Emerging evidence suggests that liquid-liquid phase separation(LLPS)represents a vital and ubiquitous phenomenon underlying the formation of membraneless organelles in eukaryotic cells(also known as biomolecular conde...Emerging evidence suggests that liquid-liquid phase separation(LLPS)represents a vital and ubiquitous phenomenon underlying the formation of membraneless organelles in eukaryotic cells(also known as biomolecular condensates or droplets).Recent studies have revealed evidences that indicate that LLPS plays a vital role in human health and diseases.In this review,we describe our current understanding of LLPS and summarize its physiological functions.We further describe the role of LLPS in the development of human diseases.Additionally,we review the recently developed methods for studying LLPS.Although LLPS research is in its infancy-but is fast-growing-it is clear that LLPS plays an essential role in the development of pathophysiological conditions.This highlights the need for an overview of the recent advances in the field to translate our current knowledge regarding LLPS into therapeutic discoveries.展开更多
Lacking a precise targeting strategy,castration-resistant prostate cancer(CRPC)is still hard to be treat effectively.Exploring treatment options that can accurately target CPRC is an important issue with urgent need.I...Lacking a precise targeting strategy,castration-resistant prostate cancer(CRPC)is still hard to be treat effectively.Exploring treatment options that can accurately target CPRC is an important issue with urgent need.In this study,a novel nanotechnologybased strategy had been developed for the precise target treatment of CRPC.By combining microwaves and photothermal therapy(PTT),this nanoplatform,cmHSP70-PL-AuNC-DOX,targets tumor tissues with outstanding precision and achieves better anti-tumor activity by simultaneously eliciting photothermal and chemotherapeutic effects.From nanotechnology,cmHSP70-modified and thermo-sensitive liposome-coated AuNC-DOX were prepared and used for CRPC-targeted photothermal ablation and chemotherapy.Doxorubicin(DOX)was selected as the chemotherapeutic agent for cytotoxicity.In terms of the curative scheme,prostate tissues were firstly pre-treated with microwaves to induce the expression of heat shock protein 70(HSP70)and its migration to the cell membrane,which was then targeted by HSP70 antibody(cmHSP70)coated on the nanoparticles to achieve accurate drug delivery.The nanoplatform then achieved precise ablation and controlled release of DOX under external near-infrared(NIR)irradiation.Through the implementation,the targeting,cell killing,and safety of this therapeutical strategy had been verified in vivo and in vitro.This work establishes an accurate,controllable,efficient,non-invasive,and safe treatment platform for targeting CRPC,provides a rational design for CRPC’s PTT,and offers new prospects for nanomedicines with great precision.展开更多
Lesions on the DNA template can impact transcription via distinct regulatory pathways.Ionizing radiation(IR)as the mainstay modality for many malignancies elicits most of the cytotoxicity by inducing a variety of DNA ...Lesions on the DNA template can impact transcription via distinct regulatory pathways.Ionizing radiation(IR)as the mainstay modality for many malignancies elicits most of the cytotoxicity by inducing a variety of DNA damages in the genome.How the IR treatment alters the transcription cycle and whether it contributes to the development of radioresistance remain poorly understood.Here,we report an increase in the paused RNA polymerase II(RNAPII),as indicated by the phosphorylation at serine 5 residue of its C-terminal domain,in recurrent nasopharyngeal carcinoma(NPC)patient samples after IR treatment and cultured NPC cells developing IR resistance.Reducing the pool of paused RNAPII by either inhibiting TFIIH-associated CDK7 or stimulating the positive transcription elongation factor b,a CDK9-CycT1 heterodimer,attenuates IR resistance of NPC cells.Interestingly,the poly(ADP-ribosyl)ation of CycT1,which disrupts its phase separation,is elevated in the IR-resistant cells.Mutation of the major poly(ADP-ribosyl)ation sites of CycT1 decreases RNAPII pausing and restores IR sensitivity.Genome-wide chromatin immunoprecipitation followed by sequencing analyses reveal that several genes involved in radiation response and cell cycle control are subject to the regulation imposed by the paused RNAPII.Particularly,we identify the NIMA-related kinase NEK7 under such regulation as a new radioresistancefactor,whose downregulation results in the increased chromosome instability,enabling the development of IR resistance.Overall,our results highlight a novel link between the alteration in the transcription cycle and the acquisition of IR resistance,opening up new opportunities to increase the efficacy of radiotherapy and thwart radioresistance in NpC.展开更多
