verified by TCAD (Technology Computer Aided Design) simulations.

ObjectiveThe aim of this study was to describe the cumulative live birth rates (CLBRs) of young women with or without low prognosis according to the POSEIDON criteria after IVF/ICSI cycles and to investigate whether the diagnosis of low prognosis increases the risk of abnormal birth outcomes.DesignRetrospective study.SettingA single reproductive medicine center.PopulationFrom January 2016 to October 2020, there were 17,893 patients (

Considerable evidence shows that oxidative stress exists in the pathophysiological process of female reproductive system diseases. At present, there have been many studies on oxidative stress of placenta during pregnancy, especially for preeclampsia. However, studies that directly focus on the effects of oxidative stress on blood vessels at the maternal-fetal interface and their associated possible outcomes are still incomplete and ambiguous. To provide an option for early clinical prediction and therapeutic application of oxidative stress in female reproductive system diseases, this paper briefly describes the composition of the maternal-fetal interface and the molecular mediators produced by oxidative stress, focuses on the sources of oxidative stress and the signaling pathways of oxidative stress at the maternal-fetal interface, expounds the adverse consequences of oxidative stress on blood vessels, and deeply discusses the relationship between oxidative stress and some pregnancy complications and other female reproductive system diseases.

Langerhans cell histiocytosis (LCH) was first proposed in 1987 to define the disorder characterized by the proliferation of abnormal Langerhans cells. It is more likely to occur in children younger than 15 years of age. Single-site and single-system LCH of rib is rare in adults. We present a rare case of isolated rib LCH in a 61-year-old male patient and expound the diagnosis and treatment of the disease. A 61-year-old male patient who presented with a 15-day history of dull pain in the left chest was admitted to our hospital. PET/CT image showed obvious osteolytic bone destruction and abnormal fluorodeoxy-glucose (FDG) uptake (maximum standardized uptake value: 14.5) in the right fifth rib with local soft tissue mass formation. The patient was eventually confirmed the diagnosis of LCH by immunohistochemistry stain and treated with rib surgery. A thorough review of the literature regarding diagnosis and treatment of LCH is presented in this study.

Abstract White adipose tissue (WAT) homeostasis substantiated by type 2 immunity is indispensable to counteract obesity and metabolic disorders. IL-33/suppression of tumorigenicity (ST) 2 signaling promotes type 2 response in WAT, while potential regulators remain to be discovered. We identified human IL-37 isoform D (IL-37D) as an effective trigger for ST2-mediated type 2 immune homeostasis in WAT. IL-37D transgene amplified ST2+ immune cells, promoted M2 macrophage polarization and type 2 cytokine secretion in WAT that mediate beiging and inflammation resolution, thereby increasing energy expenditure, reducing obesity and insulin resistance in high-fat diet (HFD)-fed mice. Mechanistically, either endogenous or exogenous IL-37D inhibited soluble ST2 (sST2) production from WAT challenged with HFD or TNF-α. Recombinant sST2 impaired the beneficial effects of IL-37D transgene in HFD-fed mice, characterized by damaged weight loss, insulin action, and type 2 cytokine secretion from WAT. In adipose-derived stem cells, IL-37D inhibited TNF-α-stimulated sST2 expression through IL-1 receptor 8 (IL-1R8)-dependent NF-κB inactivation. Collectively, human IL-37D suppresses sST2 to boost type 2 immune homeostasis in WAT, which may be a promising therapy target for obesity and metabolic disorders.

