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At least 19 recordsLinked to original sources
PubMed2026

TIGAR deficiency enhances cardiac resilience through epigenetic programming of Parkin expression.

Mitochondrial dysfunction devastates the heart in major cardiovascular diseases, yet the mechanisms governing mitochondrial quality control remain elusive. We discovered that TIGAR (TP53-induced glycolysis and apoptosis regulator) deficiency established profound cardiac protection through developmental epigenetic programming of Parkin expression. Using mice with whole-body and cardiomyocyte-specific TIGAR knockout, we demonstrated remarkable cardioprotection following myocardial infarction with maintained ejection fraction, and complete resistance to diet-induced cardiac hypertrophy despite comparable weight gain. TIGAR deficiency triggered dramatic increases in Parkin expression across all somatic tissues except testes, where Parkin levels remained extraordinarily high (100-fold greater than cardiac levels) regardless of TIGAR status, revealing tissue-specific regulatory mechanisms. This protection was entirely Parkin dependent, as double-knockout mice lost all cardioprotective benefits. Crucially, adult TIGAR manipulation failed to alter Parkin levels, demonstrating that this pathway operated exclusively during critical developmental windows to program lifelong cardiac resilience. Whole-genome bisulfite sequencing identified reduced DNA methylation in Prkn intron 10 as the key regulatory mechanism, with CRISPR deletion dramatically increasing Parkin expression in multiple cell lines. Our findings reveal how early cardiac metabolism programs lifelong cardiac function through epigenetic mechanisms, and identify developmental metabolic programming as a potential therapeutic target for preventing both ischemic heart disease and metabolic cardiomyopathy.

Animals↗
PubMed2025

Peri-mitochondrial actin filaments inhibit Parkin assembly by disrupting ER-mitochondria contacts.

Mitochondrial damage represents a dramatic change in cellular homeostasis, necessitating metabolic adaptation and clearance of the damaged organelle. One rapid response to mitochondrial damage is peri-mitochondrial actin polymerization within 2 min, which we term ADA (Acute Damage-induced Actin). ADA is vital for a metabolic shift from oxidative phosphorylation to glycolysis upon mitochondrial dysfunction. In the current study, we investigated the effect of ADA on Pink1/Parkin mediated mitochondrial quality control. We show that inhibition of proteins involved in the ADA pathway significantly accelerates Parkin recruitment onto depolarized mitochondria. Addressing the mechanism by which ADA resists Parkin recruitment onto depolarized mitochondria, we found that ADA disrupts ER-mitochondria contacts in an Arp2/3 complex-dependent manner. Interestingly, overexpression of ER-mitochondria tethers overrides the effect of ADA, allowing rapid recruitment of not only Parkin but also LC3 after mitochondrial depolarization. During chronic mitochondrial dysfunction, Parkin and LC3 recruitment are completely blocked, which is reversed rapidly by inhibiting ADA. Taken together we show that ADA acts as a protective mechanism, delaying mitophagy following acute damage, and blocking mitophagy during chronic mitochondrial damage.

Ubiquitin-Protein Ligases↗
PubMed2025

Parkin Induces Ubiquitination and Large Extracellular Vesicle Release of HMGB1 to Activate Antitumor Immunity.

UNLABELLED: Parkin (PRKN) is a mitochondria-associated E3 ubiquitin ligase that mediates mitophagy and organelle quality control. More recently, PRKN has been implicated in stimulating antitumor immunity and reprogramming the tumor immune microenvironment. In this study, we showed that PRKN ubiquitinates the alarmin molecule, high-mobility group box-1 (HMGB1) on Lys146 (K146) using predominantly K48 linkages. By molecular modeling, the in-between-ring domain of PRKN (Gln326-Leu358) made extensive contacts with the amino-terminus A-box of HMGB1 (Met1-Ser42), forming a mitochondria-associated PRKN-HMGB1 complex that juxtaposes K146 to ubiquitin active site residues Gly76 and Arg74. Instead of proteasomal degradation, PRKN ubiquitination of K146 enabled the loading of HMGB1 but not HMGB1 K146A mutant, onto autophagy- and mitochondria-derived large extracellular vesicles (LEV). In turn, released PRKN-HMGB1-LEV stimulated a potent IFN and cytokine response in recipient cells, expanding CD8+ T-cell subsets with effector (CD69+/KLRG1+), self-renewal (TCF1+/PD-1+), and cytotoxic (KLRG1+/GrzB+) properties. Conditional expression of PRKN induced HMGB1 release, activated intratumoral CD8+ T cells, and suppressed syngeneic tumor growth in vivo in a response that was abolished by HMGB1 silencing. These data identify that PRKN-LEV-regulated release of HMGB1 reprograms antitumor immunity via stimulation of IFN signaling and expansion of specialized CD8+ T-cell subsets. SIGNIFICANCE: Parkin ubiquitinates the alarmin molecule HMGB1 to enable its regulated release in large extracellular vesicles that activate interferon signaling, expand specialized CD8+ T-cell subsets, and promote antitumor immunity.

