Association between the Missense Variant of PLCE1 and the Risk of Colorectal Cancer

Colorectal cancer(CRC) is a malignancy of the digestive system that poses a serious threat to human life and health. Approximately 1.93 million new CRC cases were identified in 2020, including0.94 million CRC-related deaths worldwide, which accounted for 10% of the global cancer incidence and 9.4% of all cancer-related fatalities[1].

Proteasomal and lysosomal degradation for specific and durable suppression of immunotherapeutic targets

Cancer immunotherapy harness the body's immune system to eliminate cancer,by using a broad panel of soluble and membrane proteins as therapeutic targets.Immunosuppression signaling mediated by ligand-receptor interaction may be blocked by monoclonal antibodies,but because of repopulation of the membranevia intracellular organelles,targets must be eliminated in whole cells.Targeted protein degradation,as exemplified in proteolysis targeting chimera(PROTAC)studies,is a promising strategy for selective inhibition of target proteins.The recently reported use of lysosomal targeting molecules to eliminate immune checkpoint proteins has paved the way for targeted degradation of membrane proteins as crucial anti-cancer targets.Further studies on these molecules'modes of action,target-binding"warheads",lysosomal sorting signals,and linker design should facilitate their rational design.Modifications and derivatives may improve their cell-penetrating ability and thein vivo stability of these pro-drugs.These studies suggest the promise of alternative strategies for cancer immunotherapy,with the aim of achieving more potent and durable suppression of tumor growth.Here,the successes and limitations of antibody inhibitorsin cancer immunotherapy,as well as research progress on PROTAC-and lysosomal-dependent degradation of target proteins,are reviewed.

Pyroptosis-related genes play a significant role in the prognosis of gastric cancer

BACKGROUND Pyroptosis is an inflammatory form of programmed cell death,which has been shown to be related to the prognosis of many tumors.However,its role in gastric cancer(GC)is not fully understood.AIM To evaluate the expression of pyroptosis-related genes in GC and its correlation with prognosis.METHODS We constructed prognostic multigene markers of differentially expressed genes associated with pyroptosis by least absolute contraction and selection operator Cox regression.The risk model was analyzed by Kaplan-Meier curve,two-sided log-rank test and functional enrichment analysis.RESULTS Sixty-three pyroptosis-related genes were differentially expressed in tumor tissues and adjacent nontumor tissues.Based on these differentially expressed genes,5 gene signature were constructed and all GC patients were classified into two risk groups.Kaplan-Meier survival curve showed that the overall survival(OS)of patients in the high-risk group was significantly lower than that of the low-risk group.Multivariate Cox regression analyses showed that the risk score was an independent risk factor for OS.Receiver operating characteristic curve analysis confirmed the predictive ability of the model.External validation indicated increased OS in the low-risk group.The immune function and immune cell scores of the high-risk group were generally higher than those of the low-risk group.CONCLUSION Pyroptosis-related genes play a significant role in tumor immune microenvironment.This novel model,which contains 5 pyroptosis-related genes,is an independent predicting factor for OS in GC patients,and may help to evaluate the prognosis of GC.

Clinical Significance and Function of MALAT1 Gene Expression and the rs619586 Polymorphism in Colorectal Cancer

Colorectal cancer(CRC) is a malignant tumor of the digestive system that poses a serious threat to human health. In 2018, around 1.8 million people were newly diagnosed with CRC, and 881,000 people died from the disease. The identification of CRCrelated genes and genetic polymorphisms will aid in the prevention and treatment of this disease.

Functional PEGylated bacteria reinforce the intestinal mucosal barrier by effective mucus-penetration

Recently,the intestinal mucosal barrier has attracted considerable attention from the scientific community.With the in-depth exploration of this barrier,it has become increasingly clear that the mucosal barrier is a complicated system consisting of multiple components.In general,the intestinal mucosal barrier mainly consists of intestinal epithelial cells covered with a highly viscous gellike layer containing symbiotic microorganisms and rich antimicrobial agents that can effectively protect the human body from the invasion of harmful microorganisms and toxins.

