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Melanosomes play a pivotal role in skin color and photoprotection. In contrast to the well-elucidated pathway of melanosome biogenesis, the process of melanosome degradation, referred to as melanophagy, is largely unexplored. Previously, we discovered that 3,4,5-trimethoxycinnamate thymol ester (TCTE) effectively inhibits skin pigmentation by activating melanophagy. In this study, we discovered a new regulatory signaling cascade that controls melanophagy in TCTE-treated melanocytes. ITCH (itchy E3 ubiquitin protein ligase) facilitates ubiquitination of the melanosome membrane protein MLANA (melan-A) during TCTE-induced melanophagy. This ubiquitinated MLANA is then recognized by an autophagy receptor protein, OPTN (optineurin). Additionally, a phospho-kinase antibody array revealed that TCTE activates PTK2 (protein tyrosine kinase 2), which phosphorylates ITCH, enhancing the ubiquitination of MLANA. Furthermore, inhibition of either PTK2 or ITCH disrupts the ubiquitination of MLANA and the MLANA-OPTN interaction in TCTE-treated cells. Taken together, our findings highlight the critical role of the PTK2-ITCH-MLANA-OPTN cascade in orchestrating melanophagy progression.Abbreviations: α-MSH: alpha-melanocyte-stimulating hormone; dichlone: 2,3-dichloro-1,4-naphthoquinone; ITCH: itchy E3 ubiquitin protein ligase; MITF: melanocyte inducing transcription factor; MLANA: melan-A; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; PINK1: PTEN induced kinase 1; PTK2: protein tyrosine kinase 2; SQSTM1/p62: sequestosome 1; TCTE: 3,4,5-trimethoxycinnamate thymol ester; TPC2: two pore segment channel 2; VDAC1: voltage dependent anion channel 1. [ABSTRACT FROM AUTHOR]

Introduction: The scarcity of donors coupled with the improvements in left ventricular assist devices (LVAD) technology has led to the use of LVAD as a bridge to transplantation (BTT). Areas covered: The authors provide an overview of the current status of LVAD BTT implantation with special focus ranging from patient selection and pre-implantation optimization to post-transplant outcomes. Expert Opinion: The United Network for Organ Sharing 2018 policy amendment resulted in a significant reduction in the number of LVADs used for BTT in the US. To overcome this issue, modifications in the US allocation policy to consider factors such as days on device support, age, and type of complications may be necessary to potentially increase implantation rates. [ABSTRACT FROM AUTHOR]

Abstract Background Our study aims to evaluate the genetic and phenotypic spectrum of Frontotemporal dementia (FTD) gene variant carriers in Chinese populations, investigate mutation frequencies, and assess the functional properties of TBK1 and OPTN variants. Methods Clinically diagnosed FTD patients underwent genetic analysis through exome sequencing, repeat-primed polymerase chain reaction, and Sanger sequencing. TBK1 and OPTN variants were biologically characterized in vitro using immunofluorescence, immunoprecipitation, and immunoblotting analysis. The frequencies of genes implicated in FTD in China were analyzed through a literature review and meta-analysis. Results Of the 261 Chinese FTD patients, 61 (23.4%) carried potential causative variants in FTD-related genes, including MAPT (n = 17), TBK1 (n = 7), OPTN (n = 6), GRN (n = 6), ANXA11 (n = 4), CHMP2B (n = 3), C9orf72 GGGGCC repeats (n = 2), CYLD (n = 2), PRNP (n = 2), SQSTM1 (n = 2), TARDBP (n = 2), VCP (n = 1), CCNF (n = 1), CHCHD10 (n = 1), SIGMAR1 (n = 1), CHCHD2 (n = 1), FUS (n = 1), TMEM106B (n = 1), and UBQLN2 (n = 1). 29 variants can be considered novel, including the MAPT p.D54N, p.E342K, p.R221P, p.T263I, TBK1 p.E696G, p.I37T, p.E232Q, p.S398F, p.T78A, p.Q150P, p.W259fs, OPTN p.R144G, p.F475V, GRN p.V473fs, p.C307fs, p.R101fs, CHMP2B p.K6N, p.R186Q, ANXA11 p.Q155*, CYLD p.T157I, SQSTM1 p.S403A, UBQLN2 p.P509H, CCNF p.S160N, CHCHD10 p.A8T, SIGMAR1 p.S117L, CHCHD2 p.P53fs, FUS p.S235G & p.S236G, and TMEM106B p.L144V variants. Patients with TBK1 and OPTN variants presented with heterogeneous clinical phenotypes. Functional analysis demonstrated that TBK1 I37T and E232Q mutants showed decreased autophosphorylation, and the OPTN phosphorylation was reduced by the TBK1 I37T mutant. The OPTN-TBK1 complex formation was enhanced by the TBK1 E696G mutant, while OPTN R144G and F475V mutants exhibited reduced recruitment to autophagosomes compared to the wild-type. The overall frequency of TBK1 and OPTN in Chinese FTD patients was 2.0% and 0.3%, respectively. Conclusions Our study demonstrates the extensive genetic and phenotypic heterogeneity of Chinese FTD patients. TBK1 mutations are the second most frequent cause of clinical FTD after MAPT in the Chinese.

Background: Over one thousand pediatric kidney transplant candidates are added to the waitlist annually, yet the prospective time spent waiting is unknown for many. Our study fills this gap by identifying variables that impact waitlist time and by creating an index to predict the likelihood of a pediatric candidate receiving a transplant within 1 year of listing. This index could be used to guide patient management by giving clinicians a potential timeline for each candidate's listing based on a unique combination of risk factors. Methods: A retrospective analysis of 3757 pediatric kidney transplant candidates from the 2014 to 2020 OPTN/UNOS database was performed. The data was randomly divided into a training set, comprising two-thirds of the data, and a testing set, comprising one-third of the data. From the training set, univariable and multivariable logistic regressions were used to identify significant predictive factors affecting wait times. A predictive index was created using variables significant in the multivariable analysis. The index's ability to predict likelihood of transplantation within 1 year of listing was validated using ROC analysis on the training set. Validation of the index using ROC analysis was repeated on the testing set. Results: A total of 10 variables were found to be significant. The five most significant variables include the following: blood group, B (OR 0.65); dialysis status (OR 3.67); kidney disease etiology, SLE (OR 0.38); and OPTN region, 5 (OR 0.54) and 6 (OR 0.46). ROC analysis of the index on the training set yielded a c-statistic of 0.71. ROC analysis of the index on the testing set yielded a c-statistic of 0.68. Conclusions: This index is a modest prognostic model to assess time to pediatric kidney transplantation. It is intended as a supplementary tool to guide patient management by providing clinicians with an individualized prospective timeline for each candidate. Early identification of candidates with potential for prolonged waiting times may help encourage more living donation including paired donation chains. [ABSTRACT FROM AUTHOR]

Esophagus cancer (EC) is one of the most aggressive malignant digestive system tumors and has a high clinical incidence worldwide. Magnolol, a natural compound, has anticancer effects on many cancers, including esophageal carcinoma, but the underlying mechanism has not been fully elucidated. Here, we first find that magnolol inhibits the proliferation of esophageal carcinoma cells and enhances their autophagy activity in a dose- and time-dependent manner. This study demonstrates that magnolol increases the protein levels of LC3 II, accompanied by increased HACE1 protein levels in both esophageal carcinoma cells and xenograft tumors. HACE1-knockout (KO) cell lines are generated, and the ablation of HACE1 eliminates the anti-proliferative and autophagy-inducing effects of magnolol on esophageal carcinoma cells. Additionally, our results show that magnolol primarily promotes HACE1 expression at the transcriptional level. Therefore, this study shows that magnolol primarily exerts its antitumor effect by activating HACE1-OPTN axis-mediated autophagy. It can be considered a promising therapeutic drug for esophageal carcinoma.