HMGB1 Protein↗
PubMed2026

Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC.

High metabolic heterogeneity and plasticity of triple-negative breast cancer (TNBC) contribute to therapy resistance, necessitating identification of therapeutic vulnerabilities. Here, we identify non-canonical functions of the extracellular matrix (ECM) remodeler, lysyl oxidase (LOX), in regulating glucose metabolism and mitochondrial homeostasis and show that inhibiting LOX generates targetable vulnerability to ferroptosis. Mechanistically, LOX interacts with PARKIN and its upstream kinase PINK1, which we identified as a substrate of LOX. LOX-mediated PINK1 oxidation suppresses PARKIN phosphorylation, stabilizing hypoxia-inducible factor 1-alpha (HIF-1α) and increasing glycolysis. Concomitantly, LOX inhibits PARKIN-mediated mitophagy and maintains mitochondria-ER contacts through VDAC1 stabilization, while the LOX-HSP90 complex promotes mitochondrial Ca2+ transport and ATP production. Inhibiting LOX suppresses glycolysis, disrupts mitochondrial dynamics, reduces OXPHOS and GPX4/FSP1, and induces compensatory DHODH activity. Our "one-two punch" approach combining LOX inhibition with clinical DHODH inhibitor suppresses tumor growth in vivo in chemo-free setting. Notably, LOX protein correlates with HIF-1α/GLUT1/GPX4 in TNBC patient tumors, supporting its clinical relevance.

Ferroptosis↗
PubMed1979

Charles Dickens and the ear, nose, and throat.

Charles Dickens is known as a novelist, humorist, humanist, and a social reformist. One of his many abilities was an astute power of observation, and some of his writings included descriptions considered as original medical knowledge. Among the hundreds of characters portrayed by Dickens, many had depictions or diseases of interest to the otolaryngologist. Dickens described deaf children and was interested in the methods used in their teaching. He had a keen interest in children and their welfare and described his visits to the Childrens Hospital in London and to Parkins Institute at Boston. He described both temporary and permanent deafness following exposure to loud noise. Dickens was a medical critic and most of his writings on the subject were humorous, though mixed at times with a spicy element of satire.

Adolescent↗
PubMed1977

The difficulties of old people taking drugs.

There is considerable interest in the problems of the elderly taking drugs correctly and appropriately. A recent survey (Parkin et al. 1976) showed that these problems that have long been known in geriatric practice have now been noted by general physicians. This review was undertaken when an occupational therapist in a geriatric unit team noted that, although patients and their relatives were taught methods of dressing, toileting, shaving, bathing, eating, walking, transferring to a chair, wheelchair mobility and communication by the occupational therapist, physiotherapist and speech therapist, no advice or teaching was given concerning the accurate taking of the drugs prescribed. The results of a detailed investigation are reported elsewhere (Atkinson, Gibson & Andrews 1978). Repeatedly, patients ready for discharge were handed a batch of drugs by a nurse at the last possible moment, even while sitting by their luggage awaiting the ambulance. Following this, special attention was paid to problems such as intellectual impairment, loss of memory and confusion, poor sight, inability to handle containers, failure to take drugs and lack of patient-education. During ward rounds, particularly when a geriatric health visitor was present, attention was drawn to special topics such as the number of patients who inadvertently kill themselves and the numbers needing readmission due to failure to take drugs, overdosage or underdosage or mixing of drugs (Wade 1972). Ferguson Anderson's comment (1974) that 7.15% of hospital admissions are due to drug reactions was also noted.

Age Factors↗
PubMed2025

CNV-Finder: Streamlining Copy Number Variation Discovery.

