SUMMARY Mitochondrial permeability transition is a phenomenon in which the mitochondrial permeability transition pore (PTP) abruptly opens resulting in mitochondrial membrane potential (ΔΨm) dissipation, loss of ATP production, and cell death. Several genetic candidates have been proposed to form the PTP complex however the core component is unknown. We identified a necessary and conserved role for spastic paraplegia 7 (SPG7) in Ca2+ and ROS-induced PTP opening using RNAi based screening. Loss of SPG7 resulted in higher mitochondrial Ca2+, similar to cyclophilin D (CypD, PPIF) knockdown with sustained ΔΨm during both Ca2+ and ROS stress. Biochemical analyses revealed that the PTP is a hetero-oligomeric complex composed of VDAC, SPG7 and CypD. Silencing or disruption of SPG7-CypD binding prevented Ca2+ and ROS-induced ΔΨm depolarization and cell death. This study identifies a ubiquitously expressed IMM integral protein, SPG7, as a core component of the PTP at the OMM and IMM contact site.

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In hospitals reporting to the NCDB, volume was associated with improved mortality after RC. These associations appear to be driven by hospital- rather than surgeon-level effects. An elevated SV had a beneficial effect on mortality at the highest-volume hospitals. These findings inform efforts to regionalize complex surgical care and improve quality at community and safety net hospitals.

Worldwide, more than 2.2 million patients undergo bone graft procedures annually. In each of these procedures an interface is formed between the host tissue and the graft material. Synthetic implants exhibit an interface with the host tissue and the formation of a homogenous interface consisting of bone and void of intervening soft tissue is desired (osseointegration); recent developments have highlighted the benefit of incorporating nanostructures at that interface. Autograft and allograft bone are frequently used for bone loss, nonunion fractures, and spinal fusions; however, both are plagued with complications either due to supply or inadequate graft properties. In contrast to bone tissue engineering, which uses a top-down approach to repair bone defects, bone regenerative engineering uses a bottom-up approach focused on strategies incorporating stem cells, biomaterials, and growth factors alone or in combination to generate or regenerate bone tissue. Early constructs developed for bone regenerative engineering utilized polymeric microstructures, presenting surface features with characteristic dimensions similar to that of a cell (1µm - 1000µm). These microstructures were typically biodegradable and demonstrated an excellent ability to match the mechanics of native bone tissue. They were also osteoconductive-capable of promoting osteoblast growth. On the other hand, the osteoinductive abilities of these microstructures were lacking. Osteoinduction, or the ability to promote the progression of a preosteoblastic cell to a mature osteoblast, historically was achieved in two ways: via the addition of nanoscale ceramics to the microstructures or via an external stimulus such as the addition of bone morphogenetic proteins (BMPs). More recent developments in bone regenerative engineering have utilized polymeric nanostructures (less than 1µm) with characteristic dimensions an order of magnitude or more less than that of a cell to stimulate and drive an osteoinductive response in the absence of growth factors. Despite strong literature evidence supporting the nanostructures' ability to be both osteoconductive and osteoinductive, there is still disparity regarding how nanostructures regulate the progression towards an osteoblastic phenotype. This review will explore unique micro- and nano-architectures, how they initiate osteoinductive signals through pathways similar to BMPs, and how these unique geometries can be translated to the clinic.