‘Relax and Repair’ to restrain aging

The maintenance of genomic integrity requires the precise identification and repair of DNA damage. Since DNA is packaged and condensed into higher order chromatin, the events associated with DNA damage recognition and repair are orchestrated within the layers of chromatin. Very similar to transcription, during DNA repair, chromatin remodelling events and histone modifications act in concert to ‘open’ and relax chromatin structure so that repair proteins can gain access to DNA damage sites. One such histone mark critical for maintaining chromatin structure is acetylated lysine 16 of histone H4 (AcH4K16), a modification that can disrupt higher order chromatin organization and convert it into a more ‘relaxed’ configuration. We have recently shown that impaired H4K16 acetylation delays the accumulation of repair proteins to double strand break (DSB) sites which results in defective genome maintenance and accelerated aging in a laminopathy-based premature aging mouse model. These results support the idea that epigenetic factors may directly contribute to genomic instability and aging by regulating the efficiency of DSB repair. In this article, the interplay between epigenetic misregulation, defective DNA repair and aging is discussed

[N′-(3-Meth­oxy-2-oxidobenzyl­idene)nicotinohydrazidato]diphenyl­tin(IV)

The asymmetric unit of the title compound, [Sn(C6H5)2(C14H11N3O3)], contains two crystallographically independent mol­ecules that differ predominantly in the torsion of the phenyl rings. In both mol­ecules, the SnIV ion is in a distored trigonal-bipyramidal geometry. The Sn—O distances are in the range 2.055 (2)–2.143 (2) Å

TLR ligand-induced podosome disassembly in dendritic cells is ADAM17 dependent

Toll-like receptor (TLR) signaling induces a rapid reorganization of the actin cytoskeleton in cultured mouse dendritic cells (DC), leading to enhanced antigen endocytosis and a concomitant loss of filamentous actin–rich podosomes. We show that as podosomes are lost, TLR signaling induces prominent focal contacts and a transient reduction in DC migratory capacity in vitro. We further show that podosomes in mouse DC are foci of pronounced gelatinase activity, dependent on the enzyme membrane type I matrix metalloprotease (MT1-MMP), and that DC transiently lose the ability to degrade the extracellular matrix after TLR signaling. Surprisingly, MMP inhibitors block TLR signaling–induced podosome disassembly, although stimulated endocytosis is unaffected, which demonstrates that the two phenomena are not obligatorily coupled. Podosome disassembly caused by TLR signaling occurs normally in DC lacking MT1-MMP, and instead requires the tumor necrosis factor α–converting enzyme ADAM17 (a disintegrin and metalloprotease 17), which demonstrates a novel role for this “sheddase” in regulating an actin-based structure

Association of Lumican Gene with Susceptibility to Pathological Myopia in the Northern Han Ethnic Chinese

Pathological myopia is a severe hereditary ocular disease leading to blindness. It is urgent and very important to find the pathogenesis and therapy for this disease. The purpose of the study is to analyze sequences of lumican and decorin genes with pathological myopia(PM) and control subjects to verify the relationship between lumican, decorin genes and PM in Northern Han Chinese. We collected and analyzed the blood samples of 94 adults (including 12 pedigree cases and 82 sporadic cases) with PM and 90 controls in the northern Han ethnic Chinese. Genotyping was performed by direct sequencing after polymerase chain reaction(PCR) amplification and allele frequencies were tested for Hardy-Weinberg equilibrium. Univariate analysis revealed significant differences between two groups for three SNPs: rs3759223 (C → T) and rs17853500 (T → C) of the lumican gene and rs74419 (T → C) of decorin gene with (P < .05) for all their genotype distribution and allele frequency. There is no significant difference for incidence of these mutations between pedigree and sporadic group (P > .05). The results suggested that the sequence variants in 5′-regulatory region of lumican gene and 3'UTR of decorin gene were associated significantly with PM in Northern Han Chinese. Further studies are needed to confirm finally whether the two genes are the virulence genes of PM

CTCF Mediates the Cell-Type Specific Spatial Organization of the Kcnq5 Locus and the Local Gene Regulation

Chromatin loops play important roles in the dynamic spatial organization of genes in the nucleus. Growing evidence has revealed that the multivalent functional zinc finger protein CCCTC-binding factor (CTCF) is a master regulator of genome spatial organization, and mediates the ubiquitous chromatin loops within the genome. Using circular chromosome conformation capture (4C) methodology, we discovered that CTCF may be a master organizer in mediating the spatial organization of the kcnq5 gene locus. We characterized the cell-type specific spatial organization of the kcnq5 gene locus mediated by CTCF in detail using chromosome conformation capture (3C) and 3C-derived techniques. Cohesion also participated in mediating the organization of this locus. RNAi-mediated knockdown of CTCF sharply diminished the interaction frequencies between the chromatin loops of the kcnq5 gene locus and down-regulated local gene expression. Functional analysis showed that the interacting chromatin loops of the kcnq5 gene locus can repress the gene expression in a luciferase reporter assay. These interacting chromatin fragments were a series of repressing elements whose contacts were mediated by CTCF. Therefore, these findings suggested that the dynamical spatial organization of the kcnq5 locus regulates local gene expression