Copy Number Variations (CNVs) play pivotal roles in the etiology of complex diseases and are variable across diverse populations. Understanding the association between CNVs and disease susceptibility is significant in disease genetics research and often requires analysis of large sample sizes. One of the most cost-effective and scalable methods for detecting CNVs is based on normalized signal intensity values, such as Log R Ratio (LRR) and B Allele Frequency (BAF), from Illumina genotyping arrays. In this study, we present CNV-Finder, a novel pipeline integrating deep learning techniques on array data, specifically a Long Short-Term Memory (LSTM) network, to expedite the large-scale identification of CNVs within predefined genomic regions. This facilitates efficient prioritization of samples for time-consuming or costly subsequent analyses such as Multiplex Ligation-dependent Probe Amplification (MLPA), short-read, and long-read whole genome sequencing. We incorporate four genes to establish our methods-Parkin (PRKN), Leucine Rich Repeat And Ig Domain Containing 2 (LINGO2), Microtubule Associated Protein Tau (MAPT), and alpha-Synuclein (SNCA)-which may be relevant to neurological diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Progressive Supranuclear Palsy (PSP), or related disorders such as essential tremor (ET). By training our models on expert-annotated samples and validating them across diverse cohorts, including those from the Global Parkinson's Genetics Program (GP2) and additional dementia-specific databases, we demonstrate the efficacy of CNV-Finder in accurately detecting deletions and duplications. Our pipeline outputs app-compatible files for visualization within CNV-Finder's interactive web application. This interface enables researchers to review predictions and filter displayed samples by model prediction values, LRR range, and variant count in order to explore or confirm results. Our pipeline integrates this human feedback to enhance model performance and reduce false positive rates. Through a series of comprehensive analyses and validations using visual inspection, MLPA, short-read, and long-read sequencing data, we demonstrate the robustness and adaptability of CNV-Finder in identifying CNVs with regions of varied size, probe density, and noise. Our findings highlight the significance of contextual understanding and human expertise in enhancing the precision of CNV identification, particularly in complex genomic regions like 17q21.31. The CNV-Finder pipeline is a scalable, publicly available resource for the scientific community, available on GitHub (https://github.com/GP2code/CNV-Finder; DOI 10.5281/zenodo.14182563). CNV-Finder not only expedites accurate candidate identification but also significantly reduces the manual workload for researchers, enabling future targeted validation and downstream analyses in regions or phenotypes of interest.

Copy Number Variation (CNV)↗
PubMed2026

Apolipoprotein E promotes papillary thyroid carcinoma progression by activating PINK1/Parkin-mediated mitophagy.

BACKGROUND: Increasing evidence supports a progression-related role of apolipoprotein E (APOE) in papillary thyroid carcinoma (PTC), yet a clear mechanistic explanation for this association is still lacking. Considering the pivotal role of mitochondrial homeostasis in tumorigenesis, the potential role of APOE in promoting PTC progression through mitophagy regulation was investigated. Additionally, the involvement of the PINK1/Parkin-associated pathway in this process was examined to provide insights into its contribution to tumor progression. METHODS: APOE in thyroid carcinoma was characterized in terms of its expression profile, diagnostic relevance, and potential biological functions, based on integrative evidence derived from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. APOE and mitophagy-related protein expression were further examined in PTC tissues by immunohistochemistry. Further evaluation of APOE in PTC cell lines focused on its association with proliferation, apoptosis, and mitophagy, with bidirectional functional perturbation serving as the basis for assessment. Pharmacological inhibitors were used to assess the involvement of mitophagy-related signaling in the observed APOE-dependent phenotypes. Additionally, the in vivo impact of APOE on PTC tumor growth and mitophagy was further investigated through a nude mouse xenograft model, providing insight into its potential role in tumor progression. RESULTS: A significant upregulation of APOE was observed in thyroid carcinoma tissues and PTC cell lines, supporting its potential relevance as a diagnostic biomarker. The modulation of APOE expression significantly influenced PTC cell proliferation and apoptosis, with overexpression promoting cell proliferation and inhibiting apoptosis, while knockdown led to the opposite effects. Mechanistically, APOE overexpression increased AMP-activated protein kinase (AMPK) phosphorylation and decreased mammalian target of rapamycin (mTOR) phosphorylation, accompanied by increased PINK1 and Parkin expression and mitophagy-related changes, including altered mitochondrial membrane potential, reduced overall reactive oxygen species levels, and increased autophagosome formation. Pharmacological inhibition of mitophagy attenuated the proliferative and antiapoptotic effects of APOE. CONCLUSIONS: These findings demonstrate that APOE promotes PTC progression in association with PINK1/Parkin-related mitophagy and modulation of the AMPK/mTOR axis. The APOE-associated mitophagy axis may provide a rationale for future preclinical investigation in PTC.

