A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements.

Chromosomal instability (CIN) generates micronuclei-aberrant extranuclear structures that catalyze the acquisition of complex chromosomal rearrangements present in cancer. Micronuclei are characterized by persistent DNA damage and catastrophic nuclear envelope collapse, which exposes DNA to the cytoplasm. We found that the autophagic receptor p62/SQSTM1 modulates micronuclear stability, influencing chromosome fragmentation and rearrangements.

A high-content screen reveals new regulators of nuclear membrane stability.

Nuclear membrane rupture is a physiological response to multiple in vivo processes, such as cell migration, that can cause extensive genome instability and upregulate invasive and inflammatory pathways. However, the underlying molecular mechanisms of rupture are unclear and few regulators have been identified. In this study, we developed a reporter that is size excluded from re-compartmentalization following nuclear rupture events.

A high-content screen reveals new regulators of nuclear membrane stability.

Nuclear membrane rupture is a physiological response to multiple processes, such as cell migration, that can cause extensive genome instability and upregulate invasive and inflammatory pathways. However, the underlying molecular mechanisms of rupture are unclear and few regulators have been identified. In this study, we developed a reporter that is size excluded from re-compartmentalization following nuclear rupture events.

Chromosome length and gene density contribute to micronuclear membrane stability.

Micronuclei are derived from missegregated chromosomes and frequently lose membrane integrity, leading to DNA damage, innate immune activation, and metastatic signaling. Here, we demonstrate that two characteristics of the trapped chromosome, length and gene density, are key contributors to micronuclei membrane stability and determine the timing of micronucleus rupture. We demonstrate that these results are not due to chromosome-specific differences in spindle position or initial protein recruitment during post-mitotic nuclear envelope assembly.

Brief Report: A Preliminary Study of the Relationship between Repetitive Behaviors and Concurrent Executive Function Demands in Children with Autism Spectrum Disorder.

The present study evaluated the hypothesis that the strength of the relationship between executive function (EF) and repetitive behaviors and restricted interests (RBRI) symptomatology is moderated by the degree to which concurrent demands are placed on multiple aspects of EF. An eye movement task was used to evaluate inhibition and task switching ability (both together and in isolation) in a sample of 22 children with autism spectrum disorder (ASD). The Repetitive Behavior Scale-Revised (RBS-R) was used to assess the severity of RBRI symptoms.

BAF facilitates interphase nuclear membrane repair through recruitment of nuclear transmembrane proteins.

Nuclear membrane rupture during interphase occurs in a variety of cell contexts, both healthy and pathological. Membrane ruptures can be rapidly repaired, but these mechanisms are still unclear. Here we show barrier-to-autointegration factor (BAF), a nuclear envelope protein that shapes chromatin and recruits membrane proteins in mitosis, also facilitates nuclear membrane repair in interphase, in part through recruitment of the nuclear membrane proteins emerin and Lem-domain-containing protein 2 (LEMD2) to rupture sites.

Binning Singletons: Mentoring through Networking at ASM Microbe 2019.

The American Society for Microbiology (ASM) national conference, Microbe, is the flagship meeting for microbiologists across the globe. The presence of roughly 10,000 attendees provides enormous opportunities for networking and learning. However, such a large meeting can be intimidating to many, especially early career scientists, students, those attending alone, and those from historically underrepresented groups.

Slow-Frequency Pulsed Transcranial Electrical Stimulation for Modulation of Cortical Plasticity Based on Reciprocity Targeting with Precision Electrical Head Modeling.

In pain management as well as other clinical applications of neuromodulation, it is important to consider the timing parameters influencing activity-dependent plasticity, including pulsed versus sustained currents, as well as the spatial action of electrical currents as they polarize the complex convolutions of the cortical mantle. These factors are of course related; studying temporal factors is not possible when the spatial resolution of current delivery to the cortex is so uncertain to make it unclear whether excitability is increased or decreased with anodal vs. cathodal current flow.

RING finger nuclear factor RNF168 is important for defects in homologous recombination caused by loss of the breast cancer susceptibility factor BRCA1.

Background: RNF168 promotes chromosomal break localization of 53BP1 and BRCA1; 53BP1 loss rescues homologous recombination (HR) in BRCA1-deficient cells.

Results: RNF168 depletion suppresses HR defects caused by BRCA1 silencing; RNF168 influences HR similarly to 53BP1.

Conclusion: RNF168 is important for HR defects caused by BRCA1 loss.

I-SceI-based assays to examine distinct repair outcomes of mammalian chromosomal double strand breaks.

Chromosomal double strand breaks (DSBs) can be repaired by a number of mechanisms that result in diverse genetic outcomes. To examine distinct outcomes of chromosomal DSB repair, a panel of human cell lines has been developed that contain GFP-based reporters with recognition sites for the rare-cutting endonuclease I-SceI. One set of reporters is used to measure DSB repair events that require access to homology: homology-directed repair, homology-directed repair that requires the removal of a nonhomologous insertion, single strand annealing, and alternative end joining.

Correct end use during end joining of multiple chromosomal double strand breaks is influenced by repair protein RAD50, DNA-dependent protein kinase DNA-PKcs, and transcription context.

During repair of multiple chromosomal double strand breaks (DSBs), matching the correct DSB ends is essential to limit rearrangements. To investigate the maintenance of correct end use, we examined repair of two tandem noncohesive DSBs generated by endonuclease I-SceI and the 3' nonprocessive exonuclease Trex2, which can be expressed as an I-SceI-Trex2 fusion. We examined end joining (EJ) repair that maintains correct ends (proximal-EJ) versus using incorrect ends (distal-EJ), which provides a relative measure of incorrect end use (distal end use).

The influence of non-nociceptive factors on hot-plate latency in rats.

Unlabelled: The hot plate is a widely used test to assess nociception. The effect of non-nociceptive factors (weight, sex, activity, habituation, and repeated testing) on hot-plate latency was examined. Comparison of body weight and hot-plate latency revealed a small but significant inverse correlation (light rats had longer latencies).

53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks.

Defective DNA repair by homologous recombination (HR) is thought to be a major contributor to tumorigenesis in individuals carrying Brca1 mutations. Here, we show that DNA breaks in Brca1-deficient cells are aberrantly joined into complex chromosome rearrangements by a process dependent on the nonhomologous end-joining (NHEJ) factors 53BP1 and DNA ligase 4. Loss of 53BP1 alleviates hypersensitivity of Brca1 mutant cells to PARP inhibition and restores error-free repair by HR.

Limiting the persistence of a chromosome break diminishes its mutagenic potential.

To characterize the repair pathways of chromosome double-strand breaks (DSBs), one approach involves monitoring the repair of site-specific DSBs generated by rare-cutting endonucleases, such as I-SceI. Using this method, we first describe the roles of Ercc1, Msh2, Nbs1, Xrcc4, and Brca1 in a set of distinct repair events. Subsequently, we considered that the outcome of such assays could be influenced by the persistent nature of I-SceI-induced DSBs, in that end-joining (EJ) products that restore the I-SceI site are prone to repeated cutting.

TGF-beta activates Akt kinase through a microRNA-dependent amplifying circuit targeting PTEN.

Akt kinase is activated by transforming growth factor-beta1 (TGF-beta) in diabetic kidneys, and has important roles in fibrosis, hypertrophy and cell survival in glomerular mesangial cells. However, the mechanisms of Akt activation by TGF-beta are not fully understood. Here we show that TGF-beta activates Akt in glomerular mesangial cells by inducing the microRNAs (miRNAs) miR-216a and miR-217, both of which target PTEN (phosphatase and tensin homologue), an inhibitor of Akt activation.