Normal tension glaucoma (NTG) is a complex optic neuropathy characterized by progressive retinal ganglion cell death and glaucomatous visual field loss, despite normal intraocular pressure (IOP). This condition poses a unique clinical challenge due to the absence of elevated IOP, a major risk factor in typical glaucoma. Recent research indicates that up to 21% of NTG patients have a family history of glaucoma, suggesting a genetic predisposition. In this comprehensive review using PubMed studies from January 1990 to December 2023, our focus delves into the genetic basis of autosomal dominant NTG, the only known form of inheritance for glaucoma. Specifically exploring optineurin (OPTN), TANK binding kinase 1 (TBK1), methyltransferase-like 23 (METTL23), and myocilin (MYOC) mutations, we summarize their clinical manifestations, mutant protein behaviors, relevant animal models, and potential therapeutic pathways. This exploration aims to illuminate the intricate pathogenesis of NTG, unraveling the contribution of these genetic components to its complex development. [ABSTRACT FROM AUTHOR]

Melanosomes are specific organelles dedicated to melanin synthesis and accumulation in melanocytes. Autophagy is suggestively involved in melanosome degradation, although the potential underlying molecular mechanisms remain elusive. In selective autophagy, autophagy receptors and E3-ligases are the key factors conferring cargo selectivity. In B16F10 cells, β-mangostin efficiently induced melanosome degradation without affecting other organelles such as mitochondria, peroxisomes, and the endoplasmic reticulum. Among various autophagy receptors, optineurin (OPTN) contributes TANK-binding kinase 1 (TBK1)-dependently to melanosome degradation and its knockdown inhibited β-mangostin-mediated melanosome degradation. OPTN translocation to melanosomes was dependent on its ubiquitin-binding domain. Moreover, OPTN-mediated TBK1 activation and subsequent TBK1-mediated S187 OPTN phosphorylation were essential for melanosome degradation. β-mangostin increased K63-linked melanosome ubiquitination. Finally, the E3-ligase RCHY1 knockdown inhibited the melanosome ubiquitination required for OPTN- and TBK1-phosphorylation as well as melanosome degradation. This study suggests that melanophagy, melanosome-selective autophagy, contributes to melanosome degradation, and OPTN and RCHY1 are an essential autophagy receptor and a E3-ligase, respectively, conferring cargo selectivity in melanophagy. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to assess the impact of community-level socioeconomic deprivation on survival outcomes following heart transplantation. Background: Despite growing awareness of socioeconomic disparities in the US health care system, significant inequities in outcomes remain. While recent literature has increasingly considered the effects of structural socioeconomic deprivation, the impact of community socioeconomic distress on outcomes following heart transplantation has not yet been elucidated. Methods: All adult heart transplant recipients from 2004 to 2022 were ascertained from the Organ Procurement and Transplantation Network. Community socioeconomic distress was assessed using the previously validated Distressed Communities Index, a metric that represents education level, housing vacancies, unemployment, poverty rate, median household income, and business growth by zip code. Communities in the highest quintile were considered the Distressed cohort (others: Non-Distressed). Outcomes were considered across 2 eras (2004-2018 and 2019-2022) to account for the 2018 UNOS Policy Change. Three-and 5-year patient and graft survival were assessed using Kaplan-Meier and Cox proportional hazards models. Results: Of 36,777 heart transplants, 7450 (20%) were considered distressed. Following adjustment, distressed recipients demonstrated a greater hazard of 5-year mortality from 2004 to 2018 [hazard ratio (HR)=1.10, 95% confidence interval (CI): 1.03-1.18; P=0.005] and 3-year mortality from 2019 to 2022 (HR=1.29, 95% CI: 1.10-1.51; P=0.002), relative to nondistressed. Similarly, the distressed group was associated with increased hazard of graft failure at 5 years from 2004 to 2018 (HR=1.10, 95% CI: 1.03-1.18; P= 0.003) and at 3 years from 2019 to 2022 (HR=1.31, 95% CI: 1.11-1.53; P=0.001). Conclusions: Community-level socioeconomic deprivation is linked with inferior patient and graft survival following heart transplantation. Future interventions are needed to address pervasive socioeconomic inequities in transplantation outcomes. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor neuron (MN) death. Mutation of the superoxide dismutase 1 (SOD1) gene, which results in abnormal protein aggregation, is one of the causes of familial ALS. Autophagic dysfunction occurs in SOD1‐G93A mutant mice as the disease progresses, but the etiology of this disease is still unclear. Optineurin (OPTN) is an adaptor that is involved in autophagy and participates in aggrephagy and mitophagy. Previous studies have established that OPTN mutations contribute to diseases such as glaucoma and ALS. However, the function of OPTN in autophagy and mitophagy has not been intensively investigated in models of ALS. In this study, we assessed the beneficial effect of OPTN on autophagy and mitochondrial function by intrathecally injecting adeno‐associated virus 9 (AAV9)‐OPTN into SOD1‐G93A transgenic mice and by administering lentivirus (LV)‐OPTN to cells expressing the SOD1‐G93A mutant protein. The expression of voltage‐dependent anion channel 1 (VDAC1) was increased and autophagy was elevated after OPTN gene therapy, as shown by a lower level of p62 and a higher level of microtubule‐associated protein 1A/1B‐light chain 3 (LC3)‐II. Moreover, using electron microscopy, we observed a hyperpolarized mitochondrial transmembrane potential and reversal of mitochondrial morphological abnormalities. Furthermore, the protein level of TANK‐binding kinase 1 (TBK1) was increased, suggesting that mitophagy was increased. Our findings from both animal and cell line studies strongly suggest that OPTN gene therapy is a powerful strategy to increase autophagy and protect mitochondria to prevent the progression of ALS and could be effective in the treatment of ALS. [ABSTRACT FROM AUTHOR]

Anti-bacterial autophagy, also known as xenophagy, is a crucial innate immune process that helps maintain cellular homeostasis by targeting invading microbes. This defense pathway is widely studied in the context of infections with mycobacteria, the causative agents of human tuberculosis and tuberculosislike disease in animal models. Our previous work in a zebrafish tuberculosis model showed that host defense against Mycobacterium marinum (Mm) is impaired by deficiencies in xenophagy receptors, optineurin (Optn) or sequestome 1 (p62), and Damage-regulated autophagy modulator 1 (Dram1). However, the interdependency of these receptors and their interaction with Dram1 remained unknown. In the present study, we used single and double knockout zebrafish lines in combination with overexpression experiments. We show that Optn and p62 can compensate for the loss of each other's function, as their overexpression restores the infection susceptibility of the mutant phenotypes. Similarly, Dram1 can compensate for deficiencies in Optn and p62, and, vice versa, Optn and p62 compensate for the loss of Dram1, indicating that these xenophagy receptors and Dram1 do not rely on each other for host defense against Mm. In agreement, Dram1 overexpression in optn/p62 double mutants restored the interaction of autophagosome marker Lc3 with Mm. Finally, optn/p62 double mutants displayed more severe infection susceptibility than the single mutants. Taken together, these results suggest that Optn and p62 do not function downstream of each other in the anti-mycobacterial xenophagy pathway, and that the Dram1-mediated defense against Mm infection does not rely on specific xenophagy receptors. [ABSTRACT FROM AUTHOR]

HACE1 is a member of the HECT domain-containing E3 ligases with 909 amino acid residues, containing N-terminal ankyrin-repeats (ANK) and C-terminal HECT domain. Previously, it was shown that HACE1 is inactive in human tumors and plays a crucial role in the initiation, progression, and invasion of malignant tumors. Recent studies indicated that HACE1 might be closely involved in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. HACE1 interacts with its substrates, including Ras-related C3 botulinum toxin substrate 1 (Rac1), nuclear factor erythroid 2-related factor 2 (Nrf2), tumor necrosis factor receptor (TNFR), and optineurin (OPTN), through which participates in several pathophysiological processes, such as oxidative stress, autophagy and inflammation. Therefore, in this review, we elaborately describe the essential substrates of HACE1 and illuminate the pathophysiological processes by which HACE1 is involved in neurodegenerative diseases. We provide a new molecular target for neurodegenerative diseases.