Bio-inspired dual-adhesive particles from microfluidic electrospray for bone regeneration

Bioadhesive hydrogels have demonstrated great potential in bone regeneration.However,the relatively simple adhesion mechanism and lack of intricate structural design restrict their further applications.Herein,inspired by multiple adhesion mechanisms of pollen particles and marine mussels,we present a novel type of dual-adhesive hydrogel particles fabricated from microfluidic electrospray for bone regeneration.As the particles are rapidly solidified via liquid nitrogen-assisted cryogelation,they exhibit pollen-mimicking hierarchical porous morphology and gain structure-related adhesion.Besides,the particles are further coated by polydopamine(PDA)to achieve molecular-level adhesion especially to physiological wet surfaces of bone issues.Benefiting from such dual-adhesion mechanisms,the particles can strongly adhere to bone tissue defects,and function as porous scaffolds.Moreover,the dual-adhesive particles can serve as effective vehicles to release key growth factors more than two weeks.In vitro experiments showed that the growth factors-loaden particles have excellent biocompatibility and more significantly promote angiogenesis(~2-fold)and osteogenic differentiation(~3-fold)than control.In vivo experiments indicated that the dual-adhesive particles could significantly enhance bone regeneration(~4-fold)than control by coupling osteogenesis and angiogenesis effects.Based on these features,the bio-inspired dual-adhesive particles have great potentials for bone repair and wound healing applications.

Cryo-shocked cancer cell microgels for tumor postoperative combination immunotherapy and tissue regeneration

Prevention of recurrence/metastasis and tissue regeneration are critical for post-surgery treatment of malignant tumors. Here, to address these needs, a novel type of microgel co-loading cryo-shocked cancer cells, immunoadjuvant, and immune checkpoint inhibitor is presented by microfluidic electrospray technology and liquid nitrogen treatment. Owing to the encapsulation of cryo-shocked cancer cells and immunoadjuvant, the microgels can recruit dendritic cells and activate them in situ, and evoke a robust immune response. Moreover, with the combination of the immune checkpoint inhibitor, the antitumor immune response is further enhanced by inhibiting the interaction of PD1 and PDL1. With this, the excellent anti-recurrence and anti-metastasis efficacy of the microgels are demonstrated in an orthotopic breast cancer mouse model. Besides, because of the excellent biocompatibility and appropriate degradation performance, the microgels can provide support for normal cell adhesion and growth, which is beneficial to tissue reconstruction. These properties indicate the great value of the cryo-shocked cancer cell microgels for efficient tumor postoperative combination immunotherapy and tissue regeneration.

DNA-Polyelectrolyte Composite Responsive Microparticles for Versatile Chemotherapeutics Cleaning

Drug therapy is among the most widely used methods in disease treatment.However,there remains a trade-off problem between drug dosage and toxicity.Blood purification by adsorption of excessive drugs during clinical treatment could be a solution for enhancing therapeutic efficacy while maintaining normal body function.Here,inspired by the intrinsic action mechanism of chemotherapeutic agents in targeting DNA in the cell nucleus,we present DNA-polyelectrolyte composite responsive microparticles for chemotherapeutics cleaning.The presence of DNA in the microparticles enabled the adsorption of multiple common chemotherapy drugs.Moreover,the microparticles are endowed with a porous structure and a photothermal-responsive ability,both of which contribute to improved adsorption by enhancing the contact of the microparticles with the drug solution.On the basis of that,the microparticles are integrated into a herringbone-structured microfluidic chip.The fluid mixing capacity and the enhanced drug cleaning efficiency of the microfluidic platform are validated on-chip.These results indicate the value of the DNA-polyelectrolyte composite responsive microparticles for drug capture and blood purification.We believe the microparticle-integrated microfluidic platform could provide a solution for settling the dosage-toxicity trade-off problems in chemotherapy.

