MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis.

Oncogene-induced replication stress generates endogenous DNA damage that activates cGAS-STING-mediated signalling and tumour suppression1-3. However, the precise mechanism of cGAS activation by endogenous DNA damage remains enigmatic, particularly given that high-affinity histone acidic patch (AP) binding constitutively inhibits cGAS by sterically hindering its activation by double-stranded DNA (dsDNA)4-10. Here we report that the DNA double-strand break sensor MRE11 suppresses mammary tumorigenesis through a pivotal role in regulating cGAS activation. We demonstrate that binding of the MRE11-RAD50-NBN complex to nucleosome fragments is necessary to displace cGAS from acidic-patch-mediated sequestration, which enables its mobilization and activation by dsDNA. MRE11 is therefore essential for cGAS activation in response to oncogenic stress, cytosolic dsDNA and ionizing radiation. Furthermore, MRE11-dependent cGAS activation promotes ZBP1-RIPK3-MLKL-mediated necroptosis, which is essential to suppress oncogenic proliferation and breast tumorigenesis. Notably, downregulation of ZBP1 in human triple-negative breast cancer is associated with increased genome instability, immune suppression and poor patient prognosis. These findings establish MRE11 as a crucial mediator that links DNA damage and cGAS activation, resulting in tumour suppression through ZBP1-dependent necroptosis.

Healthcare Worker Serious Safety Events: Applying Concepts from Patient Safety to Improve Healthcare Worker Safety.

INTRODUCTION: Patient safety has improved pediatric healthcare by defining when patient safety events meet criteria as serious safety events (SSEs). Similar concepts apply to healthcare worker (HCW) safety. We describe the newly designed process for HCW injury reporting, the process for evaluating HCW SSEs, and early experience with the new systems. METHODS: The work to redesign our approach to HCW safety included 2 parts: (1) process flow mapping and redesigning the work for HCW injury reporting; and (2) creating a process to categorize HCW injuries and determine when such injuries rise to a HCW SSE level. We evaluated the mean time per month from HCW injury to reporting and compared those values during the postimplementation time. We also evaluated the team's experience with the first 4 potential HCW SSEs. RESULTS: By improving the process flow, the mean time to reporting decreased significantly from 28 days implementation time-period (September-October 2019) to 9 days during the postimplementation time-period (November 2019-May 2020) (P = 0.0002). Of the first 4 HCW events identified and reviewed as possible HCW SSE events, there were 2 defined as HCW SSE level 4, one defined as a precursor event, and one defined as a nonsafety event. CONCLUSION: Adapting infrastructure and definitions used previously to improve patient safety can improve HCW safety.

Reaching beyond our walls: library outreach to veterinary practitioners.

The Texas A&M University Medical Sciences Library (MSL) supports lifelong learning for Texas veterinarians and College of Veterinary Medicine and Biomedical Sciences (CVMBS) alumni through several ongoing outreach efforts. The MSL provides free document delivery and literature search services to practicing veterinarians in support of patient care. The MSL also responded to unique opportunities to expand services and increase its visibility through collaborations with the American Association of Equine Practitioners and CABI, provider of VetMed Resource. The MSL continues to explore ways to expand its mission-critical veterinary outreach work and market library services to veterinarians through participation in continuing education, regional meetings, and veterinary student instruction.

Heart rate responses to small-sided games among elite junior rugby league players.

This study investigated the influences of player number and playing area size on the heart rate (HR) responses elicited by junior male rugby league players during small-sided games (SSGs). Twenty-two players from a professional club (n = 22, mean age: 14.5 +/- 1.5 years; stature: 172.5 +/- 11.4 cm; body mass: 67.8 +/- 15.1 kg; Vo2peak: 53.3 +/- 5.6 mL.kg.min; HRmax: 198 +/- 7.8 beats.min) participated in 2 repeated trials of six 4-minute conditioned SSGs over a 2-week period. The SSGs varied by playing area size-15 x 25 m, 20 x 30 m, and 25 x 35 m-and player number-4v4 and 6v6. HRs were recorded continuously in each game and expressed as overall and age-related (15-16 and 12-13 years) means and percent of maximum (%HRmax). Analysis revealed nonsignificant (p > 0.05) effects of trials and playing area size on HRs but a significant effect of player number in the 15-16 age group only (p < 0.001), with HRs being higher in the 4v4 (90.6% HRmax) than the 6v6 SSGs (86.2% HRmax). The HR responses were found to be repeatable in all SSG conditions (within +/- 1.9% HRmax), apart from the small 6v6 condition in the older players. The findings demonstrate that these SSGs generate physiological responses suitable for aerobic conditioning that, although unaffected by the size of the area used, are sensitive to the player number. Accordingly, among such players it is advisable that coaches use 4v4 SSGs to achieve an appropriate and consistent aerobic conditioning stimulus.

