Cardiolipin, the signature phospholipid of mitochondria, is a lipid dimer that is important for a diverse range of mitochondrial activities beyond the process of ATP production. Thus not ...surprisingly, derangements in cardiolipin metabolism are now appreciated to contribute to an assortment of pathological conditions. A comprehensive inventory of enzymes involved in cardiolipin biosynthesis and remodeling was just recently obtained. Post-biosynthesis, the acyl chain composition of cardiolipin is modified by up to three distinct remodeling enzymes that produce either a homogeneous tissue-specific mature form of cardiolipin or alternatively ‘bad’ cardiolipin that has been linked to mitochondrial dysfunction. In this review, we initially focus on the newly identified players in cardiolipin metabolism and then shift our attention to how changes in cardiolipin metabolism contribute to human disease.
Mitochondria are essential regulators of cellular energy and metabolism, and have a crucial role in sustaining the growth and survival of cancer cells. A central function of mitochondria is the ...synthesis of ATP by oxidative phosphorylation, known as mitochondrial bioenergetics. Mitochondria maintain oxidative phosphorylation by creating a membrane potential gradient that is generated by the electron transport chain to drive the synthesis of ATP
. Mitochondria are essential for tumour initiation and maintaining tumour cell growth in cell culture and xenografts
. However, our understanding of oxidative mitochondrial metabolism in cancer is limited because most studies have been performed in vitro in cell culture models. This highlights a need for in vivo studies to better understand how oxidative metabolism supports tumour growth. Here we measure mitochondrial membrane potential in non-small-cell lung cancer in vivo using a voltage-sensitive, positron emission tomography (PET) radiotracer known as 4-
Ffluorobenzyl-triphenylphosphonium (
F-BnTP)
. By using PET imaging of
F-BnTP, we profile mitochondrial membrane potential in autochthonous mouse models of lung cancer, and find distinct functional mitochondrial heterogeneity within subtypes of lung tumours. The use of
F-BnTP PET imaging enabled us to functionally profile mitochondrial membrane potential in live tumours.
Defined mutations in the mitochondrial ADP/ATP carrier (AAC) are associated with certain types of progressive external ophthalmoplegia. AAC is required for oxidative phosphorylation (OXPHOS), and ...dysregulation of AAC has been implicated in apoptosis. Little is known about the AAC interactome, aside from a known requirement for the phospholipid cardiolipin (CL) and that it is thought to function as a homodimer. Using a newly developed dual affinity tag, we demonstrate that yeast AAC2 physically participates in several protein complexes of distinct size and composition. The respiratory supercomplex and several smaller AAC2-containing complexes, including other members of the mitochondrial carrier family, are identified here. In the absence of CL, most of the defined interactions are destabilized or undetectable. The absence of CL and/or AAC2 results in distinct yet additive alterations in respiratory supercomplex structure and respiratory function. Thus, a single lipid can significantly alter the functional interactome of an individual protein.
Current options for treating elbow instability include bony and/or ligamentous fixation with orthosis or cast immobilization, transarticular cross-pinning, temporary bridge plating, and hinged or ...rigid external fixation. Our purpose was to evaluate the recently developed internal joint stabilizer (IJS), which acts as an internal external fixator of the elbow. Our primary end point was to assess whether use of the device results in a stable and congruent reduction of the ulnohumeral and radiocapitellar joints in patients with acute or chronic elbow instability as a result of trauma. In our series, patients with elbow instability as a result of acute or chronic trauma were treated with an IJS.
This retrospective study reviewed 20 patients who underwent placement of a U.S. Food and Drug Administration (FDA)–approved IJS for elbow instability. Serial physical examinations and radiographs were performed to verify stability. Patients were instructed that, if they are dissatisfied with their postoperative motion, a secondary contracture release operation will be offered to them. Patients were asked to complete outcome-scoring questionnaires including the Disabilities of the Arm, Shoulder, and hand (DASH) and Mayo Elbow Performance (MEP) score. Complications were monitored for all patients.
Twenty patients who underwent placement of an IJS for persistent elbow instability were reviewed. Patients with a flexion-extension arc of 70° or less at 12 weeks were offered a staged arthroscopic contracture release. The average MEP score improved from 12.2 ± 12.4 to 82.5 ± 14.3 and the average DASH score improved from 85.3 ± 23.0 to 37.26 ± 29.3. The average postoperative flexion-extension arc at most recent follow-up was 124.3° ± 14.9°, with a median follow-up of 17 months (8 weeks–25 months).
Use of an IJS allows for early, congruent, and stable ulnohumeral and radiocapitellar range of motion in instances of persistent elbow instability.
Therapeutic IV.
SCL25A46 is a mitochondrial carrier protein that surprisingly localizes to the outer membrane and is distantly related to Ugo1. Here we show that a subset of SLC25A46 interacts with mitochondrial ...dynamics components and the MICOS complex. Decreased expression of SLC25A46 results in increased stability and oligomerization of MFN1 and MFN2 on mitochondria, promoting mitochondrial hyperfusion. A mutation at L341P causes rapid degradation of SLC25A46, which manifests as a rare disease, pontocerebellar hypoplasia. The E3 ubiquitin ligases MULAN and MARCH5 coordinate ubiquitylation of SLC25A46 L341P, leading to degradation by organized activities of P97 and the proteasome. Whereas outer mitochondrial membrane-associated degradation is typically associated with apoptosis or a specialized type of autophagy termed mitophagy, SLC25A46 degradation operates independently of activation of outer membrane stress pathways. Thus SLC25A46 is a new component in mitochondrial dynamics that serves as a regulator for MFN1/2 oligomerization. Moreover, SLC25A46 is selectively degraded from the outer membrane independently of mitophagy and apoptosis, providing a framework for mechanistic studies in the proteolysis of outer membrane proteins.