ABSTRACTTank-binding kinase 1 (TBK1) plays a pivotal role as a cellular factor in regulating the immune response against herpes simplex virus type 1 (HSV-1). TBK1’s role in defending against HSV-1 is attributed to its capacity to induce the type I interferon response. Recent discoveries emphasize TBK1’s involvement in the regulation of optineurin (OPTN), an autophagy adaptor protein that plays a direct role in enhancing the antiviral response against HSV-1 through selective autophagy. Intriguingly, OPTN can also reciprocally regulate TBK1, leading to a limited understanding of the precise role of the OPTN-TBK1 axis in HSV-1 infection. In our study, we shed light on the relationship between OPTN and TBK1 in influencing the outcome of HSV-1 infection. Surprisingly, when TBK1 or OPTN was absent in cells, the spread and infectivity of HSV-1 did not align as expected. Furthermore, it was unexpected to note that cells lacking OPTN showed higher interferon expression compared to normal cells, yet they exhibited enhanced viral growth. Our investigations revealed that OPTN can directly degrade HSV-1 through autophagy even in the absence of active TBK1. Interestingly, we identified that another protein, Polo-like kinase 1 (PLK1), can compensate for the absence of TBK1 and trigger autophagy to restrict HSV-1. In summary, our findings highlight that OPTN significantly impacts the outcome of HSV-1 infection, regardless of the conventional antiviral response mediated by TBK1. Additionally, by introducing a new role for PLK1, this research provides valuable insights into the intricate interplay among OPTN, TBK1, and autophagy in shaping the course of HSV-1 infection.IMPORTANCEHerpes simplex virus type 1 (HSV-1) is globally prevalent, with latent infections observed in up to 80% of the population. The virus is known for subverting host defense mechanisms and infiltrating the nervous system to establish latency in peripheral ganglia. Multiple stressors can reactivate the virus, and recurrent herpes has been linked to vision loss and neurodegeneration. Identifying critical host factors that limit the spread of HSV-1 and the subsequent establishment of latent infection holds the potential to drive new intervention strategies for eradicating the virus. Numerous pieces of evidence underscore the significance of Tank-binding kinase 1 (TBK1) in restricting HSV-1. Reports have also suggested that phosphorylation of optineurin (OPTN) by TBK1 is required for triggering OPTN-mediated autophagy for HSV degradation. This report adds new insights into the roles of OPTN and TBK1 in HSV-1 infection and provides proof of a TBK1-independent HSV-1 restriction through OPTN. It confirms that TBK1 activation can be substituted by PLK1 to provide protection against HSV-1. In contrast, the activation of OPTN is likely an indispensable host defense mechanism for optimal defense against HSV-1.

Glaucoma is the second leading cause of irreversible blindness worldwide. Although genetic background contributes differently to rare early-onset glaucoma (before age 40) or common adult-onset glaucoma, it is now considered an important factor in all major forms of the disease. Genetic and genomic studies, including GWAS, are contributing to identifying novel loci associated with glaucoma or to endophenotypes across ancestries to enrich the knowledge about glaucoma genetic susceptibility. Moreover, new high-throughput functional genomics contributes to defining the relevance of genetic results in the biological pathways and processes involved in glaucoma pathogenesis. Such studies are expected to advance significantly our understanding of glaucoma’s genetic basis and provide new druggable targets to treat glaucoma. This review gives an overview of the role of genetics in the pathogenesis or risk of glaucoma.

Transplantation is a high‐risk, high‐cost treatment for end‐stage diseases and is the most strictly regulated area of healthcare in the United States. Thus, achieving success for patients and the program requires skillful and collaborative leadership. Various factors, such as outcomes, volume, and financial health, may measure the success of a transplant program. Strong collaboration between clinical and administrative leaders is key to achieving and maintaining success in those three categories. Clinical leaders of adult programs, such as medical and surgical directors, bear the primary responsibility for a program's volume, outcomes, and patient safety, while administrative directors are focused on business intelligence and regulatory compliance. This paper aims to provide readers with insights into the critical role of collaborative leadership in running a successful program, with a focus on clinical, business, and regulatory perspectives. [ABSTRACT FROM AUTHOR]

Gefitinib, a well-known epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor for the targeted therapy of lung cancer, induces autophagy in association with drug resistance. However, it remains unclear whether gefitinib treatment can affect the selective form of autophagy (i.e., mitophagy) and be beneficial for the treatment of human diseases with decreased autophagy, such as neurodegenerative diseases. Here, we show that gefitinib treatment promotes PINK1/Parkin-mediated mitophagy in both nonneuronal and neuronal cells, and this effect is independent of EGFR. Moreover, we found that gefitinib treatment increases the recruitment of the autophagy receptor optineurin (OPTN) to damaged mitochondria, which is a downstream signaling event in PINK1/Parkin-mediated mitophagy. In addition, gefitinib treatment significantly alleviated neuronal damage in TBK1-deficient neurons, resulting in impeded mitophagy. In conclusion, our study suggests that gefitinib promotes PINK1/Parkin-mediated mitophagy via OPTN and may be beneficial for the treatment of neurodegenerative diseases that are associated with defective mitophagy.

As life span rises, dementia has become a growing public health issue. According to current estimates, almost 50 million people worldwide have dementia, and the number is expected to grow. Next generation sequencing (NGS) methods have helped significantly with identifying causative gene variants related to various cognitive disorders. Our study aimed to analyze the genetic basis of cognitive disorders using NGS clinical exome panel. The study included a total number of 15 unrelated cases diagnosed with cognitive disorders, all negative after standard targeted genetic testing was performed (available at Neurology Clinic, UCCS, Belgrade, Serbia). Preference was given to familial cases with early presentation or complex phenotype. Sequencing of a clinical exome (CE) panel for 4813 genes with known associated clinical phenotypes was performed using TruSight One sequencing panel on an Illumina MiSeq NGS platform according to the manufacturer's instructions (Illumina, San Diego, CA, USA). Variants were analyzed with Illumina Variant Studio v3 software provided by Illumina as well as a previously developed pipeline. Variants analysis and interpretation were based on phenotype gene target approach, literature and databases search, allele frequency, and pathogenicity prediction by in silico software. All causative variants were confirmed by Sanger sequencing. Whenever possible, additional family members were studied for segregation analysis. CE panel analysis revealed a likely genetic cause in four patients. We have detected two missense heterozygous pathogenic variants in the PSEN1 gene in one patient each and homozygous nonsense pathogenic variant in the OPTN gene in two more patients. Detected pathogenic variants are in line with the clinical phenotype of our patients. In the rest of the 11 cases, genetic diagnosis remains unclear. The results of our study emphasize the significance of CE panel analysis in establishing a diagnosis for patients with dementia. Furthermore, give us insight into the complexity of the genetic background of this group of disorders. [ABSTRACT FROM AUTHOR]