The outdoor air quality flag program in central California: a school-based educational intervention to potentially help reduce children's exposure to environmental asthma triggers.

This paper describes a novel school-based, visual environmental public health educational intervention intended to help reduce the exposure of children-and adults-to outdoor air pollution, including known environmental asthma triggers like ozone and particles. The overarching goal was to enhance the learning, recreational, and work environments of students and staff. The specific purpose of the Asthma-Friendly Outdoor (Ambient) Air Quality Flag Program was to establish an education and communication tool for Central California communities that would accomplish two things: (1) Establish permanent local policy change to existing operating procedures in school districts and schools to help reduce the exposure of students, teachers, staff, and nearby communities to outdoor environmental asthma triggers and (2) provide education on air quality and potential health effects of exposure to air pollutants. Data on the program from its initial years are presented. To date, the following important lessons have been learned: (1) Science-based, simple, visual, low-cost school-based educational interventions to help reduce human exposure to outdoor environmental asthma triggers (i.e., ozone, particles, and pollens) can work in socioeconomically and ethnically diverse urban and rural or agricultural communities, and (2) local health and environmental justice groups such as asthma coalitions can successfully lead school-based environmental interventions to help improve children's quality of life.

New superfamily members identified for Schiff-base enzymes based on verification of catalytically essential residues.

Enzymes that utilize a Schiff-base intermediate formed with their substrates and that share the same alpha/beta barrel fold comprise a mechanistically diverse superfamily defined in the SCOPS database as the class I aldolase family. The family includes the "classical" aldolases fructose-1,6-(bis)phosphate (FBP) aldolase, transaldolase, and 2-keto-3-deoxy-6-phosphogluconate aldolase. Moreover, the N-acetylneuraminate lyase family has been included in the class I aldolase family on the basis of similar Schiff-base chemistry and fold. Herein, we generate primary sequence identities based on structural alignment that support the homology and reveal additional mechanistic similarities beyond the common use of a lysine for Schiff-base formation. The structural and mechanistic correspondence comprises the use of a catalytic dyad, wherein a general acid/base residue (Glu, Tyr, or His) involved in Schiff-base chemistry is stationed on beta-strand 5 of the alpha/beta barrel. The role of the acid/base residue was probed by site-directed mutagenesis and steady-state and pre-steady-state kinetics on a representative member of this family, FBP aldolase. The kinetic results are consistent with the participation of this conserved residue or position in the protonation of the carbinolamine intermediate and dehydration of the Schiff base in FBP aldolase and, by analogy, the class I aldolase family.

Overview of protein structural and functional folds.

This overview provides an illustrated, comprehensive survey of some commonly observed protein-fold families and structural motifs, chosen for their functional significance. It opens with descriptions and definitions of the various elements of protein structure and associated terminology. Following is an introduction into web-based structural bioinformatics that includes surveys of interactive web servers for protein fold or domain annotation, protein-structure databases, protein-structure-classification databases, structural alignments of proteins, and molecular graphics programs available for personal computers. The rest of the overview describes selected families of protein folds in terms of their secondary, tertiary, and quaternary structural arrangements, including ribbon-diagram examples, tables of representative structures with references, and brief explanations pointing out their respective biological and functional significance.

Crystal structure of the human natural killer (NK) cell activating receptor NKp46 reveals structural relationship to other leukocyte receptor complex immunoreceptors.

Natural cytotoxicity receptors (NCR) mediate lysis of a variety of tumor and virus-infected cells by natural killer (NK) cells. Upon engagement, NCR trigger the cytolytic activity and cytokine release of NK cells through association with ITAM-containing signaling molecules. To further understand the function of these receptors in activation of natural cytotoxicity, we determined the crystal structure of the extracellular ligand binding domain of human NKp46, one of three known NCR, at 2.2-A resolution. The overall fold and disposition of the two C2-set immunoglobulin domains are similar to the D1D2 domains of inhibitory killer cell Ig-like receptor (KIR) and Ig-like transcript (ILT) receptors. As the cellular ligands of NKp46 have not yet been defined, the known ligand binding sites of KIR and ILT were compared with the corresponding structural regions of NKp46 in an effort to identify potential areas suitable for molecular recognition. A potential binding site for influenza hemagglutinin is located near the interdomain hinge, a region that mediates ligand binding in KIR. The structural similarity of NKp46 to inhibitory KIR receptors may have implications for how NK cells balance activating and inhibitory signals.