Cryo-EM structure of DNA-bound Smc5/6 reveals DNA clamping enabled by multi-subunit conformational changes

Structural maintenance of chromosomes (SMC) complexes are essential for chromatin organization and functions throughout the cell cycle. The cohesin and condensin SMCs fold and tether DNA, while Smc5/6 directly promotes DNA replication and repair. The functions of SMCs rely on their abilities to engage DNA, but how Smc5/6 binds and translocates on DNA remains largely unknown. Here, we present a 3.8 Å cryogenic electron microscopy (cryo-EM) structure of DNA-bound Saccharomyces cerevisiae Smc5/6 complex containing five of its core subunits, including Smc5, Smc6, and the Nse1-3-4 subcomplex. Intricate interactions among these subunits support the formation of a clamp that encircles the DNA double helix. The positively charged inner surface of the clamp contacts DNA in a nonsequence-specific manner involving numerous DNA binding residues from four subunits. The DNA duplex is held up by Smc5 and 6 head regions and positioned between their coiled-coil arm regions, reflecting an engaged-head and open-arm configuration. The Nse3 subunit secures the DNA from above, while the hook-shaped Nse4 kleisin forms a scaffold connecting DNA and all other subunits. The Smc5/6 DNA clamp shares similarities with DNA-clamps formed by other SMCs but also exhibits differences that reflect its unique functions. Mapping cross-linking mass spectrometry data derived from DNA-free Smc5/6 to the DNA-bound Smc5/6 structure identifies multi-subunit conformational changes that enable DNA capture. Finally, mutational data from cells reveal distinct DNA binding contributions from each subunit to Smc5/6 chromatin association and cell fitness. In summary, our integrative study illuminates how a unique SMC complex engages DNA in supporting genome regulation.

Structural maintenance of chromosomes (SMC) complexes are essential genome regulators in both prokaryotes and eukaryotes. In eukaryotes, the cohesin and condensin SMC complexes organize DNA, while the Smc5/6 complex (referred to as Smc5/6) directly regulates DNA replication and repair (1). At the structural level, SMC complexes share similarities while possessing unique attributes (1). Each complex contains a pair of SMC subunits and a set of non-SMC subunits. The SMC subunits define the tripartite filamentous architecture of the complex: their approximal 50-nm long coiled coil arm region connects their dimerized hinge and adenosine triphosphatase (ATPase) head regions (1). A non-SMC kleisin subunit uses its N- and C-terminal domains to link the head of one SMC to the head-proximal arm region (neck) of another SMC, forming a trimeric SMC-kleisin structure. In cohesin and condensin, two large U-shaped HEAT (Huntington, elongation factor 3, PR65/A, TOR) repeat HAWK (HEAT proteins associated with kleisins) subunits attach to the middle region of the kleisin. By contrast, the Smc5/6 kleisin (Nse4) binds to smaller WH (winged helix)-containing KITE (kleisin interacting tandem WH elements) subunits (Nse1 and Nse3) (2).SMC-mediated functions depend on interactions with DNA. Recent cryogenic electron microscopy (cryo-EM) structures of DNA-bound cohesin and condensin revealed that their HAWK subunits and the SMC head-neck regions form a clamp to enclose a single DNA double helix (3–7). DNA clamping can be critical for cohesin and condensin to extrude DNA loops for chromatin folding (5, 7–9). DNA loop extrusion additionally requires arm bending at a region called the elbow, which is found in both cohesin and condensin (5, 7–9). By contrast, a lack of arm bending in Smc5/6 was suggested by negative stain EM and cross-linking mass spectrometry (CLMS) data (10–14). Since Smc5/6 does not contain HAWK proteins nor shows arm-bending, it has remained unclear how Smc5/6 engages DNA to accomplish its multiple functions.Here we address the molecular mechanisms by which this unique SMC complex binds DNA using an integrative approach, coupling a cryo-EM-based structural characterization with CLMS analyses and functional investigation. Our atomic structure of a DNA-bound Saccharomyces cerevisiae Smc5/6 complex reveals that the head-neck Smc5-6 regions and the Nse1-3-4 subcomplex together form a clamp entrapping the DNA helix. The structure further reveals protein subunit folds and association, as well as how the subunits collaborate to entrap DNA. Comparison of CLMS analyses of DNA-free Smc5/6 with the structure of the DNA-bound Smc5/6 unveils large scale, multi-subunit conformational changes that enable Smc5/6 to encircle DNA. Finally, our mutational data suggest distinct contributions from each of the DNA binding regions to Smc5/6 chromatin association and cellular fitness. Comparison of our findings with those of other SMCs reveals that diverse SMC complexes use a similar DNA clamping strategy despite structural differences, and that Smc5/6 possesses unique features distinct from cohesin, condensin, and prokaryotic SMCs. Our work lays the foundation for an in-depth understanding of how Smc5/6 fulfills unique roles in genome protection.     