Cell-to-cell communication must occur through molecular transport in the intercellular fluid space. Nanoparticles, such as exosomes, diffuse or move more slowly in fluids than small molecules. To find a microfluidic technology for real-time exosome experiments on intercellular communication between living cells, we use the microfluidic culture dish’s quaternary ultra-slow microcirculation flow field to accumulate nanoparticles in a specific area. Taking stem cell–tumor cell interaction as an example, the ultra-slow microcirculatory flow field controls stem cell exosomes to interfere with tumor cells remotely. Under static coculture conditions (without microfluidics), the tumor cells near stem cells (

The BBIBP-CorV severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inactivated vaccine has been authorized for emergency use and widely distributed. We used single-cell transcriptome sequencing to characterize the dynamics of immune responses to the BBIBP-CorV inactivated vaccine. In addition to the expected induction of humoral immunity, we found that the inactivated vaccine induced multiple, comprehensive immune responses, including significantly increased proportions of CD16+ monocytes and activation of monocyte antigen presentation pathways; T cell activation pathway upregulation in CD8+ T cells, along with increased activation of CD4+ T cells; significant enhancement of cell-cell communications between innate and adaptive immunity; and the induction of regulatory CD4+ T cells and co-inhibitory interactions to maintain immune homeostasis after vaccination. Additionally, comparative analysis revealed higher neutralizing antibody levels, distinct expansion of naive T cells, a shared increased proportion of regulatory CD4+ T cells, and upregulated expression of functional genes in booster dose recipients with a longer interval after the second vaccination. Our research will support a comprehensive understanding of the systemic immune responses elicited by the BBIBP-CorV inactivated vaccine, which will facilitate the formulation of better vaccination strategies and the design of new vaccines.

BackgroundThis study aimed to perform a meta‐analysis to evaluate the diagnostic performance of radiomics in predicting axillary lymph node metastasis (ALNM) and sentinel lymph node metastasis (SLNM) in breast cancer.Materials and methodsMultiple electronic databases were systematically searched to identify relevant studies published before April 29, 2022: PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, and Wanfang Data. The quality of the included studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. The overall diagnostic odds ratio (DOR), sensitivity, specificity, and area under the curve (AUC) were calculated to evaluate the diagnostic performance of radiomic features for lymph node metastasis (LNM) in patients with breast cancer. Spearman’s correlation coefficient was determined to assess the threshold effect, and meta-regression and subgroup analyses were performed to explore the possible causes of heterogeneity.ResultsA total of 30 studies with 5611 patients were included in the meta-analysis. Pooled estimates suggesting overall diagnostic accuracy of radiomics in detecting LNM were determined: DOR, 23 (95% CI, 16-33); sensitivity, 0.86 (95% CI, 0.82-0.88); specificity, 0.79 (95% CI, 0.73-0.84); and AUC, 0.90 (95% CI, 0.87-0.92). The meta-analysis showed significant heterogeneity between sensitivity and specificity across the included studies, with no evidence for a threshold effect. Meta-regression and subgroup analyses showed that combined clinical factors, modeling method, region, and imaging modality (magnetic resonance imaging [MRI], ultrasound, computed tomography [CT], and X-ray mammography [MMG]) contributed to the heterogeneity in the sensitivity analysis (P < 0.05). Furthermore, modeling methods, MRI, and MMG contributed to the heterogeneity in the specificity analysis (P < 0.05).ConclusionOur results show that radiomics has good diagnostic performance in predicting ALNM and SLNM in breast cancer. Thus, we propose this approach as a clinical method for the preoperative identification of LNM.