Optineurin (OPTN) is an autophagy receptor that participates in the degradation of damaged mitochondria, protein aggregates, and invading pathogens. OPTN is closely related to various types of neurodegenerative diseases. However, the role of OPTN in the central nervous system is unclear. Here, we found that OPTN dysregulation in the compact part of substantia nigra (SNc) led to motor and learning deficits in animal models. Knockdown of OPTN increased total and phosphorylated α-synuclein levels which induced microglial activation and dopaminergic neuronal loss in the SNc. Overexpression of OPTN can't reverse the motor and learning phenotypes. Mechanistic analysis revealed that upregulation of OPTN increased α-synuclein phosphorylation independent of its autophagy receptor activity, which further resulted in microglial activation and dopaminergic neuronal loss similar to OPTN downregulation. Our study uncovers the crucial role of OPTN in maintaining dopaminergic neuron survival and motor and learning functions which are disrupted in PD patients., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Donation after circulatory death (DCD) could account for the largest expansion of the donor allograft pool in the contemporary era. However, the organ yield and associated costs of normothermic regional perfusion (NRP) compared to super-rapid recovery (SRR) with ex-situ normothermic machine perfusion, remain unreported. The Organ Procurement and Transplantation Network (December 2019 to June 2023) was analyzed to determine the number of organs recovered per donor. A cost analysis was performed based on our institution's experience since 2022. Of 43 502 donors, 30 646 (70%) were donors after brain death (DBD), 12 536 (29%) DCD-SRR and 320 (0.7%) DCD-NRP. The mean number of organs recovered was 3.70 for DBD, 3.71 for DCD-NRP (P < .001), and 2.45 for DCD-SRR (P < .001). Following risk adjustment, DCD-NRP (adjusted odds ratio 1.34, confidence interval 1.04-1.75) and DCD-SRR (adjusted odds ratio 2.11, confidence interval 2.01-2.21; reference: DBD) remained associated with greater odds of allograft nonuse. Including incomplete and completed procurement runs, the total average cost of DCD-NRP was $9463.22 per donor. By conservative estimates, we found that approximately 31 donor allografts could be procured using DCD-NRP for the cost equivalent of 1 allograft procured via DCD-SRR with ex-situ normothermic machine perfusion. In conclusion, DCD-SRR procurements were associated with the lowest organ yield compared to other procurement methods. To facilitate broader adoption of DCD procurement, a comprehensive understanding of the trade-offs inherent in each technique is imperative., Competing Interests: Declaration of competing interest The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. John Gutowski and Jordan Hoffman are individual shareholders in TransMedics. Jordan Hoffman is a member of the Donor Alliance Advisory Board and recipient of the ISHLT/O.H. “Bud” Frazier Grant in MCS Translational Research sponsored by Medtronic (ended 2022). Joseph Cleveland received payment from Abbott Medical for serving as the chair of the CEC for the ARiES HM3 trial. Elizabeth Pomfret is the President of the American Society of Transplant Surgeons. Syed Shahyan Bakhtiyar, Tiffany Maksimuk, Sarah Park, Michael Cain, Jessica Rove, T. Brett Reece, James Pomposelli, Yanik Bababekov, Trevor Nydam, and Jesse Schold have no financial disclosures or conflicts of interest to report., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Avibirnavirus, specifically Infectious Bursal Disease Virus (IBDV), is a highly contagious pathogen that causes significant economic losses in the poultry industry. The polymerase protein VP1 of IBDV is critical to the viral life cycle, facilitating the synthesis of viral mRNA and the genome. Previous studies have suggested that various host factors influence the regulation of IBDV polymerase activity. In this study, we identified that IBDV infection induces the expression of optineurin (OPTN), a mitophagy receptor and a protein associated with amyotrophic lateral sclerosis (ALS), as well as a negative regulator of interferon I production. The induced expression of OPTN acts as a suppressor of IBDV replication, a function dependent on its ubiquitin-binding domain (UBAN). Furthermore, we demonstrated that OPTN exerts its antiviral effects through direct interactions with VP1 and VP3, which inhibit the polymerase activity of VP1 by preventing K63-linked ubiquitination of VP1. To our knowledge, this study is the first to report that OPTN, upregulated during IBDV infection, functions as a novel antiviral host factor that limits the virus's replicative capacity, offering a potential target for anti-IBDV therapeutic strategies., Competing Interests: Declaration of Competing Interest All of the authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: While structural socioeconomic inequity has been linked with inferior health outcomes, some have postulated reduced access to high-quality care to be the mediator. We assessed whether treatment at high-volume centers (HVC) would mitigate the adverse impact of area deprivation on heart transplantation (HT) outcomes., Methods: All HT recipients ≥18 years were identified in the 2005-2022 Organ Procurement and Transplantation Network. Neighborhood socioeconomic deprivation was assessed using the previously validated Area Deprivation Index. Recipients with scores in the highest quintile were considered Most Deprived (others: Less Deprived). Hospitals in the highest quartile by cumulative center volume (≥21 transplants/year) were classified as HVC. The primary outcome was post-transplant survival., Results: Of 38,022 HT recipients, 7,579 (20%) were considered Most Deprived. Following risk adjustment, Most Deprived demonstrated inferior survival at 3 (hazard ratio [HR] 1.14, 95% confidence interval [CI] 1.06-1.21) and 5 years following transplantation (HR 1.13, CI 1.07-1.20). Similarly, Most Deprived faced greater graft failure at 3 (HR 1.14, CI 1.06-1.22) and 5 years (HR 1.13, CI 1.07-1.20). Evaluating patients transplanted at HVC, Most Deprived continued to face greater mortality at 3 (HR 1.10, CI 1.01-1.21) and 5 years (HR 1.10, CI 1.01-1.19). The interaction between Most Deprived status and care at HVC was not significant, such that transplantation at HVC did not ameliorate the survival disparity between Most and Less Deprived., Conclusions: Area socioeconomic disadvantage is independently associated with inferior survival. Transplantation at HVC did not eliminate this inequity. Future efforts are needed to increase engagement with longitudinal follow-up care and address systemic root causes to improve outcomes., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The American Transplant Congress (ATC) is the largest national transplant meeting in the United States jointly sponsored by the American Society of Transplantation and the American Society of Transplant Surgeons. The 2024 ATC was held in Philadelphia, Pennsylvania during which a number of peer-reviewed scientific abstracts were censored from the program by the Health Resources and Services Administration. These abstract presentations were redacted from the program for perceived conflict with current government policy effectively restricting dissemination of highly rated findings and discussion in a scientific forum. In this viewpoint, we describe the content of the abstracts that were withdrawn from the annual ATC meeting and the implications of this censorship by the Health Resources and Services Administration. We further consider the ramifications of this action for the prospective evaluation of government policy and the relationship of the contract agency with the transplant community in the context of ongoing discussions of modernizing the transplant system which has previously been critiqued for lack of transparency., Competing Interests: Declaration of competing interest The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. J. D. Schold reports being the current chair of the Data Advisory Committee at the United Network for Organ Sharing. E. A. Pomfret reports being the immediate past president of the American Society of Transplant Surgeons. T. B. Dunn reports being the vice chair of the Pancreas Committee at the United Network for Organ Sharing., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Low back pain is thought to be mainly caused by intervertebral disc degeneration (IVDD), and there is a lack of effective treatments. Cellular senescence and matrix degradation are important factors that cause disc degeneration. Mitochondrial dysfunction induced by oxidative stress is an important mechanism of cellular senescence and matrix degradation in the nucleus pulposus (NP), and mitophagy can effectively remove damaged mitochondria, restore mitochondrial homeostasis, and mitigate the damage caused by oxidative stress. Optineurin (OPTN) is a selective mitophagy receptor, and its role in intervertebral disc degeneration remains unclear. Here, we aimed to explore the effect of OPTN on H2O2-induced nucleus pulposus cell (NPCs) senescence and matrix degradation in a rat model of disc degeneration. Western blot analysis showed that OPTN expression was reduced in degenerative human and rat nucleus pulposus tissues and increased in H2O2-induced senescent NPCs. OPTN overexpression significantly inhibited H2O2-induced senescence and increased matrix-associated protein expression in NPCs, but OPTN knockdown showed the opposite effect. As previous reports have suggested that mitophagy significantly reduces mitochondrial damage and reactive oxygen species (ROS) caused by oxidative stress, and we used the mitophagy agonist CCCP, the mitophagy inhibitor cyclosporin A (CsA), and the mitochondrial ROS (mtROS) scavenger mitoTEMPO and confirmed that OPTN attenuated NPCs senescence and matrix degeneration caused by oxidative stress by promoting mitophagy to scavenge damaged mitochondria and excess reactive oxygen species, thereby slowing the progression of IVDD. In conclusion, our research suggests that OPTN is involved in IVDD and exerts beneficial effects against IVDD. [ABSTRACT FROM AUTHOR]