A System-Level Dynamic Binary Translator using Automatically-Learned Translation Rules

System-level emulators have been used extensively for system design, debugging and evaluation. They work by providing a system-level virtual machine to support a guest operating system (OS) running on a platform with the same or different native OS that uses the same or different instruction-set architecture. For such system-level emulation, dynamic binary translation (DBT) is one of the core technologies. A recently proposed learning-based DBT approach has shown a significantly improved performance with a higher quality of translated code using automatically learned translation rules. However, it has only been applied to user-level emulation, and not yet to system-level emulation. In this paper, we explore the feasibility of applying this approach to improve system-level emulation, and use QEMU to build a prototype. ... To achieve better performance, we leverage several optimizations that include coordination overhead reduction to reduce the overhead of each coordination, and coordination elimination and code scheduling to reduce the coordination frequency. Experimental results show that it can achieve an average of 1.36X speedup over QEMU 6.1 with negligible coordination overhead in the system emulation mode using SPEC CINT2006 as application benchmarks and 1.15X on real-world applications.Comment: 10 pages, 19 figures, to be published in International Symposium on Code Generation and Optimization (CGO) 202

Leader-following identical consensus for Markov jump nonlinear multi-agent systems subjected to attacks with impulse

The issue of leader-following identical consensus for nonlinear Markov jump multiagent systems (NMJMASs) under deception attacks (DAs) or denial-of-service (DoS) attacks is investigated in this paper. The Bernoulli random variable is introduced to describe whether the controller is injected with false data, that is, whether the systems are subjected to DAs. A connectivity recovery mechanism is constructed to maintain the connection among multi-agents when the systems are subjected to DoS attack. The impulsive control strategy is adopted to ensure that the systems can normally work under DAs or DoS attacks. Based on graph theory, Lyapunov stability theory, and impulsive theory, using the Lyapunov direct method and stochastic analysis method, the sufficient conditions of identical consensus for Markov jump multi-agent systems (MJMASs) under DAs or DoS are obtained, respectively. Finally, the correctness of the results and the effectiveness of the method are verified by two numerical examples

The combination of chest compression synchronized ventilation and aortic balloon occlusion improve the outcomes of cardiopulmonary resuscitation in swine

AimThe primary mission of cardiopulmonary resuscitation (CPR) is to provide adequate blood flow and oxygen delivery for restoring spontaneous circulation from cardiac arrest (CA) events. Previously, studies demonstrated that chest compression synchronized ventilation (CCSV) improved systemic oxygen supply during CPR, and aortic balloon occlusion (ABO) augments the efficacy of external CPR by increasing blood perfusion to vital organs. However, both them failed to make a significant improvement in return of spontaneous circulation (ROSC). In this study, we investigated the effects of combined CCSV and ABO on the outcomes of CPR in swine.MethodsThirty-one male domestic swine were subjected to 8 min of electrically induced and untreated CA followed by 8 min of CPR. CPR was performed by continuous chest compressions and mechanical ventilation. At the beginning of CPR, the animals were randomized to receive intermittent positive pressure ventilation (IPPV, n = 10), CCSV (n = 7), IPPV + ABO (n = 7), or CCSV + ABO (n = 7). During CPR, gas exchange and systemic hemodynamics were measured, and ROSC was recorded. After resuscitation, the function and injury biomarkers of vital organs including heart, brain, kidney, and intestine were evaluated.ResultsDuring CPR, PaO2 was significantly higher accompanied by significantly greater regional cerebral oxygen saturation in the CCSV and CCSV + ABO groups than the IPPV group. Coronary perfusion pressure, end-tidal carbon dioxide, and carotid blood flow were significantly increased in the IPPV + ABO and CCSV + ABO groups compared with the IPPV group. ROSC was achieved in five of ten (IPPV), five of seven (CCSV), six of seven (IPPV + ABO), and seven of seven (CCSV + ABO) swine, with the rate of resuscitation success being significantly higher in the CCSV + ABO group than the IPPV group (P = 0.044). After resuscitation, significantly improved myocardial and neurological function, and markedly less cardiac, cerebral, renal, and intestinal injuries were observed in the CCSV + ABO group compared with the IPPV group.ConclusionThe combination of CCSV and ABO improved both ventilatory and hemodynamic efficacy during CPR, promoted ROSC, and alleviated post-resuscitation multiple organ injury in swine