新型冠状病毒肺炎后潜水员适潜性评估

新型冠状病毒肺炎（COVID?19）自2019年底爆发以来,对人类生命健康造成了极其严重的危害。作为一种呼吸系统疾病,COVID?19对全身几乎所有器官都会产生影响,其中最主要的受累器官为肺和心脏。随着COVID?19 “康复”患者数量不断增加,越来越多的证据表明,因COVID?19而住院治疗得到“康复”的患者中有相当大比例的人群存在着后遗症,主要表现为呼吸系统和心血管系统的症状。对于潜水员,COVID-19后运动耐受、心肺功能的恢复对于其适潜性具有重要的影响。一些组织和机构对于潜水员COVID-19后的适潜性评估,发布了指南。本文对COVID-19后呼吸和心血管后遗症以及相关的适潜性评估方案进行简要介绍,并基于已有的相关要求和我国实际,初步提出我国潜水员COVID-19后的适潜性评估要求。     

Human influenza A (H5N1) cases, urban areas of People's Republic of China, 2005-2006

We investigated potential sources of infection for 6 confirmed influenza A (H5N1) patients who resided in urban areas of People's Republic of China. None had known exposure to sick poultry or poultry that died from illness, but all had visited wet poultry markets before illness.     

辽宁省家蝇抗药性研究

目的：了解辽宁省家蝇对常用杀虫剂的抗药性状况。方法：常规点滴法。结果：在供试的４种杀虫剂中,以溴氰菊酯的抗药性最为突出,４地家蝇对该杀虫剂的抗性系数分别为１１８．３、５９．７、３４和１２．８;以下依次为顺式氯氰菊酯、二氯苯醚菊酯和敌敌畏,抗性系数分别为３８．２、２８．７、２４．５、１４．２和４８．７、２９．２、２１．４、１４．８以及２６．６、２２．５、２０．７、１６．８。结论：４地家蝇对供试的４种     

Unraveling the Phase Stability and Physical Property of Modulated Martensite in Ni2Mn1.5In0.5 Alloys by First-Principles Calculations

Large magnetic field-induced strains can be achieved in modulated martensite for Ni-Mn-In alloys; however, the metastability of the modulated martensite imposes serious constraints on the ability of these alloys to serve as promising sensor and actuator materials. The phase stability, magnetic properties, and electronic structure of the modulated martensite in the Ni₂Mn_1.5In_0.5 alloy are systematically investigated. Results show that the 6M and 5M martensites are metastable and will eventually transform to the NM martensite with the lowest total energy in the Ni₂Mn_1.5In_0.5 alloy. The physical properties of the incommensurate 7M modulated martensite (7M–IC) and nanotwinned 7M martensite (7M−(52¯)2) are also calculated. The austenite (A) and 7M−(52¯)2 phases are ferromagnetic (FM), whereas the 5M, 6M, and NM martensites are ferrimagnetic (FIM), and the FM coexists with the FIM state in the 7M–IC martensite. The calculated electronic structure demonstrates that the splitting of Jahn–Teller effect and the strong Ni–Mn bonding interaction lead to the enhancement of structural stability.     