Background: Organ Procurement and Transplantation Network (OPTN) implemented medical eligibility and safety‐net policy on 8/10/17 to optimize simultaneous liver‐kidney (SLK) utilization. We examined impact of this policy on SLK listings and number of kidneys used within 1‐yr. of receiving liver transplantation (LT) alone. Methods and results: OPTN database (08/10/14‐06/12/20) on adults (N = 66 709) without previous transplant stratified candidates to listings for SLK or LT alone with pre‐LT renal dysfunction at listing (eGFR < 30 mL/min or on dialysis). Outcomes were compared for pre (08/10/14‐08/09/17) vs. post (08/10/17‐06/12/20) policy era. SLK listings decreased in post vs. pre policy era (8.7% vs. 9.6%; P <.001), with 22% reduced odds of SLK listing in the postpolicy era, with a decrease in all OPTN regions except regions 6 and 8, which showed an increase. Among LT‐alone recipients with pre‐LT renal dysfunction (N = 3272), cumulative 1‐year probability was higher in post vs. prepolicy period for dialysis (5.6% vs. 2.3%; P <.0001), KT listing (11.4% vs. 2.0%; P <.0001), and KT (3.7% vs..25%; P <.0001). Sixty‐seven (2.4%) kidneys were saved in post policy era, with 18.1%, 16.6%, 4.3%, and 2.9% saving from regions 7, 2, 11, and 1, respectively. Conclusion: Medical eligibility and safety‐net OPTN policy resulted in decreased SLK use and improved access to LT alone among those with pre‐LT renal dysfunction. Although decreased in postpolicy era, regional variation of SLK listings remains. In spite of increased use of KT within 1‐year of receiving LT alone under safety net, less number of kidneys were used without impact on patient survival in postpolicy era. [ABSTRACT FROM AUTHOR]

Introduction: Non-Alcoholic Steatohepatitis is an increasing reason for liver transplantation in the western world. Knowledge of recipient life expectancy may assist in prudent allocation of a relatively scarce supply of donor livers. Research Questions: We calculated life expectancies for Non-alcoholic steatohepatitis (NASH) patients both at time of transplant and one year later, stratified by key risk factors, and examined whether survival has improved in recent years. Design: Data on 6635 NASH patients who underwent liver transplantation in the MELD era (2002-2018) from the United States OPTN database were analyzed using the Cox proportional hazards regression model and life table methods. Results: Factors related to survival were age, presence of diabetes or hepatic encephalopathy (HE), and whether the patient required dialysis in the week prior to transplant. Other important factors were whether the patient was working, hospitalization prior to transplant, ventilator support, and length of hospital stay (LOS). Survival improved over the study period at roughly 4.5% per calendar year during the first year posttransplant, though no improvement was observed in those who had survived one year. Conclusion: Life expectancy in NASH transplant patients was much reduced from normal, and varied according to age, medical factors, status at transplant, and post transplant course. Over the 17-year study period, patient survival improved markedly during the first year posttransplant, though not thereafter. The results given here may prove helpful in medical decision-making regarding treatment for both liver disease and other medical conditions, as they provide both clinicians and their patients with evidence-based information on prognosis. [ABSTRACT FROM AUTHOR]

In recent years, considerable progress has been made in the study of glaucoma, especially primary open angle glaucoma(POAG). A series of POAG genes has been identified through genetic linkage analysis and genome-wide association studies(GWAS), which significantly advanced the study of glaucoma genetics. The latest perspective suggests that glaucoma is a disease of the central nervous system(CNS). A large number of basic clinical studies have demonstrated the close association between CNS disease and glaucoma. Among these studies, discoveries related to genetics are of prominence.

Objective: To explore the therapeutic potential and the underlying mechanism of metformin, an adenosine monophosphate‐activated kinase (AMPK) activator, in ocular melanoma. Methods: CCK8, transwell, and colony formation assays were performed to detect the proliferation and migration ability of ocular melanoma cells. A mouse orthotopic xenograft model was built to detect ocular tumor growth in vivo. Western blot, immunofluorescence, and electron microscopy were adopted to evaluate the autophagy levels of ocular melanoma cells, and high‐throughput proteomics and CUT & Tag assays were performed to analyze the candidate for autophagy alteration. Results: Here, we revealed for the first time that a relatively low dose of metformin induced significant tumorspecific inhibition of the proliferation and migration of ocular melanoma cells both in vitro and in vivo. Intriguingly, we found that metformin significantly attenuated autophagic influx in ocular melanoma cells. Through high‐throughput proteomics analysis, we revealed that optineurin (OPTN), which is a key candidate for autophagosome formation and maturation, was significantly downregulated after metformin treatment. Moreover, excessive OPTN expression was associated with an unfavorable prognosis of patients. Most importantly, we found that a histone deacetylase, SIRT1, was significantly upregulated after AMPK activation, resulting in histone deacetylation in the OPTN promoter. Conclusions: Overall, we revealed for the first time that metformin significantly inhibited the progression of ocular melanoma, and verified that metformin acted as an autophagy inhibitor through histone deacetylation of OPTN. This study provides novel insights into metformin ‐ guided suppression of ocular melanoma and the potential mechanism underlying the dual role of metformin in autophagy regulation. [ABSTRACT FROM AUTHOR]