Abstract Background Recent studies have consistently shown that AFC and serum AMH are good predictors of ovarian response and have shown strong correlations. However, it is not unusual for reproductive medicine specialists to encounter discordance between them. This is the first study to investigate the efficacies of the different COS protocols when the AFC and AMH levels are discordant. Based on the association between COS protocols and pregnancy outcomes, we attempt to explain the controversial results and clarify the predictive value of AMH and AFC in this context. Methods 19,239 patients undergoing their first fresh in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles with GnRH antagonist protocols, GnRH-a long protocols or GnRH-a ultra-long protocols between January 1, 2016, and December 31, 2019, were enrolled and then divided into four groups in accordance with the boundaries for the AFC and serum AMH level provided by the Poseidon Classification. Our study was divided into two parts. Firstly, we retrospectively compared the effects of the three COS protocols in patients with discordant AMH and AFC. Multivariate logistic regression models were conducted in a forward manner to exclude the influence of confounding factors. Afterward, to increase comparability between Group 2 (low AMH and normal AFC) and Group 3 (normal AMH and low AFC), propensity score matching (PSM) analysis was performed based on age, BMI, the number of embryos transferred, and COS protocol. IVF intermediate and reproductive outcomes were compared between Group 2 and Group 3. Results For people with low AMH and normal AFC (Group 2), the number of total oocytes, clinical pregnancy rate (CPR), live birth rate (LBR) and cumulative live birth rate (CLBR) were significantly higher in GnRH-a ultra-long protocol compared with GnRH antagonist protocol. In multivariate logistic regression models, significant associations of COS protocol with fresh LBR and CPR were found after adjusting for age, BMI, AFC, AMH and the number of embryos transferred. Whereas, in patients with normal AMH and low AFC (Group 3), the number of total oocytes, CLBR, LBR and CPR were highest in the long GnRH-a protocol although there was no statistically significant difference. After PSM, the results showed that although oocytes yield and available embryos in patients with normal AMH and low AFC were significantly higher, there was no significant difference in reproductive outcomes between Group 2 and Group 3. Conclusions We found that women with normal AFC and low AMH may benefit from the GnRH-a ultra-long protocol. Nevertheless, for women with normal AMH and low AFC, the long GnRH-a protocol seems to be associated with better clinical outcomes. Furthermore, after eliminating the confounding factors including the COS protocol, we found that AMH can only predict the number of oocytes but not the quality of oocytes when there was discordance between AFC and AMH.

Salmonella enterica serovar Dublin (S. Dublin) is an important zoonotic pathogen with high invasiveness. In the prevention and control of the Salmonella epidemic, the live attenuated vaccine plays a very important role. To prevent and control the epidemic of S. Dublin in cattle farms, the development of more effective vaccines is necessary. In this study, we constructed two gene deletion mutants, Sdu189ΔspiC and Sdu189ΔspiCΔaroA, with the parental strain S. Dublin Sdu189. The immunogenicity and protective efficacy were evaluated in the mice model. First, both mutant strains were much less virulent than the parental strain, as determined by the 50% lethal dose (LD50) for specific pathogen-free (SPF) 6-week-old female BALB/c mice. Second, the specific IgG antibody level and the expression level of cytokine TNF-α, IFN-γ, IL-4, and IL-18 were increased significantly in the vaccinated mice compared to the control group. In addition, the deletion strains were cleared rapidly from organs of immunized mice within 14 d after immunization, while the parental strain could still be detected in the spleen and liver after 21 d of infection. Compared with the parental strain infected group, no obvious lesions were detected in the liver, spleen, and cecum of the deletion strain vaccinated groups of mice. Immunization with Sdu189ΔspiC and Sdu189ΔspiCΔaroA both provided 100% protection against subsequent challenges with the wild-type Sdu189 strain. These results demonstrated that these two deletion strains showed the potential as live attenuated vaccines against S. Dublin infection. The present study established a foundation for screening a suitable live attenuated Salmonella vaccine.