Bioinspired Jellyfish Microparticles from Microfluidics

Nonspherical particles have attracted increasing interest because of their shape anisotropy.However,the current methods to prepare anisotropic particles suffer from complex generation processes and limited shape diversity.Here,we develop a piezoelectric microfluidic system to generate complex flow configurations and fabricatejellyfish-like microparticles.In this delicate system,the piezoelectric vibration could evolve a jellyfish-like flow configuration in the microchannel and the in situ photopolymerization could instantly capture the flow architecture.The sizes and morphologies of the particles are precisely controlled by tuning the piezoelectric and microfluidic parameters.Furthermore,multi-compartmental microparticles with a dual-layer structure are achieved by modifying the injecting channel geometry.Moreover,such unique a shape endows the particles with flexible motion ability especially when stimuliresponsive materials are incorporated.On the basis of that,we demonstrate the capability of the jellyfish-like microparticles in highly efficient adsorption of organic pollutants under external control.Thus,it is believed that such jellyfish-like microparticles are highly versatile in potential applications and the piezoelectricintegrated microfluidic strategy could open an avenue for the creation of such anisotropic particles.

TBC1D15 deficiency protects against doxorubicin cardiotoxicity via inhibiting DNAPKcs cytosolic retention and DNA damage

Clinical application of doxorubicin(DOX)is heavily hindered by DOX cardiotoxicity.Several theories were postulated for DOX cardiotoxicity including DNA damage and DNA damage response(DDR),although the mechanism(s)involved remains to be elucidated.This study evaluated the potential role of TBC domain family member 15(TBC1D15)in DOX cardiotoxicity.Tamoxifen-induced cardiac-specific Tbcldi5 knockout(Tbcldi5^(CKO))or Tbcldi5 knockin(Tbcldi5^(CKI))male mice were challenged with a single dose of DOx prior to cardiac assessment 1 week or 4 weeks following DOX challenge.Adenoviruses encoding TBC1D15 or containing shRNA targeting Tbcld15 were used for Tbcld15 overexpression or knockdown in isolated primary mouse cardiomyocytes.Our results re-vealed that DOX evoked upregulation of TBC1D15 with compromised myocardial function and overt mortality,the effects of which were ameliorated and accentuated by Tbcldi5 deletion and Tbcld15 overexpression,respectively.DOX overtly evoked apoptotic cell death,the effect of which was alleviated and exacerbated by Tbcld15 knockout and overexpression,respectively.Meanwhile,DOX provoked mitochondrial membrane potential collapse,oxidative stress and DNA damage,the effects of which were mitigated and exacerbated by Tbcld15 knockdown and overexpression,respectively.Further scrutiny revealed that TBC1D15 fostered cytosolic accumulation of the cardinal DDR element DNA-dependent protein kinase catalytic subunit(DNA-PKcs).Liquid chromatography-tandem mass spectrometry and coimmunoprecipitation denoted an interaction between TBCID15 and DNA-PKcs at the segment 594-624 of TBC1D15.Moreover,overexpression of TBC1D15 mutant(A594-624,deletion of segment 594-624)failed to elicit accentuation of DOX-induced cytosolic retention of DNA-PKcs,DNA damage and cardiomyocyte apoptosis by TBC1D15 wild type.However,Tbcld15 deletion ameliorated DOXinduced cardiomyocyte contractile anomalies,apoptosis,mitochondrial anomalies,DNA damage and cytosolic DNA-PKcs accumulation,which were canceled off by DNA-PKcs inhibition or ATM activation.Taken together,our findings denoted a pivotal role for TBCID15 in DOX-induced DNA damage,mitochondrial injury,and apoptosis possibly through binding with DNA-PKcs and thus gate-keeping its cytosolic retention,a route to accentuation of cardiac contractile dysfunction in DOX-induced cardiotoxicity.

CBX4 deletion promotes tumorigenesis under Kras^(G12D) background by inducing genomic instability

Chromobox protein homolog 4(CBX4)is a component of the Polycomb group(PcG)multiprotein Polycomb repressive complexes 1(PRC1),which is participated in several processes including growth,senescence,immunity,and tissue repair.CBX4 has been shown to have diverse,even opposite functions in different types of tissue and malignancy in previous studies.