Background: Alcohol-associated liver disease is the leading cause of liver transplantation in the western world. For these patients we calculated life expectancies both at time of transplant and several years later, stratified by key risk factors, and determined if survival has improved in recent years. Methods: Data on 14 962 patients with alcohol-associated liver disease who underwent liver transplantation in the MELD era (2002-2018) from the United States Organ Procurement and Transplantation Network database were analyzed using the Cox proportional hazards regression model and life table methods. Results: Demographic and past medical history factors related to survival were patient age, presence of diabetes or severe hepatic encephalopathy, and length of hospital stay. Survival improved over the study period, at roughly 3% per calendar year during the first 5 years posttransplant and 1% per year thereafter. Conclusions: Life expectancy in transplanted patients with alcohol-associated liver disease was much reduced from normal, and varied according to age, medical risk factors, and functional status. Survival improved modestly over the study period. Information on patient longevity can be helpful in making treatment decisions. [ABSTRACT FROM AUTHOR]

Abstract Objective To explore the therapeutic potential and the underlying mechanism of metformin, an adenosine monophosphate‐activated kinase (AMPK) activator, in ocular melanoma. Methods CCK8, transwell, and colony formation assays were performed to detect the proliferation and migration ability of ocular melanoma cells. A mouse orthotopic xenograft model was built to detect ocular tumor growth in vivo. Western blot, immunofluorescence, and electron microscopy were adopted to evaluate the autophagy levels of ocular melanoma cells, and high‐throughput proteomics and CUT & Tag assays were performed to analyze the candidate for autophagy alteration. Results Here, we revealed for the first time that a relatively low dose of metformin induced significant tumorspecific inhibition of the proliferation and migration of ocular melanoma cells both in vitro and in vivo. Intriguingly, we found that metformin significantly attenuated autophagic influx in ocular melanoma cells. Through high‐throughput proteomics analysis, we revealed that optineurin (OPTN), which is a key candidate for autophagosome formation and maturation, was significantly downregulated after metformin treatment. Moreover, excessive OPTN expression was associated with an unfavorable prognosis of patients. Most importantly, we found that a histone deacetylase, SIRT1, was significantly upregulated after AMPK activation, resulting in histone deacetylation in the OPTN promoter. Conclusions Overall, we revealed for the first time that metformin significantly inhibited the progression of ocular melanoma, and verified that metformin acted as an autophagy inhibitor through histone deacetylation of OPTN. This study provides novel insights into metformin ‐ guided suppression of ocular melanoma and the potential mechanism underlying the dual role of metformin in autophagy regulation.

Bw4 and Bw6 are strongly immunogenic epitopes routinely assigned based on HLA-B typing results per Organ Procurement and Transplantation Network (OPTN) policies. These public epitopes and their variants are shared by some cross-reactive HLA-A and -C antigens. Although epitope mismatch has been associated with poor transplant outcomes, previous studies did not find such associations for Bw4/6 mismatch as defined by HLA-B antigens only. We hypothesized that a broader definition for Bw4/Bw6 mismatch that includes cross-reactive HLA-A and -C antigens may reveal the risk associated with these epitopes. In this retrospective cohort study, we examined kidney transplantations between 2000 and 2016 in the OPTN database and determined the association of Bw4/6 mismatch across all class I HLA antigens and renal graft outcomes. Even by this broader definition, Bw4/6 mismatch was not independently associated with 1-year graft rejection (adjusted OR: 0.99, 95%CI 0.93–1.06) or death-censored graft survival (adjusted HR: 1.02, 95%CI 1.00–1.05). There was no significant association among recipients who were already sensitized at transplant either. Our findings suggest that Bw4/6 mismatch alone is not associated with poor renal graft outcomes despite their strong immunogenicity, and the load of epitope mismatches over a certain threshold is likely required to cause adverse clinical consequences. [ABSTRACT FROM AUTHOR]

TANK-binding kinase 1 (TBK1) is a multifunctional kinase with an essential role in mitophagy, the selective clearance of damaged mitochondria. More than 90 distinct mutations in TBK1 are linked to amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia, including missense mutations that disrupt the abilities of TBK1 to dimerize, associate with the mitophagy receptor optineurin (OPTN), autoactivate, or catalyze phosphorylation. We investigated how ALS-associated mutations in TBK1 affect Parkin-dependent mitophagy using imaging to dissect the molecular mechanisms involved in clearing damaged mitochondria. Some mutations cause severe dysregulation of the pathway, while others induce limited disruption. Mutations that abolish either TBK1 dimerization or kinase activity were insufficient to fully inhibit mitophagy, while mutations that reduced both dimerization and kinase activity were more disruptive. Ultimately, both TBK1 recruitment and OPTN phosphorylation at S177 are necessary for engulfment of damaged mitochondra by autophagosomal membranes. Surprisingly, we find that ULK1 activity contributes to the phosphorylation of OPTN in the presence of either wild-type or kinase-inactive TBK1. In primary neurons, TBK1 mutants induce mitochondrial stress under basal conditions; network stress is exacerbated with further mitochondrial insult. Our study further refines the model for TBK1 function in mitophagy, demonstrating that some ALS-linked mutations likely contribute to disease pathogenesis by inducing mitochondrial stress or inhibiting mitophagic flux. Other TBK1 mutations exhibited much less impact on mitophagy in our assays, suggesting that cell-type–specific effects, cumulative damage, or alternative TBK1-dependent pathways such as innate immunity and inflammation also factor into the development of ALS in affected individuals. [ABSTRACT FROM AUTHOR]

Lung transplantation in the United States, under oversight by the Organ Procurement Transplantation Network (OPTN) in the 1990s, operated under a system of allocation based on location within geographic donor service areas, wait time of potential recipients, and ABO compatibility. On May 4, 2005, the lung allocation score (LAS) was implemented by the OPTN Thoracic Organ Transplantation Committee to prioritize patients on the wait list based on a balance of wait list mortality and posttransplant survival, thus eliminating time on the wait list as a factor of prioritization. Patients were categorized into four main disease categories labeled group A (obstructive lung disease), B (pulmonary hypertension), C (cystic fibrosis), and D (restrictive lung disease/interstitial lung disease) with variables within each group impacting the calculation of the LAS. Implementation of the LAS led to a decrease in the number of wait list deaths without an increase in 1-year posttransplant survival. LAS adjustments through the addition, modification or elimination of covariates to improve the estimates of patient severity of illness, have since been made in addition to establishing criteria for LAS value exceptions for pulmonary hypertension patients. Despite the success of the LAS, concerns about the prioritization, and transplantation of older, sicker individuals have made some aspects of the LAS controversial. Future changes in US lung allocation are anticipated with the current development of a continuous distribution model that incorporates the LAS, geographic distribution, and unaccounted aspects of organ allocation into an integrated score. [ABSTRACT FROM AUTHOR]

Background: Hepatocelluar carcinoma typically occurs with underlying cirrhosis. However roughly 20% of cases arise in a non-cirrhotic liver. There is limited literature that addresses the long-term survival of the narrow subgroup who received transplantation. For such patients we sought to calculate life expectancies both at time of transplant and several years later, stratified by key risk factors, and to determine if survival has improved in recent years. Such information can be helpful in making treatment decisions. Methods: Data on 4,373 non-cirrhotic HCC patients who underwent liver transplantation in the MELD era (2002-2018) from the United States OPTN database were analyzed using the Cox proportional hazards regression model and life table methods. Results: Demographic and past medical history factors related to survival were patient age, donor age over 20, and the presence of ascites or severe hepatic encephalopathy. Survival did not vary by race or sex. HCC-specific factors significantly related to survival were the total number of tumors, extrahepatic spread, lymph node involvement, satellite lesions, micro- or macrovascular invasion, tumor differentiation (grade), and pre-transplant treatment. Survival improved over the study period, at 4% per calendar year during the first 5 years post transplant and 1% per year thereafter. Conclusions: Life expectancy in non-cirrhotic HCC transplant patients is much reduced from normal, and varies according to age and tumor-related factors. Survival improved modestly over the study period. [ABSTRACT FROM AUTHOR]