Apolipoprotein E (APOE)↗
PubMed2026

Mitochondrial resilience: a convergent framework for pathogenesis and neuroprotection in Parkinson's disease.

Parkinson's disease (PD) is traditionally described as a dopaminergic neurodegenerative disorder driven by α-synuclein aggregation and selective neuronal loss in the substantia nigra pars compacta. While this characterization captures the core clinical and pathological features, it does not fully explain disease initiation and progression. Converging evidence from human genetics, cellular and structural biology, and systems neuroscience now supports a unified framework in which PD results from the progressive erosion of mitochondrial resilience. Here, mitochondrial resilience denotes the capacity of neuronal mitochondrial networks to withstand stress and recover bioenergetic and cellular homeostasis through coordinated quality control, metabolic adaptation, and organelle communication. Rare, high-impact monogenic mutations in PINK1, PRKN (encoding Parkin), PARK7 (DJ-1), LRRK2, and SNCA, along with common risk variants identified in genome-wide association studies, converge on interconnected pathways that govern mitochondrial quality control, bioenergetics, organelle dynamics, and cellular stress responses. These vulnerabilities are most pronounced in the highly energetic dopaminergic neurons of the substantia nigra, where sustained calcium cycling, high bioenergetic demand, and environmental stressors increase cellular susceptibility. Research has moved beyond early observations of respiratory chain impairment and oxidative stress to reveal context-specific disruptions in PINK1/Parkin-mediated mitophagy, lysosomal trafficking, mitochondrial-derived vesicle dynamics, and neuroimmune signaling. This integrated framework reframes PD as a disorder of impaired cellular maintenance rather than solely a consequence of late-stage degenerative processes. It provides a translational shift from mechanism-based biomarkers to early detection of mitochondrial failure and supports therapeutic strategies aimed at restoring mitochondrial function and resilience, offering a direct route to disease-modifying neuroprotection in PD and potentially other neurodegenerative disorders.

LRRK2↗
PubMed1975

The modified Tokyo larynx: an improved pneumatic speech aid.

The Tokyo, or Japanese, artificial larynx is a pneumatic speech aid with superior sound production used in the rehabilitation of laryngectomized patients. Although there are some difficulties with its use, modifications have been developed that eliminate the major problems. Three brief case reports demonstrate the effectiveness of this speech aid when properly prescribed.

Aged↗
PubMed1976

Blindness and total ophthalmoplegia. A complication of transantral ligation of the internal maxillary artery for epistaxis.

Unilateral blindness and total ophthalmoplegia developed on the same side on which transantral ligation of the internal maxillary artery was performed for persistent posterior epistaxis. Evaluation with arteriograms and phlebograms showed no compromise of retinal vessels or cavernous sinus thrombosis. At reexploration of the maxillary antrum, marked swelling of previously placed oxidized cellulose gauze was found. An experimental model, using the rabbit, was designed to determine if implantation of oxidized cellulose gauze adjacent to the optic nerve would produce blindness and ophthalmoplegia.

Adult↗
PubMed1976

Skin flap survival. Influence of infection, anemia, and tubing.

The use of regional skin flaps in reconstructive head and neck surgery is well established. The specific factors that influence the survival of the various skin flaps are numerous. An experimental approach to this problem has been outlined and carried out. Rabbits were used to evaluate the effect of severe anemia on pedicle skin flap survival. Infected as well as noninfected flaps were studied. Skin flaps of various length-to-width ratios were placed on the backs of each rabbit. These flaps included the full-thickness skin and the panniculus carnosus. Some animals were infected with pure cultures of Staphylococcus aureus and Pseudomonas aeruginosa. Some animals were made anemic by slowly bleeding them until the desired hematocrit leading was achieved. The best flap survivals occurred in the noninfected, anemic group. The next best survival percentage was noted in the noninfected group with normal hematocrit readings. The poorest survival was noted in rabbits with a normal hematocrit reading and infection. In all groups, flattened pedicled grafts had better survival than tubed pedicled grafts.