Coronaviruses RNA interacts with host miR-500a-5p and miR-501-5p to regulate multiple pathways

The Coronavirus disease is the contagious disease. Clinical manifests vary from no symptoms, upper and lower respiratory tract infections, and even severe acute respiratory distress syndrome and multiple organs failure. Recently, three of new beta-coronaviruses have emerged to cause serious and widespread illness and death, such as the Severe Acute Respiratory Syndrome Coronaviruses (SARS-CoV), Middle East Respiratory Syndrome Coronaviruses (MERS-CoV), and 2019-nCoV (the causative pathogen of Coronavirus Disease 2019 (COVID-19). The COVID-19 is continuing to spread globally. However, the detailed molecular mechanisms have not yet been fully clarified. Since the similarity of the pathological features among 2019-nCoV, SARS-CoV and MERS-CoV, we could speculate the biological features of current COVID-19 by researching those of MERS-CoV and SARS-CoV. Therefore, we analyzed expression levels of miRNA and mRNA profiles of MERS-CoV, SARS-CoV and 2019-nCoV from five public GEO datasets (Table S1). As a result, we found 16 miRNAs potentially target a group of hub genes clustering together to tune the immune response. Notably, viral RNAs have the ability to sponge miR-500a-5p and miR-501-5p, indicating viral RNAs sequestering these two miRNAs to trigger genes expression and contribute to pathogenesis. We hope this study will pave the way to better understand 2019-nCoV pathogenesis and develop the innovative therapeutics.

Pollen-Inspired Photonic Barcodes with Prickly Surface for Multiplex Exosome Capturing and Screening

Exosomes,which play an important role in intercellular communication,are closely related to the pathogenesis of disease.However,their effective capture and multiplex screening are still challenging.Here,inspired by the unique structure of pollens,we present novel photonic crystal(PhC)barcodes with prickly surface by hydrothermal synthesis for multiplex exosome capturing and screening.These pollen-inspired PhC barcodes are imparted with extremely high specific surface area and excellent prickly surface nanostructures,which can improve the capture rate and detection sensitivity of exosomes.As the internal periodic structures are kept during the hydrothermal synthesis process,the pollen-inspired PhC barcodes exhibit obvious and stable structural colors for identification,which enables multiplex detection of exosomes.Thus,the pollen-inspired PhC barcodes can not only effectively capture and enrich cancer-related exosomes but also support multiplex screening of exosomes with high sensitivity.These features make the prickly PhC barcodes ideal for the analysis of exosomes in medical diagnosis.

Kruppel-like factor 10 protects against acute viral myocarditis by negatively regulating cardiac MCP-1 expression

Viral myocarditis(VMC)is a cardiac disease associated with myocardial inflammation and injury induced by virus infection.Cardiomyocytes have recently been regarded as key players in eliciting and modulating inflammation within the myocardium.Kruppel-like factor 10(KLF10)is a crucial regulator of various pathological processes and plays different roles in a variety of diseases.However,its role in VMC induced by coxsackievirus B3(CVB3)infection remains unknown.In this study,we report that cardiac KLF10 confers enhanced protection against viral myocarditis.We found that KLF10 expression was downregulated upon CVB3 infection.KLF10 deficiency enhanced cardiac viral replication and aggravated VMC progress.Bone marrow chimera experiments indicated that KLF10 expression in nonhematopoietic cells was involved in the pathogenesis of VMC.We further identified MCP-1 as a novel target of KLF10 in cardiomyocytes,and KLF10 cooperated with histone deacetylase 1(HDAC1)to negatively regulate MCP-1 expression by binding its promoter,leading to activation of MCP-1 transcription and recruitment of Ly6C^(high) monocytes/macrophages into the myocardium.This novel mechanism of MCP-1 regulation by KLF10 might provide new insights into the pathogenesis of VMC and a potential therapeutic target for VMC.

Chinese herb microneedle patch for wound healing

Traditional Chinese medicine and Chinese herbs have a demonstrated value for disease therapy and sub-health improvement.Attempts in this area tend to develop new forms to make their applications more convenient and wider.Here,we propose a novel Chinese herb microneedle(CHMN)patch by integrating the herbal extracts,Premna microphylla and Centella asiatica,with microstructure of microneedle for wound healing.Such path is composed of sap extracted from the herbal leaves via traditional kneading method and solidified by plant ash derived from the brine induced process of tofu in a well-designed mold.Because the leaves of the Premna microphylla are rich in pectin and various amino acids,the CHMN could be imparted with medicinal efficacy of heat clearing,detoxicating,detumescence and hemostatic.Besides,with the excellent pharmaceutical activity of Asiatic acid extracted from Centella asiatica,the CHMN is potential in promoting relevant growth factor genes expression in fibroblasts and showing excellent performance in anti-oxidant,anti-inflammatory and anti-bacterial activity.Taking advantages of these pure herbal compositions,we have demonstrated that the derived CHMN was with dramatical achievement in anti-bacteria,inhibiting inflammatory,collagen deposition,angiogenesis and tissue reconstruction during the wound closure.These results indicate that the integration of traditional Chinese herbs with progressive technologies will facilitate the development and promotion of traditional Chinese medicine in modern society.