Abstract Background Colorectal cancer (CRC) is one of the most common malignant tumours. The recurrence and metastasis of CRC seriously affect the survival rate of patients. Angiogenesis is an extremely important cause of tumour growth and metastasis. Circular RNAs (circRNAs) have been emerged as vital regulators for tumour progression. However, the regulatory role, clinical significance and underlying mechanisms still remain largely unknown. Methods High-throughput sequencing was used to analyse differential circRNAs expression in tumour and non-tumour tissues of CRC. In situ hybridization (ISH) and qRT-PCR were used to determine the level of circ3823 in CRC tissues and serum samples. Then, functional experiments in vitro and in vivo were performed to investigate the effects of circ3823 on tumour growth, metastasis and angiogenesis in CRC. Sanger sequencing, RNase R and Actinomycin D assay were used to verify the ring structure of circ3823. Mechanistically, dual luciferase reporter assay, fluorescent in situ hybridization (FISH), RNA immunoprecipitation (RIP) and RNA pull-down experiments were performed to confirm the underlying mechanisms of circ3823. Results Circ3823 was evidently highly expressed in CRC and high circ3823 expression predicted a worse prognosis of CRC patients. Receiver operating characteristic curves (ROCs) indicated that the expression of circ3823 in serum showed high sensitivity and specificity for detecting CRC which means circ3823 have the potential to be used as diagnostic biomarkers. Functional experiments in vitro and in vivo indicated that circ3823 promote CRC cell proliferation, metastasis and angiogenesis. Mechanism analysis showed that circ3823 act as a competing endogenous RNA of miR-30c-5p to relieve the repressive effect of miR-30c-5p on its target TCF7 which upregulates MYC and CCND1, and finally facilitates CRC progression. In addition, we found that N6-methyladenosine (m6A) modification exists on circ3823. And the m6A modification is involved in regulating the degradation of circ3823. Conclusions Our findings suggest that circ3823 promotes CRC growth, metastasis and angiogenesis through circ3823/miR-30c-5p/TCF7 axis and it may serve as a new diagnostic marker or target for treatment of CRC patients. In addition, m6A modification is involved in regulating the degradation of circ3823.

The endometrium thickness increases by which endometrial angiogenesis occurs in parallel with the rapid growth of endometrium during the proliferative phase, which is orchestrated by complex cell–cell interactions and cytokine networks. However, the intercellular communication has not been fully delineated. In the present work, we studied the cell–cell interactome among cells of human proliferative phase endometrium using single-cell transcriptomics. The transcriptomes of 33,240 primary endometrial cells were profiled at single-cell resolution. CellChat was used to infer the cell–cell interactome by assessing the gene expression of receptor–ligand pairs across cell types. In total, nine cell types and 88 functionally related signaling pathways were found. Among them, growth factors and angiogenic factor signaling pathways, including EGF, FGF, IGF, PDGF, TGFb, VEGF, ANGPT, and ANGPTL that are highly associated with endometrial growth, were further analyzed and verified. The results showed that stromal cells and proliferating stromal cells represented cell–cell interaction hubs with a large number of EGF, PDGF incoming signals, and FGF outgoing signals. Endothelial cells exhibited cell–cell interaction hubs with a plenty of VEGF, TGFb incoming signals, and ANGPT outgoing signals. Unciliated epithelial cells, ciliated epithelial cells, and macrophages exhibited cell–cell interaction hubs with substantial EGF outgoing signals. Ciliated epithelial cells represented cell–cell interaction hubs with a large number of IGF and TGFb incoming signals. Smooth muscle cells represented lots of PDGF incoming signals and ANGPT and ANGPTL outgoing signals. This study deconvoluted complex intercellular communications at the single-cell level and predicted meaningful biological discoveries, which deepened the understanding of communications among endometrial cells.

Abstract Background Glycolysis plays an essential role in the growth and metastasis of solid cancer and has received increasing attention in recent years. However, the complex regulatory mechanisms of tumour glycolysis remain elusive. This study aimed to explore the molecular effect and mechanism of the noncoding RNA miR-103a-3p on glycolysis in colorectal cancer (CRC). Methods We explored the effects of miR-103a-3p on glycolysis and the biological functions of CRC cells in vitro and in vivo. Furthermore, we investigated whether miR-103a-3p regulates HIF1A expression through the Hippo/YAP1 pathway, and evaluated the role of the miR-103a-3p-LATS2/SAV1-YAP1-HIF1A axis in promoting glycolysis and angiogenesis in CRC cells and contributed to invasion and metastasis of CRC cells. Results We found that miR-103a-3p was highly expressed in CRC tissues and cell lines compared with matched controls and the high expression of miR-103a-3p was associated with poor patient prognosis. Under hypoxic conditions, a high level of miR-103a-3p promoted the proliferation, invasion, migration, angiogenesis and glycolysis of CRC cells. Moreover, miR-103a-3p knockdown inhibited the growth, proliferation, and glycolysis of CRC cells and promoted the Hippo-YAP1 signalling pathway in nude mice in a xenograft model. Here, we demonstrated that miR-103a-3p could directly target LATS2 and SAV1. Subsequently, we verified that TEAD1, a transcriptional coactivator of Yes-associated protein 1 (YAP1), directly bound to the HIF1A promoter region and the YAP1 and TEAD1 proteins co-regulated the expression of HIF1A, thus promoting tumour glycolysis. Conclusions MiR-103a-3p, which is highly expressed in CRC cells, promotes HIF1A expression by targeting the core molecules LATS2 and SAV1 of the Hippo/YAP1 pathway, contributing to enhanced proliferation, invasion, migration, glycolysis and angiogenesis in CRC. Our study revealed the functional mechanisms of miR-103a-3p/YAP1/HIF1A axis in CRC glycolysis, which would provide potential intervention targets for molecular targeted therapy of CRC.