无症状心肌缺血与心绞痛患者血浆内皮素-1变化的临床研究

目的探讨无症状心肌缺血与心绞痛患者血浆内皮素-1变化的临床意义。方法采用放射免疫法测定ET-1含量,并查心电图及超声心动图。结果SMI与对照组无显著差异,其病变程度与ET-1变化呈零相关,AP组ET-1明显高于对照组,其病变程度与ET-1变化呈正相关,治疗后ET-1降至正常水平,AP非发作期ET-1亦有显著差异。结论结果显示血浆ET-1水平可能在冠心病心肌缺血类型和临床症状等方面起作用。     

Production of butanol from lignocellulosic biomass: recent advances,challenges, and prospects

Due to energy and environmental concerns, biobutanol is gaining increasing attention as an alternative renewable fuel owing to its desirable fuel properties. Biobutanol production from lignocellulosic biomass through acetone–butanol–ethanol (ABE) fermentation has gained much interest globally due to its sustainable supply and non-competitiveness with food, but large-scale fermentative production suffers from low product titres and poor selectivity. This review presents recent developments in lignocellulosic butanol production, including pretreatment and hydrolysis of hemicellulose and cellulose during ABE fermentation. Challenges are discussed, including low concentrations of fermentation sugars, inhibitors, detoxification, and carbon catabolite repression. Some key process improvements are also summarised to guide further research and development towards more profitable and commercially viable butanol fermentation.

Due to energy and environmental concerns, biobutanol is gaining increasing attention as an alternative renewable fuel owing to its desirable fuel properties.     

PDCA在住院医师规范化培训师资教学查房督导中的应用

目的探讨PDCA循环在师资教学查房督导中运用成效,充分发挥督导作用,从而提升师资教学查房质量。方法将2019年师资作为对照组,采用旧的教学查房督导方法,2020年师资作为实验组,在教学查房督导中采取PDCA循环,每季度循环1次,对比2组师资查房考核成绩。结果对照组师资教学查房成绩为86.1175±5.51864,实验组师资教学查房成绩为87.9536±4.20446,差异具有统计学意义(P<0.05);趋势图显示对照组第1季度至第4季度师资查房成绩分别为87.6、84.95、85.51、86.29,成绩无明显差异,而实验组中第1季度至第4季度师资查房成绩分别为86.8、87.32、88.36、90.15,成绩呈现季度递增。2年度教学查房共性失分点季度改变对比趋势图中显示,PDCA循环后英语教授、检查护理问题、病例特点总结得分呈现季度递增。结论将PDCA循环运用于在师资教学查房督导中,可以有效解决查房中存在的实际问题,使整改更具有目的性,有效提高整改质量,有助于稳步提升师资教学查房水平,具有重要参考意义。     

护理人员对慢性病移动健康管理体验的Meta整合

目的 系统评价护理人员利用移动健康进行慢性病管理的体验,为改善移动健康管理服务提供依据。方法 计算机检索Medline (Ovid)、Embase、Cochrane Library、Web of Science、CINAHL、中国知网、万方数据库和维普数据库,检索有关护理人员利用移动健康进行慢性病管理体验的质性研究,检索时限为建库至2023年2月。依据JBI质性研究质量评价标准评价文献质量,采用Meta整合方法对原始研究结果进行整合。结果 共纳入8篇文献,提炼出66个原始研究结果,归纳为10个新类别,综合为2个整合。护士使用移动健康进行慢性病管理感知益处;护士使用移动健康进行慢性病管理感知障碍。结论 移动健康有助于护理人员进行慢性病管理,但其使用仍存在一些障碍,应从移动健康的易用性、移动健康与传统管理手段的融合、健全相关制度保障等方面完善。     

中枢神经系统炎性脱髓鞘损伤髓鞘再生的细胞学治疗

多发性硬化（MS）损伤的病理特征是髓鞘脱失。髓鞘再生近年来被认为是自身免疫性脱髓鞘疾病，尤其是MS治疗中非常有前景的方向。髓鞘再生治疗可分为内源性和外源性，所以大量的临床和实验研究都集中于通过外源性移植细胞或通过促进内源性再生机制来获得中枢神经系统脱髓鞘区域的髓鞘再生，并均取得一定的成功。本文对近年来MS髓鞘再生的细胞学治疗的现状和神经科学背景及再生髓鞘治疗的将来可能发展方向进行了评述。