Introduction: This study is designed to explore the biomechanical principles of posterior bilateral pedicle screw on steps progressively and tight closure on every step for severe angular kyphosis and the indication c...Introduction: This study is designed to explore the biomechanical principles of posterior bilateral pedicle screw on steps progressively and tight closure on every step for severe angular kyphosis and the indication conditions and clinical pathways of above new technique. Materials and Methods: A total of 90 patients have severe angular kyphosis, 37 males and 53 females, with an average age of 47 years. All patients were treated with posterior bilateral pedicle screw and step tight closure for gradual shortening and orthopedic technology. Results: Average intraoperative blood loss was 2089 ml. Average operation time was 326 minutes. Kyphotic angle changed from 90.1° averagely preoperatively to 41.6° averagely postoperatively with an improvement rate of 65%. The distance from C<sub>7</sub> plumb line to posterior upper edge of the S<sub>1</sub> vertebral body was averagely 5.2 mm postoperatively, with a correction rate of 73%. Neurological complications occurred in 2 cases, accounting for 6%. Non-neurological complications occurred in 2 cases, accounting for 6%. Anatomical parameters were significantly improved postoperatively (P < 0.05). All patients were averagely followed up for 28 months. Segments undergoing osteotomy achieved bone fusion, without loss of orthopedic angle. Conclusions: The orthopedic technology of bilateral pedicle screw and step tight closure designed by human physiology and biomechanical principles can protect spinal cord cells from injury to the utmost. To choose an appropriate osteotomy plane during pre-surgical planning can make the repair results closer to the normal function of the spine. Intraoperative nerve root protection, full release and bone graft fusion are effective safeguards to ensure kyphosis correction and to avoid spine lateral offset.展开更多
In a recent study published in Nature,Levo et al.reported that paralogous genes separated by long distances are regulated by specialized DNA stretches called tethering elements,which enable their physical associations...In a recent study published in Nature,Levo et al.reported that paralogous genes separated by long distances are regulated by specialized DNA stretches called tethering elements,which enable their physical associations and co-dependent transcriptional coupling during Drosophila embryogenesis.展开更多
基金This work was supported by a special program from the Ministry of Science and Technology of China(2016YFA0502500 to L.Z.)the Chinese National Natural Science Funds(31925013,31671457,and 91753139 to L.Z.+9 种基金31871405 and 31571460 to FZ.92053114,32070632 to H.L.)Zhejiang Provincial Natural Science Foundation of China under Grant(LBY21H060001 to L.Z.)the Medical and the Medical and Health Research Project of Zhejiang Province(2020RC115 to L.Z.)Jiangsu National Science Foundation(BK20180043 and 19KJA550003 to F.Z.)the Zhejiang Natural Science Fund(LD19C070001to L.Z.)the China National Postdoctoral Program for Innovative Talents(BX2021208 to T.D.)the China Postdoctoral Science Foundation(2021M692350 to T.D.)the Key Project of University Natural Science Foundation of Jiangsu Province(19KJA550003)A project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘Emerging evidence suggests that liquid-liquid phase separation(LLPS)represents a vital and ubiquitous phenomenon underlying the formation of membraneless organelles in eukaryotic cells(also known as biomolecular condensates or droplets).Recent studies have revealed evidences that indicate that LLPS plays a vital role in human health and diseases.In this review,we describe our current understanding of LLPS and summarize its physiological functions.We further describe the role of LLPS in the development of human diseases.Additionally,we review the recently developed methods for studying LLPS.Although LLPS research is in its infancy-but is fast-growing-it is clear that LLPS plays an essential role in the development of pathophysiological conditions.This highlights the need for an overview of the recent advances in the field to translate our current knowledge regarding LLPS into therapeutic discoveries.
基金This study was supported by the National Natural Science Foundation of China(Nos.82172679 and 82104405)Zhejiang Provincial Medicine and Health Science Foundation(No:2021KY010).
文摘Lacking a precise targeting strategy,castration-resistant prostate cancer(CRPC)is still hard to be treat effectively.Exploring treatment options that can accurately target CPRC is an important issue with urgent need.In this study,a novel nanotechnologybased strategy had been developed for the precise target treatment of CRPC.By combining microwaves and photothermal therapy(PTT),this nanoplatform,cmHSP70-PL-AuNC-DOX,targets tumor tissues with outstanding precision and achieves better anti-tumor activity by simultaneously eliciting photothermal and chemotherapeutic effects.From nanotechnology,cmHSP70-modified and thermo-sensitive liposome-coated AuNC-DOX were prepared and used for CRPC-targeted photothermal ablation and chemotherapy.Doxorubicin(DOX)was selected as the chemotherapeutic agent for cytotoxicity.In terms of the curative scheme,prostate tissues were firstly pre-treated with microwaves to induce the expression of heat shock protein 70(HSP70)and its migration to the cell membrane,which was then targeted by HSP70 antibody(cmHSP70)coated on the nanoparticles to achieve accurate drug delivery.The nanoplatform then achieved precise ablation and controlled release of DOX under external near-infrared(NIR)irradiation.Through the implementation,the targeting,cell killing,and safety of this therapeutical strategy had been verified in vivo and in vitro.This work establishes an accurate,controllable,efficient,non-invasive,and safe treatment platform for targeting CRPC,provides a rational design for CRPC’s PTT,and offers new prospects for nanomedicines with great precision.