Electrophysiological source imaging (ESI) refers to the process of reconstructing underlying activated sources on the cortex given the brain signal measured by Electroencephalography (EEG) or Magnetoencephalography (MEG). Due to the ill-posed nature of ESI, solving ESI requires the design of neurophysiologically plausible regularization or priors to guarantee a unique solution. Recovering focally extended sources is more challenging, and traditionally uses a total variation regularization to promote spatial continuity of the activated sources. In this paper, we propose to use graph Fourier transform (GFT) based bidirectional long-short term memory (BiLSTM) neural network to solve the ESI problem. The GFT delineates the 3D source space into spatially high, medium and low frequency subspaces spanned by corresponding eigenvectors. The low frequency components can naturally serve as a spatially low-band pass filter to reconstruct extended areas of source activation. The BiLSTM is adopted to learn the mapping relationship between the projection of low-frequency graph space and the recorded EEG. Numerical results show the proposed GFT-BiLSTM outperforms other benchmark algorithms in synthetic data under varied signal-to-noise ratios (SNRs). Real data experiments also demonstrate its capability of localizing the epileptogenic zone of epilepsy patients with good accuracy.

Clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease9 (CRISPR/Cas9) gene editing technology implements precise programming of the human genome through RNA guidance. At present, it has been widely used in the construction of animal tumor models, the study of drug resistance regulation mechanisms, epigenetic control and innovation in cancer treatment. Tumor immunotherapy restores the normal antitumor immune response by restarting and maintaining the tumor-immune cycle. CRISPR/Cas9 technology has occupied a central position in further optimizing anti-programmed cell death 1(PD-1) tumor immunotherapy. In this review, we summarize the recent progress in exploring the regulatory mechanism of tumor immune PD-1 and programmed death ligand 1(PD-L1) based on CRISPR/Cas9 technology and its clinical application in different cancer types. In addition, CRISPR genome-wide screening identifies new drug targets and biomarkers to identify potentially sensitive populations for anti-PD-1/PD-L1 therapy and maximize antitumor effects. Finally, the strong potential and challenges of CRISPR/Cas9 for future clinical applications are discussed.

Abstract Background Salmonella Enteritidis (SE) is one of the major foodborne zoonotic pathogens of worldwide importance which can induce activation of NLRC4 and NLRP3 inflammasomes during infection. Given that the inflammasomes play an essential role in resisting bacterial infection, Salmonella has evolved various strategies to regulate activation of the inflammasome, most of which largely remain unclear. Results A transposon mutant library in SE strain C50336 was screened for the identification of the potential factors that regulate inflammasome activation. We found that T3SS-associated genes invC, prgH, and spaN were required for inflammasome activation in vitro. Interestingly, C50336 strains with deletion or overexpression of Dam were both defective in activation of caspase-1, secretion of IL-1β and phosphorylation of c-Jun N-terminal kinase (Jnk). Transcriptome sequencing (RNA-seq) results showed that most of the differentially expressed genes and enriched KEGG pathways between the C50336-VS-C50336Δdam and C50336-VS-C50336::dam groups overlapped, which includes multiple signaling pathways related to the inflammasome. C50336Δdam and C50336::dam were both found to be defective in suppressing the expression of several anti-inflammasome factors. Moreover, overexpression of Dam in macrophages by lentiviral infection could specifically enhance the activation of NLRP3 inflammasome independently via promoting the Jnk pathway. Conclusions These data indicated that Dam was essential for modulating inflammasome activation during SE infection, there were complex and dynamic interplays between Dam and the inflammasome under different conditions. New insights were provided about the battle between SE and host innate immunological mechanisms.

