A New Role for Translation Initiation Factor 2 in Maintaining Genome Integrity

Escherichia coli translation initiation factor 2 (IF2) performs the unexpected function of promoting transition from recombination to replication during bacteriophage Mu transposition in vitro, leading to initiation by replication restart proteins. This function has suggested a role of IF2 in engaging cellular restart mechanisms and regulating the maintenance of genome integrity. To examine the potential effect of IF2 on restart mechanisms, we characterized its influence on cellular recovery following DNA damage by methyl methanesulfonate (MMS) and UV damage. Mutations that prevent expression of full-length IF2-1 or truncated IF2-2 and IF2-3 isoforms affected cellular growth or recovery following DNA damage differently, influencing different restart mechanisms. A deletion mutant (del1) expressing only IF2-2/3 was severely sensitive to growth in the presence of DNA-damaging agent MMS. Proficient as wild type in repairing DNA lesions and promoting replication restart upon removal of MMS, this mutant was nevertheless unable to sustain cell growth in the presence of MMS; however, growth in MMS could be partly restored by disruption of sulA, which encodes a cell division inhibitor induced during replication fork arrest. Moreover, such characteristics of del1 MMS sensitivity were shared by restart mutant priA300, which encodes a helicase-deficient restart protein. Epistasis analysis indicated that del1 in combination with priA300 had no further effects on cellular recovery from MMS and UV treatment; however, the del2/3 mutation, which allows expression of only IF2-1, synergistically increased UV sensitivity in combination with priA300. The results indicate that full-length IF2, in a function distinct from truncated forms, influences the engagement or activity of restart functions dependent on PriA helicase, allowing cellular growth when a DNA–damaging agent is present

Alzheimer disease models and human neuropathology: similarities and differences

Animal models aim to replicate the symptoms, the lesions or the cause(s) of Alzheimer disease. Numerous mouse transgenic lines have now succeeded in partially reproducing its lesions: the extracellular deposits of Aβ peptide and the intracellular accumulation of tau protein. Mutated human APP transgenes result in the deposition of Aβ peptide, similar but not identical to the Aβ peptide of human senile plaque. Amyloid angiopathy is common. Besides the deposition of Aβ, axon dystrophy and alteration of dendrites have been observed. All of the mutations cause an increase in Aβ 42 levels, except for the Arctic mutation, which alters the Aβ sequence itself. Overexpressing wild-type APP alone (as in the murine models of human trisomy 21) causes no Aβ deposition in most mouse lines. Doubly (APP × mutated PS1) transgenic mice develop the lesions earlier. Transgenic mice in which BACE1 has been knocked out or overexpressed have been produced, as well as lines with altered expression of neprilysin, the main degrading enzyme of Aβ. The APP transgenic mice have raised new questions concerning the mechanisms of neuronal loss, the accumulation of Aβ in the cell body of the neurons, inflammation and gliosis, and the dendritic alterations. They have allowed some insight to be gained into the kinetics of the changes. The connection between the symptoms, the lesions and the increase in Aβ oligomers has been found to be difficult to unravel. Neurofibrillary tangles are only found in mouse lines that overexpress mutated tau or human tau on a murine tau −/− background. A triply transgenic model (mutated APP, PS1 and tau) recapitulates the alterations seen in AD but its physiological relevance may be discussed. A number of modulators of Aβ or of tau accumulation have been tested. A transgenic model may be analyzed at three levels at least (symptoms, lesions, cause of the disease), and a reading key is proposed to summarize this analysis

A systematic review of bone graft products used in lumbar interbody fusion procedures for degenerative disc disease

Background: Degenerative disc disease (DDD) is associated with chronic lower back pain that may have impacts on individual's quality of life and functional ability. Lumbar interbody fusion can be carried out with a variety of bone grafting products, the choice depends on several factors including the patient, site, procedure, cost and indication. This systematic review (SR) intends to validate and consolidate the existing evidence base supporting bone graft materials related to lumbar interbody fusion procedures for DDD, specifically anterior lumbar interbody fusion (ALIF) and oblique lumbar interbody fusion (OLIF). Methods: An SR was conducted in February 2023. Clinical and economic studies of adults with DDD in regions L2 to S1 undergoing lumbar interbody fusion with Infuse™, allograft, synthetic bone grafts, demineralized bone matrices or cell-based matrices were eligible for inclusion. Results: Twenty-one studies (reported in 25 publications) were included in the review. Eighteen studies (reported in 22 publications) reported clinical outcomes, while 4 studies reported economic outcomes. Nine studies (in 5 publications) investigated Infuse™, including 3 randomized controlled trials (RCTs), one cohort study and 4 case series. Ten studies investigated allograft bone, bone harvested from the vertebral spur combined with apacerum powder, or tricalcium phosphate soaked in autologous bone marrow aspirate, including one RCT, 2 cohort studies, and 7 case series. Conclusions: The SR shows that Infuse™ offers comparable results to iliac crest bone graft with the benefit of not requiring harvested bone and offers significant benefits in surgical time and blood loss. There is a lack of comparative evidence for any other bone grafts identified in this SR, highlighting the need for further well-designed studies to be conducted in this area