基金This project has been supported by grants from the National Natural ScienceFoundation of China(32170821 and 92153301 to K.Y.and 32101034 to F.C.)the Ministry of Science and Technologyyof the People's Republic of China(2021YFC2701202)+2 种基金Department of Science&Technology of Hunan Province(2021J10054 and 2019SK1012 to K.Y.,2021J41049 to C.Y.,and the Innovative Team Program 2019RS1010)Central South University(the Innovationdriven Team Project 2020CX016)K.Y.is supported by the National Thousand Talents Program for Young Outstanding Scientists.
文摘Lesions on the DNA template can impact transcription via distinct regulatory pathways.Ionizing radiation(IR)as the mainstay modality for many malignancies elicits most of the cytotoxicity by inducing a variety of DNA damages in the genome.How the IR treatment alters the transcription cycle and whether it contributes to the development of radioresistance remain poorly understood.Here,we report an increase in the paused RNA polymerase II(RNAPII),as indicated by the phosphorylation at serine 5 residue of its C-terminal domain,in recurrent nasopharyngeal carcinoma(NPC)patient samples after IR treatment and cultured NPC cells developing IR resistance.Reducing the pool of paused RNAPII by either inhibiting TFIIH-associated CDK7 or stimulating the positive transcription elongation factor b,a CDK9-CycT1 heterodimer,attenuates IR resistance of NPC cells.Interestingly,the poly(ADP-ribosyl)ation of CycT1,which disrupts its phase separation,is elevated in the IR-resistant cells.Mutation of the major poly(ADP-ribosyl)ation sites of CycT1 decreases RNAPII pausing and restores IR sensitivity.Genome-wide chromatin immunoprecipitation followed by sequencing analyses reveal that several genes involved in radiation response and cell cycle control are subject to the regulation imposed by the paused RNAPII.Particularly,we identify the NIMA-related kinase NEK7 under such regulation as a new radioresistancefactor,whose downregulation results in the increased chromosome instability,enabling the development of IR resistance.Overall,our results highlight a novel link between the alteration in the transcription cycle and the acquisition of IR resistance,opening up new opportunities to increase the efficacy of radiotherapy and thwart radioresistance in NpC.
文摘Introduction: This study is designed to explore the biomechanical principles of posterior bilateral pedicle screw on steps progressively and tight closure on every step for severe angular kyphosis and the indication conditions and clinical pathways of above new technique. Materials and Methods: A total of 90 patients have severe angular kyphosis, 37 males and 53 females, with an average age of 47 years. All patients were treated with posterior bilateral pedicle screw and step tight closure for gradual shortening and orthopedic technology. Results: Average intraoperative blood loss was 2089 ml. Average operation time was 326 minutes. Kyphotic angle changed from 90.1° averagely preoperatively to 41.6° averagely postoperatively with an improvement rate of 65%. The distance from C<sub>7</sub> plumb line to posterior upper edge of the S<sub>1</sub> vertebral body was averagely 5.2 mm postoperatively, with a correction rate of 73%. Neurological complications occurred in 2 cases, accounting for 6%. Non-neurological complications occurred in 2 cases, accounting for 6%. Anatomical parameters were significantly improved postoperatively (P < 0.05). All patients were averagely followed up for 28 months. Segments undergoing osteotomy achieved bone fusion, without loss of orthopedic angle. Conclusions: The orthopedic technology of bilateral pedicle screw and step tight closure designed by human physiology and biomechanical principles can protect spinal cord cells from injury to the utmost. To choose an appropriate osteotomy plane during pre-surgical planning can make the repair results closer to the normal function of the spine. Intraoperative nerve root protection, full release and bone graft fusion are effective safeguards to ensure kyphosis correction and to avoid spine lateral offset.
基金National Natural Science Foundation of China(grants 92053114,32070632 to H.L.and 82172679 to Z.W.)Zhejiang Provincial Natural Science Foundation of China(grant LR21C060002)to H.L.Zhejiang Provincial Medicine and Health Science Foundation(2021KY010)to Z.W.
文摘In a recent study published in Nature,Levo et al.reported that paralogous genes separated by long distances are regulated by specialized DNA stretches called tethering elements,which enable their physical associations and co-dependent transcriptional coupling during Drosophila embryogenesis.
