Summary An intronic GGGGCC repeat expansion in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but its pathogenic mechanism remains unclear. Here we use human induced motor neurons (iMNs) to show that repeat-expanded C9ORF72 is haploinsufficient in ALS. We show that C9ORF72 interacts with endosomes and is required for normal vesicle trafficking and lysosomal biogenesis in motor neurons. Repeat expansion reduces C9ORF72 expression, triggering neurodegeneration through two mechanisms: accumulation of glutamate receptors leading to excitotoxicity, and impaired clearance of neurotoxic dipeptide repeat proteins derived from the repeat expansion. Thus, cooperativity between gain- and loss-of-function mechanisms leads to neurodegeneration. Restoring C9ORF72 levels or augmenting its function with constitutively active RAB5 or chemical modulators of RAB5 effectors rescues patient neuron survival and ameliorates neurodegenerative processes in both gain- and loss-of function C9ORF72 mouse models. Thus, modulating vesicle trafficking can rescue neurodegeneration caused by the C9ORF72 repeat expansion. Coupled with rare mutations in ALS2, FIG4, CHMP2B, OPTN, and SQSTM1, our results reveal mechanistic convergence on vesicle trafficking in ALS/FTD.

Background:A technique of a free nipple graft with an inframammary incision and no vertical incision offers promising postoperative results as a safe and aesthetic alternative. Methods: This was a retrospective chart review of patients who presented to a single surgeon for breast reduction surgery using a free nipple graft with an inframammary incision from June 1999 to March 2021. Baseline patient demographics and clinical information along with postoperative complications were recorded and compared between patients who presented for concomitant reconstruction or just reduction. A narrative literature review on surgical techniques and outcomes was also conducted. Results: From the literature search, there have been minimal prior mentions of breast reductions using a free nipple graft with an inframammary incision and no vertical incision. Fifty-five cases were identified for breast reduction surgery in the author's 22-year study period, of which 46 had adequate clinical documentation and follow-up. An estimated 22 patients had either both or one breast reconstructed with opposite side breast reduction, and 24 patients underwent breast reduction alone with free nipple grafting. No implants were used in any of the patients. Conclusions:The free nipple graft technique with an inframammary incision can be performed on patients with excessively large or ptotic breasts. It is possible to reduce the volume of the breast and obtain good projection with this method. Furthermore, avoidance of the vertical incision reduces breakdown at the T-junction and is aesthetically beneficial.