BACKGROUND AND OBJECTIVES: Despite the high morbidity associated with glenohumeral dysplasia (GHD) in children with brachial plexus birth injuries, the progression of this condition often remains ...unnoticed, even after correcting for the underlying brachial plexus birth injuries. GHD, driven by a multifactorial process involving disruptions in both direct and indirect neural regulation of bony and muscular structures, can lead to intermittent or permanent shoulder mobility imbalances, significantly impacting the quality of life of those affected. Recent research efforts are increasingly directed toward identifying the root causes, managing the deformity, and determining effective treatment options for correcting GHD. METHODS: A comprehensive search strategy was used by the authors to identify relevant literature relating to the progression, pathoanatomy, clinical presentation, and management of GHD following brachial plexus birth injuries across various search engines, such as PubMed, Scopus, and Embase. Considering the topic's interdisciplinary nature, articles were retrieved from both neurosurgical and orthopaedic journals to enrich the review. RESULTS: Given the challenges in managing patients with brachial plexus birth injuries, a multidisciplinary care team consisting of certified occupational hand therapists, neurosurgeons, plastic surgeons, and orthopedic surgeons, specializing in brachial plexus injuries should be advocated for. The aim of this collaborative effort is to correct brachial plexus birth injuries and prevent the persistence of GHD. CONCLUSION: As research continues to focus on understanding the complexities of this condition, the aim of this review article is to summarize the current literature on the course of brachial plexus birth injury and the development of GHD. By doing so, we hope to provide neurosurgeons with the necessary knowledge and essential tools needed to identify and effectively treat GHD during management of brachial plexus birth injuries.
Many scientific disciplines rely on computational methods for data analysis, model generation, and prediction. Implementing these methods is often accomplished by researchers with domain expertise ...but without formal training in software engineering or computer science. This arrangement has led to underappreciation of sustainability and maintainability of scientific software tools developed in academic environments. Some software tools have avoided this fate, including the scientific library Rosetta. We use this software and its community as a case study to show how modern software development can be accomplished successfully, irrespective of subject area. Rosetta is one of the largest software suites for macromolecular modeling, with 3.1 million lines of code and many state-of-the-art applications. Since the mid 1990s, the software has been developed collaboratively by the RosettaCommons, a community of academics from over 60 institutions worldwide with diverse backgrounds including chemistry, biology, physiology, physics, engineering, mathematics, and computer science. Developing this software suite has provided us with more than two decades of experience in how to effectively develop advanced scientific software in a global community with hundreds of contributors. Here we illustrate the functioning of this development community by addressing technical aspects (like version control, testing, and maintenance), community-building strategies, diversity efforts, software dissemination, and user support. We demonstrate how modern computational research can thrive in a distributed collaborative community. The practices described here are independent of subject area and can be readily adopted by other software development communities.
Purpose
Brachial plexus birth injury (BPBI) is a common injury with the spectrum of disease prognosis ranging from spontaneous recovery to lifelong debilitating disability. A common sequela of BPBI ...is glenohumeral dysplasia (GHD) which, if not addressed early on, can lead to shoulder dysfunction as the child matures. However, there are no clear criteria for when to employ various surgical procedures for the correction of GHD.
Methods
We describe our approach to correcting GDH in infants with BPBIs using a reverse end-to-side (ETS) transfer from the spinal accessory to the suprascapular nerve. This technique is employed in infants that present with GHD with poor external rotation (ER) function who would not necessitate a complete end-to-end transfer and are still too young for a tendon transfer. In this study, we present our outcomes in seven patients.
Results
At presentation, all patients had persistent weakness of the upper trunk and functional limitations of the shoulder. Point-of-care ultrasounds confirmed GHD in each case. Five patients were male, and two patients were female, with a mean age of 3.3 months age (4 days–7 months) at presentation. Surgery was performed on average at 5.8 months of age (3–8.6 months). All seven patients treated with a reverse ETS approach had full recovery of ER according to active movement scores at the latest follow-up. Additionally, ultrasounds at the latest follow-up showed a complete resolution of GHD.
Conclusion
In infants with BPBI and evidence of GHD with poor ER, end-to-end nerve transfers, which initially downgrade function, or tendon transfers, that are not age-appropriate for the patient, are not recommended. Instead, we report seven successful cases of infants who underwent ETS spinal accessory to suprascapular nerve transfer for the treatment of GHD following BPBI.
The wide-awake local anesthesia with no tourniquet (WALANT) technique has become popularized for various hand/upper extremity procedures. Before surgery, patients receive local anesthetic, consisting ...of lidocaine with epinephrine, and remain awake for the entire procedure. The purpose of this review was to investigate the advantages, diverse application, outcomes, cost benefits, use in challenging environments, patient considerations, and contraindications associated with WALANT.
A comprehensive review of the literature on the WALANT technique was conducted. Search terms included: WALANT, wide-awake surgery, no tourniquet, local anesthesia, hand, wrist, cost, and safety.
The WALANT technique has proven to be successful for common procedures such as flexor tendon repair, tendon transfer, trigger finger releases, Depuytren disease, and simple bony procedures. Recently, the use of WALANT has expanded to more extensive soft-tissue repair, fracture management, and bony manipulation. Advantages include negating preoperative evaluation and testing for anesthesia clearance, eliminating risk of monitored anesthesia care, removal of anesthesia providers and ancillary staff, significant cost savings, and less waste produced. Intraoperative evaluations can be performed through active patient participation, and postoperative recovery and monitoring time are reduced. WALANT is associated with high patient satisfaction rates and low infection rates.
The WALANT technique has proven to be valuable to both patients and providers, optimizing patient satisfaction and providing substantial healthcare savings. As its application continues to grow, current literature suggests positive outcomes.
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