Abstract N6-methyladenosine (m6A), the most abundant modification in eukaryotic cells, regulates RNA transcription, processing, splicing, degradation, and translation. Circular RNA (circRNA) is a class of covalently closed RNA molecules characterized by universality, diversity, stability and conservatism of evolution. Accumulating evidence shows that both m6A modification and circRNAs participate in the pathogenesis of multiple diseases, such as cancers, neurological diseases, autoimmune diseases, and infertility. Recently, m6A modification has been identified for its enrichment and vital biological functions in regulating circRNAs. In this review, we summarize the role of m6A modification in the regulation and function of circRNAs. Moreover, we discuss the potential applications and possible future directions in the field.

The immune microenvironment has profound impacts on the initiation and progression of colorectal cancer (CRC). Therefore, the goal of this article is to identify two robust immune subtypes in CRC, further provide novel insights for the underlying mechanisms and clinical management. In this study, two CRC immune subtypes were identified using the consensus clustering of immune-related gene expression profiles in the meta-GEO dataset (n = 1,198), and their reproducibility was further verified in the TCGA-CRC dataset (n = 638). Subsequently, we characterized the immune escape mechanisms, gene alterations, and clinical features of two immune subtypes. Cluster 1 (C1) was defined as the “immune cold subtype” with immune cell depletion and deficiency, while cluster 2 (C2) was designed as the “immune hot subtype”, with abundant immune cell infiltration and matrix activation. We also underlined the potential immune escape mechanisms: lack of MHC molecules and defective tumor antigen presentation capacity in C1, increased immunosuppressive molecules in C2. The prognosis and sensitivity to 5-FU, Cisplatin and immunotherapy differed between two subtypes. According to the two immune subtypes, we developed a prognosis associated risk score (PARS) with the accurate performance for predicting the prognosis. Additionally, two nomograms for overall survival (OS) and disease-free survival (DFS) were further constructed to facilitate clinical management. Overall, our research provides new references and insights for understanding and refining the CRC.

Cancer drug resistance has always been a major difficulty in cancer therapy. In the face of drug pressure, resistant cancer cells show complex molecular mechanisms including epigenetic changes to maintain survival. Studies prove that cancer cells exhibit abnormal m6A modification after acquiring drug resistance. m6A modification in the target RNA including non-coding RNA can be a controller to determine the fate and metabolism of RNA by regulating their stability, subcellular localization, or translation. In particular, m6A-modified non-coding RNA plays multiple roles in multiple drug-resistant cancer cells, which can be a target for cancer drug resistance. Here, we provide an overview of the complex regulatory mechanisms of m6A-modified non-coding RNA in cancer drug resistance, and we discuss its potential value and challenges in clinical applications.

The tumor microenvironment (TME), which includes immune cells, fibroblasts, and other components, is the site of tumor cell growth and metastasis and significantly impacts tumor development. Among them, N6-methyladenosine RNA modifications (m6A RNA modifications) are the most abundant internal modifications in coding and non-coding RNAs, which can significantly influence the cancer process and have potential as biomarkers and potential therapeutic targets for tumor therapy. This manuscript reviews the role of m6A RNA modifications in TME and their application in tumor therapy. To some extent, an in-depth understanding of the relationship between TME and m6A RNA modifications will provide new approaches and ideas for future cancer therapy.