Thriving microfluidic technology

Microfluidics refers to the technology that processes a small volume of fluids and exploits their specific properties at the sub-microliter scale in microchannels.When the fluid dimensions scale down to the microscale level,the specific surface area of the fluids increases,thus exhibiting behaviors divergent from those of the bulk fluids.Compared with the bulk systems,microfluidics technology offers many salient advantages.

Tiny water droplet with huge power

Water occupies 70% of the earth’s surface.It not only supports our life but also contains abundant energy.Water exists in different forms,including in oceans,rivers,and lakes,where they can evaporate upon solar radiation.The temperature difference in the atmosphere acts like a pump to pull up the evaporated water,through which the water in the cloud obtains the gravitational potential energy.Such energy then transfers into kinetic energy in the raindrops falling down[1].How to utilize the raindrops’energy has long been a fascinating question.Although traditional hydraulic power generation is more applicable to continuous flow of water,it becomes inefficient with relatively less rainfall supply[2].Therefore,a new strategy to harvest the kinetic energy stored in the form of raindrops is highly desired.

Living Materials for Regenerative Medicine

Regenerative medicine has been attracting tremendous attention during the past few decades because it is promising in overcoming the limitations of donor shortage and immune complications in direct transplantations.The ongoing progress in this field calls for the rapid growth of living materials,which consist of live biological agents and can be designed together with synthetic materials to meet the application demands of regenerative medicine.In this review,we present a summary of the state-of-the-art progress of living materials that are applied in regenerative medicine.We first introduce the advanced engineering approaches that are employed to prepare living materials containing live cells,typically including genetic engineering,cell coating,microfluidics,and bioprinting,etc.Afterwards,we enumerate different application aspects of living materials in regenerative medicine,including tissue scaffold,cell therapy,tissue models,and so on.Finally,we give a concise conclusion and provide a perspective of this field.

Boston Ivy-Inspired Disc-Like Adhesive Microparticles for Drug Delivery

Microparticles with strong adherence are expected as efficient drug delivery vehicles.Herein,we presented an ingenious hydrogel microparticle recapitulating the adhesion mechanism of Boston ivy tendrils adhesive discs(AD)for durable drug delivery.The particles were achieved by replicating a silica colloidal crystal aggregates assembled in a droplet template after rapid solvent extraction.Due to their unique shape,the nanostructure,and the sticky hydrogel component,such novel microparticles exhibited prominent adhesive property to the wet tissue environment.It was demonstrated that the bioinspired microcarriers loading with dexamethasone had a good therapeutic effect for ulcerative colitis due to the strong adhesion ability for prolonging the maintenance of drug availability.These virtues make the biomimetic microparticles potentially ideal for many practical clinical applications,such as drug delivery,bioimaging,and biodiagnostics.

Responsive Janus Structural Color Hydrogel Micromotors for Label-Free Multiplex Assays

Micromotors with self-propelling ability demonstrate great values in highly sensitive analysis.Developing novel micromotors to achieve label-free multiplex assay is particularly intriguing in terms of detection efficiency.Herein,structural color micromotors(SCMs)were developed and employed for this purpose.The SCMs were derived from phase separation of droplet templates and exhibited a Janus structure with two distinct sections,including one with structural colors and the other providing catalytic selfpropelling functions.Besides,the SCMs were functionalized with ion-responsive aptamers,through which the interaction between the ions and aptamers resulted in the shift of the intrinsic color of the SCMs.It was demonstrated that the SCMs could realize multiplex label-free detection of ions based on their optical coding capacity and responsive behaviors.Moreover,the detection sensitivity was greatly improved benefiting from the autonomous motion of the SCMs which enhanced the ion-aptamer interactions.We anticipate that the SCMs can significantly promote the development of multiplex assay and biomedical fields.