Maternal exposure to glucocorticoids has been associated with adverse outcomes in offspring. However, the consequences and mechanisms of gestational exposure to prednisone on susceptibility to osteoporosis in the offspring remain unclear. Here, we found that gestational prednisone exposure enhanced susceptibility to osteoporosis in adult mouse offspring. In a further exploration of myogenic mechanisms, results showed that gestational prednisone exposure down-regulated FNDC5/irisin protein expression and activation of OPTN-dependent mitophagy in skeletal muscle of adult offspring. Additional experiments elucidated that activated mitophagy significantly inhibited the expression of FNDC5/irisin in skeletal muscle cells. Likewise, we observed delayed fetal bone development, downregulated FNDC5/irisin expression, and activated mitophagy in fetal skeletal muscle upon gestational prednisone exposure. In addition, an elevated total m6A level was observed in fetal skeletal muscle after gestational prednisone exposure. Finally, gestational supplementation with S-adenosylhomocysteine (SAH), an inhibitor of m6A activity, attenuated mitophagy and restored FNDC5/irisin expression in fetal skeletal muscle, which in turn reversed fetal bone development. Overall, these data indicate that gestational prednisone exposure increases m6A modification, activates mitophagy, and decreases FNDC5/irisin expression in skeletal muscle, thus elevating osteoporosis susceptibility in adult offspring. Our results provide a new perspective on the earlier prevention and treatment of fetal-derived osteoporosis. [Display omitted] • Maternal prednisone increases susceptibility to osteoporosis in adult offspring. • Prednisone reduces myogenic FNDC5 level to decrease bone mass in offspring. • Prednisone activates mitophagy to degrade FNDC5 in skeletal muscle of offspring. • Prednisone enhances the m6A level to activate mitophagy in fetal skeletal muscle. [ABSTRACT FROM AUTHOR]

HACE1 is a member of the HECT domain-containing E3 ligases with 909 amino acid residues, containing N-terminal ankyrin-repeats (ANK) and C-terminal HECT domain. Previously, it was shown that HACE1 is inactive in human tumors and plays a crucial role in the initiation, progression, and invasion of malignant tumors. Recent studies indicated that HACE1 might be closely involved in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. HACE1 interacts with its substrates, including Ras-related C3 botulinum toxin substrate 1 (Rac1), nuclear factor erythroid 2-related factor 2 (Nrf2), tumor necrosis factor receptor (TNFR), and optineurin (OPTN), through which participates in several pathophysiological processes, such as oxidative stress, autophagy and inflammation. Therefore, in this review, we elaborately describe the essential substrates of HACE1 and illuminate the pathophysiological processes by which HACE1 is involved in neurodegenerative diseases. We provide a new molecular target for neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease involving the upper and lower motor neurons of the spinal cord, brainstem, and cerebral cortex. At least 30 genes have been implicated in familial ALS (fALS) and sporadic ALS (sALS). Kaneb et al. (2015) first carried out a large-scale sequencing study in ALS patients and identified two loss-of-function (LOF) variants in the GLE1 gene. The LOF mutation-induced disruption of RNA metabolism through the haploinsufficiency mechanism is implicated in ALS pathogenesis. A total of 628 ALS patients and 522 individuals without neurodegenerative disorders were enrolled in this study to explore the GLE1 gene contribution to ALS in the Chinese population. All 16 exons and the flanking intron of GLE1 were screened by Sanger sequencing. In total, we identified seven rare GLE1 coding variants, including one novel nonsense mutation and six rare missense mutations in 628 ALS patients. The frequency of GLE1 LOF mutations was 0.16% (1/628) among Chinese sALS patients, implying that it is an uncommon genetic determinant of ALS in Chinese patients. Additionally, the rare missense variants in the hCG1-binding domain of GLE1 impairing the distribution of the hGle1B isoform at the nuclear pore complex (NPC) region may be involved in the pathogenesis of ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease involving the upper and lower motor neurons of the spinal cord, brainstem, and cerebral cortex. At least 30 genes have been implicated in familial ALS (fALS) and sporadic ALS (sALS). Kaneb et al. (2015) first carried out a large-scale sequencing study in ALS patients and identified two loss-of-function (LOF) variants in the GLE1 gene. The LOF mutation-induced disruption of RNA metabolism through the haploinsufficiency mechanism is implicated in ALS pathogenesis. A total of 628 ALS patients and 522 individuals without neurodegenerative disorders were enrolled in this study to explore the GLE1 gene contribution to ALS in the Chinese population. All 16 exons and the flanking intron of GLE1 were screened by Sanger sequencing. In total, we identified seven rare GLE1 coding variants, including one novel nonsense mutation and six rare missense mutations in 628 ALS patients. The frequency of GLE1 LOF mutations was 0.16% (1/628) among Chinese sALS patients, implying that it is an uncommon genetic determinant of ALS in Chinese patients. Additionally, the rare missense variants in the hCG1-binding domain of GLE1 impairing the distribution of the hGle1B isoform at the nuclear pore complex (NPC) region may be involved in the pathogenesis of ALS. [ABSTRACT FROM AUTHOR]

Objectives: Dysfunction of autophagy results in accumulation of depolarized mitochondria and breakdown of self‐renewal and pluripotency in ESCs. However, the regulators that control how mitochondria are degraded by autophagy for pluripotency regulation remains largely unknown. This study aims to dissect the molecular mechanisms that regulate mitochondrial homeostasis for pluripotency regulation in mouse ESCs. Materials and methods: Parkin+/+ and parkin−/− ESCs were established from E3.5 blastocysts of parkin+/− x parkin+/− mating mice. The pink1−/−, optn−/− and ndp52−/− ESCs were generated by CRISPR‐Cas9. shRNAs were used for function loss assay of target genes. Mito‐Keima, ROS and ATP detection were used to investigate the mitophagy and mitochondrial function. Western blot, Q‐PCR, AP staining and teratoma formation assay were performed to evaluate the PSC stemness. Results: PINK1 or OPTN depletion impairs the degradation of dysfunctional mitochondria during reprogramming, and reduces the reprogramming efficiency and quality. In ESCs, PINK1 or OPTN deficiency leads to accumulation of dysfunctional mitochondria and compromised pluripotency. The defective mitochondrial homeostasis and pluripotency in pink1−/− ESCs can be compensated by gain expression of phosphomimetic Ubiquitin (Ub‐S65D) together with WT or a constitutively active phosphomimetic OPTN mutant (S187D, S476D, S517D), rather than constitutively inactive OPTN (S187A, S476A, S517A) or a Ub‐binding dead OPTN mutant (D477N). Conclusions: The mitophagy receptor OPTN guards ESC mitochondrial homeostasis and pluripotency by scavenging damaged mitochondria through TBK1‐activated OPTN binding of PINK1‐phosphorylated Ubiquitin. [ABSTRACT FROM AUTHOR]