Anemia↗
PubMed1979

Salmonella typhimurium. Transmission by fiberoptic upper gastrointestinal endoscopy.

During a four-month period, Salmonella typhimurium developed in seven persons within five days of fiberoptic upper gastrointestinal (GI) endoscopy. A retrospective cohort study confirmed the association between S typhimurium infection and fiberoptic upper GI endoscopy. Salmonella typhimurium was cultured from the endoscopic equipment and the accessory suction equipment. The Salmonella isolated from the endoscopic and accessory suction equipment was identical to that recovered from the seven patients with salmonellosis by serotype, antimicrobial susceptibility pattern, and bacteriophage lysis pattern. Salmonella transmission was attributed to inadequate disinfection of the endoscope and accessory equipment between procedures. The original source of the contamination was not discovered.

Aged↗
PubMed1979

Morphologic and ultrastructural characteristics of T-cell acute lymphoblastic leukemia.

The morphology, ultrastructure, and acid phosphatase activity of the leukemic cells of 11 cases of T-cell acute lymphoblastic leukemia (T-ALL) were studied. Distinctive small cells with markedly hyperchromatic convoluted nuclei comprised from 2 to 25% of the leukemic cells in the blood and bone marrow smears of 10 of the 11 patients. Similar cells were found in only four of 47 cases on non-T, non-B-ALL. Many of these small leukemic cells exhibited ultrastructurally nuclear membrane reduplication and nuclear blebs and splits. The presence of these small leukemic cells with markedly hyperchromatic convoluted nuclei in ALL is strongly suggestive of T-ALL. This cytomorphologic finding, when combined with the presence of strong focal acid phosphatase activity, lends even greater predictability of a T-cell process.

Acid Phosphatase↗
PubMed1979

Immobilization and characterization of D-amino acid oxidase.

Optimal conditions with respect to pH, concentration of glutaraldehyde and enzyme, and order of addition of enzyme and crosslinking reagent were established for the immobilization of hog kidney D-amino acid oxidase to an attapulgite support. Yields of 40 to 70% were generally attained although when low concentrations of enzyme were used yields were consistently greater than 100%. It is suggested that this is due to a dimer leads to monomer shift at low protein concentrations. The stability of soluble D-amino acid oxidase was dependent on the buffer in which it was stored (pyrophosphate-phosphate greater than borate greater than Tris). Stability of immobilized enzyme was less than soluble in pyrophosphate-phosphate buffer, but storage in the presence of FAD improved stability. In addition, treatment of stored, immobilized enzyme with FAD before assay restored some of its activity. The immobilized D-amino acid oxidase was less stable to heat (50 degrees C) than the soluble enzyme from pH 6 to 8 but was more stable above and below these values. Apparent Km values for D-alanine, D-valine, and D-tryptophan decreased for the immobilized enzyme compared to the soluble.

Chemical Phenomena↗
PubMed1975

Carcinoembryonic antigen in patients suffering from ulcerative proctocolitis.

Carcinoembryonic antigen (CEA) has been measured by radioimmunoassay in samples obtained from all patients suffering from ulcerative proctocolitis and seen within a four-month period. The characteristics of this group of patients have been compared with reported epidemiological studies in this disease, and have been found to have a similar sex ratio and age of onset, but a more limited disease. Among 59 patients, 11 were found to have elevated circulating CEA values. One of the 11 had a colonic carcinoma and another was pregnant. Excluding these two patients, an overall prevalence of elevated CEA levels of 17.5% was found. The prevelance in ulcerative proctitis was 7.1%, and in colitis was 19.9%. The patients in whom elelvated plasma CEA values were found were compared with the remaining patients in relation to factors known to be associated with an increased propensity for the development of colorectal carcinoma complicating ulcerative colitis. There was no difference in mean age of the patients at disease onset, nor was there any difference in disease duration, extent, and control. A significant correlation was found between elevated plasma CEA levels and the severity of the initial attack. One patient with premalignant changes in the rectal mucosa had consistently normal concentrations of plasma CEA. There was no significant correlation between elevated plasma CEA values and disease activity. The mean age of the two groups of patients was similar. No carcinoma has manifested in any patient during follow-up periods of at least 18 months.

Adult↗