DNA double-strand break-capturing nuclear envelope tubules drive DNA repair.

Current models suggest that DNA double-strand breaks (DSBs) can move to the nuclear periphery for repair. It is unclear to what extent human DSBs display such repositioning. Here we show that the human nuclear envelope localizes to DSBs in a manner depending on DNA damage response (DDR) kinases and cytoplasmic microtubules acetylated by α-tubulin acetyltransferase-1 (ATAT1). These factors collaborate with the linker of nucleoskeleton and cytoskeleton complex (LINC), nuclear pore complex (NPC) protein NUP153, nuclear lamina and kinesins KIF5B and KIF13B to generate DSB-capturing nuclear envelope tubules (dsbNETs). dsbNETs are partly supported by nuclear actin filaments and the circadian factor PER1 and reversed by kinesin KIFC3. Although dsbNETs promote repair and survival, they are also co-opted during poly(ADP-ribose) polymerase (PARP) inhibition to restrain BRCA1-deficient breast cancer cells and are hyper-induced in cells expressing the aging-linked lamin A mutant progerin. In summary, our results advance understanding of nuclear structure-function relationships, uncover a nuclear-cytoplasmic DDR and identify dsbNETs as critical factors in genome organization and stability.

Observational study methods used to assess pharmacotherapy effects of type 2 diabetes on fracture risk: a scoping review protocol.

OBJECTIVE: The objective of this review is to summarize observational research methods employed to study fracture risk and the use of type 2 diabetes mellitus medications. The methods summary will be used as a case study to illustrate current practices in the study of medication effects on fracture risk. INTRODUCTION: Observational studies examining drug effects on fracture risk fill knowledge gaps left by clinical trials but require specific design considerations. In recent years, several pharmacoepidemiologic studies have examined fracture risk as a possible adverse effect of type 2 diabetes mellitus medications using varying methodologies; these studies can illustrate design considerations for studies of fracture risk. INCLUSION CRITERIA: This scoping review will consider peer-reviewed observational studies that examine the effects of type 2 diabetes mellitus medications on fracture risk. Primary literature comprising empirical pharmacoepidemiologic studies, such as cohort, case-control, case-crossover, self-controlled, case series, and case-cohort designs, that evaluate fracture risk associated with at least one type 2 diabetes mellitus medication will be eligible. Studies without use of an administrative database and those with an experimental, cross-sectional, or time-series design will be excluded. METHODS: This scoping review will follow JBI methodology for scoping reviews. MEDLINE (Ovid), Embase (Ovid), and CINAHL Plus with Full Text (EBSCO) will be searched from January 1, 2000 (to capture recent methodologies) to the present to identify eligible articles. After de-duplication, titles and abstracts will be screened independently by two reviewers, then full texts will be reviewed. Data on study methods will be extracted from eligible texts using a piloted form developed by the authors, and study methods will be aggregated in tabular format.

Addressing the Challenges of Precepting Students Enrolled in Remote Research Advanced Pharmacy Practice Experiences.

As a result of restrictions imposed by COVID-19, many researchers have responded to the call for remote, advanced pharmacy practice experiences (APPEs) that do not involve direct patient care. The influx of materials on online pedagogy may be difficult for new preceptors to digest while familiarizing themselves with the APPE program. To complement the available guidance on remote learning for new preceptors, we describe our experiences with implementing a remote, research-focused APPE during COVID-19. Common challenges are discussed and potential solutions that may help new preceptors anticipate and overcome barriers to achieving the educational outcomes of research-focused APPE are proposed.

Severe-combined immunodeficient rats can be used to generate a model of perinatal hypoxic-ischemic brain injury to facilitate studies of engrafted human neural stem cells.

Cerebral palsy (CP) encompasses a group of non-progressive brain disorders that are often acquired through perinatal hypoxic-ischemic (HI) brain injury. Injury leads to a cascade of cell death events, resulting in lifetime motor and cognitive deficits. There are currently no treatments that can repair the resulting brain damage and improve functional outcomes. To date, preclinical research using neural precursor cell (NPC) transplantation as a therapy for HI brain injury has shown promise. To translate this treatment to the clinic, it is essential that human-derived NPCs also be tested in animal models, however, a major limitation is the high risk of xenograft rejection. A solution is to transplant the cells into immune-deficient rodents, but there are currently no models of HI brain injury established in such a cohort of animals. Here, we demonstrate that a model of HI brain injury can be generated in immune-deficient Prkdc knockout (KO) rats. Long-term deficits in sensorimotor function were similar between KO and wildtype (WT) rats. Interestingly, some aspects of the injury were more severe in KO rats. Additionally, human induced pluripotent stem cell derived (hiPSC)-NPCs had higher survival at 10 weeks post-transplant in KO rats when compared to their WT counterparts. This work establishes a reliable model of neonatal HI brain injury in Prkdc KO rats that will allow for future transplantation, survival, and long-term evaluation of the safety and efficacy of hiPSC-NPCs for neonatal brain damage. This model will enable critical preclinical translational research using human NPCs.