Background: Hepatocelluar carcinoma, the most common primary liver cancer, has a historically dire prognosis. For hepatic cancer patients with cirrhosis who underwent liver transplantation, we sought to calculate life expectancies both at time of transplant and several years later, stratified by some key variables, and to determine if survival has improved in recent years. Methods: Data on 13,797 hepatic cancer patients with cirrhosis who underwent liver transplantation in the MELD era (2002-2018) from the US Organ Procurement and Transplantation Network database were analyzed using the Cox proportional hazards regression model and life table methods. Results: The major factors related to survival were age, donor age, transplant year, diabetes, functional status, and the presence of severe hepatic encephalopathy. Survival was significantly worse with increasing age and decreasing functional status level. There was no significant difference in survival between males and females. Survival improved over the study period, at 5% per calendar year during the first 5 years post transplant, and 1% per year thereafter. Conclusions: Life expectancies were markedly reduced from normal, even among 5-year survivors with the most favorable characteristics. Survival improved modestly over the years 2002-2018. [ABSTRACT FROM AUTHOR]

Melanosomes are specific organelles dedicated to melanin synthesis and accumulation in melanocytes. Autophagy is suggestively involved in melanosome degradation, although the potential underlying molecular mechanisms remain elusive. In selective autophagy, autophagy receptors and E3-ligases are the key factors conferring cargo selectivity. In B16F10 cells, β-mangostin efficiently induced melanosome degradation without affecting other organelles such as mitochondria, peroxisomes, and the endoplasmic reticulum. Among various autophagy receptors, optineurin (OPTN) contributes TANK-binding kinase 1 (TBK1)-dependently to melanosome degradation and its knockdown inhibited β-mangostin-mediated melanosome degradation. OPTN translocation to melanosomes was dependent on its ubiquitin-binding domain. Moreover, OPTN-mediated TBK1 activation and subsequent TBK1-mediated S187 OPTN phosphorylation were essential for melanosome degradation. β-mangostin increased K63-linked melanosome ubiquitination. Finally, the E3-ligase RCHY1 knockdown inhibited the melanosome ubiquitination required for OPTN- and TBK1-phosphorylation as well as melanosome degradation. This study suggests that melanophagy, melanosome-selective autophagy, contributes to melanosome degradation, and OPTN and RCHY1 are an essential autophagy receptor and a E3-ligase, respectively, conferring cargo selectivity in melanophagy., Competing Interests: Competing interests statement:The authors declare no competing interest.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder caused by the loss of motor neurons from the brain and spinal cord. The ALS community has made remarkable strides over three decades by identifying novel familial mutations, generating animal models, elucidating molecular mechanisms, and ultimately developing promising new therapeutic approaches. Some of these approaches reduce the expression of mutant genes and are in human clinical trials, highlighting the need to carefully consider the normal functions of these genes and potential contribution of gene loss-of-function to ALS. Here, we highlight known loss-of-function mechanisms underlying ALS, potential consequences of lowering levels of gene products, and the need to consider both gain and loss of function to develop safe and effective therapeutic strategies. In this review, Kim et al. discuss evidence for loss-of-function mutations and mechanisms in amyotrophic lateral sclerosis (ALS) and propose the need to consider both gain and loss of function for designing effective and safe therapeutic strategies. [ABSTRACT FROM AUTHOR]

Connexin-43 (Cx43) is the most abundant gap junction protein in the nervous system. It enables cell communication and has important physiological roles including ion transport and substrate exchange, all of which have been implicated in cerebral ischemia injury. Our previous in vitro and in vivo studies have demonstrated that Cx43 is internalized and degraded during ischemia stress. However, the significance of ischemia-induced degradation of Cx43 remains unclear. Herein, we demonstrated that Cx43 degradation during ischemia injury is mediated by selective autophagy; additionally, we identified two related autophagy receptors—OPTN and NDP52. Cx43 degradation during ischemia requires its phosphorylation and ubiquitination, which are mediated by PKC, Src kinases, and ubiquitin kinase PINK1. Using point mutagenesis, we identified three phosphorylation sites underlying Cx43 autophagy degradation under ischemic stress. Cx43 degradation inhibition promoted the transition of astrocytes from a pro-inflammatory to an anti-inflammatory status, based on the levels of IL-10 and TNF in ischemia. Knockdown or accelerated degradation of Cx43 protected astrocytes from apoptosis under ischemic stress. These findings elucidate the underlying mechanism of astrocytic Cx43 autophagic degradation during ischemia. The study has identified potentially novel therapeutic strategies against ischemic stroke and evidence of crosstalk between autophagic degradation of Cx43, astrocytic apoptosis, and neuroinflammation.

A sophisticated and delicate balance between bone resorption by osteoclasts and bone formation by osteoblasts regulates bone metabolism. Optineurin (OPTN) is a gene involved in primary open-angle glaucoma and amyotrophic lateral sclerosis. Although its function has been widely studied in ophthalmology and neurology, recent reports have shown its possible involvement in bone metabolism through negative regulation of osteoclast differentiation. However, little is known about the role of OPTN in osteoblast function. Here, we demonstrated that OPTN controls not only osteoclast but also osteoblast differentiation. Different parameters involved in osteoblastogenesis and osteoclastogenesis were assessed in Optn−/- mice. The results showed that osteoblasts from Optn−/- mice had impaired alkaline phosphatase activity, defective mineralized nodules, and inability to support osteoclast differentiation. Moreover, OPTN could bind to signal transducer and activator of transcription 1 (STAT1) and regulate runt-related transcription factor 2 (RUNX2) nuclear localization by modulating STAT1 levels in osteoblasts. These data suggest that OPTN is involved in bone metabolism not only by regulating osteoclast function but also by regulating osteoblast function by mediating RUNX2 nuclear translocation via STAT1. • OPTN was identified as an important regulator of bone metabolism. • Impaired dynamic bone formation indices in Optn-/- mice indicated the role of OPTN in osteogenesis. • OPTN regulated the nuclear localization of RUNX2 by modulating the STAT1 level in osteoblasts differentiation. [ABSTRACT FROM AUTHOR]

Background: Primary biliary cholangitis (PBC) is progressive and can cause end-stage liver disease necessitating a liver transplant (LT). PBC patients may be disadvantaged on LT waitlist due to MELD-based priority listing or other factors.Aim: The aim was to assess waitlist duration, waitlist mortality, and post-LT outcomes of PBC patients.Methods: The Scientific Registry of Transplant Recipients data for 1994-2016 was utilized. Adult patients with PBC without hepatocellular carcinoma (HCC) were selected. Their clinico-demographic parameters and waitlist and post-transplant outcomes were compared to those of patients with hepatitis C (HCV) without HCC.Results: Out of 223,391 listings for LT in 1994-2016, 8133 (3.6%) was for PBC without HCC. Mean age was 55.5 years, 76.9% white, 86.2% female, mean MELD score 21, 6.6% retransplants. There were 52,017 patients with hepatitis C included for comparison. The mean waitlist mortality was 17.9% for PBC and 17.6% for HCV (p > 0.05). The average transplantation rate was 57.7% for PBC and 53.3% for HCV (p < 0.0001), while waitlist dropout (death or removal due to deterioration) rate was 25.0% for PBC and 25.4% for HCV (p > 0.05). There was no significant difference in median waiting duration till transplantation between PBC patients and HCV after 2002 (103 vs. 95 days, p > 0.05). Post-LT mortality and graft loss rates were significantly lower in PBC than in HCV patients (all p < 0.02).Conclusions: Despite no evidence of impaired waitlist outcomes and favorable post-transplant survival in patients with PBC, there is still a high waitlist dropout rate suggesting the presence of an unmet need for effective treatment. [ABSTRACT FROM AUTHOR]