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Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide, mainly affecting the elderly. The disease progresses gradually, with core motor presentations and a multitude of non-motor manifestations. There are two neuropathological hallmarks of PD, the dopaminergic neuronal loss and the alpha-synuclein-containing Lewy body inclusions in the substantia nigra. While the exact pathomechanisms of PD remain unclear, genetic investigations have revealed evidence of the involvement of mitochondrial function, alpha-synuclein (α-syn) aggregation, and the endo-lysosomal system, in disease pathogenesis. Due to the high energy demand of dopaminergic neurons, mitochondria are of special importance acting as the cellular powerhouse. Mitochondrial dynamic fusion and fission, and autophagy quality control keep the mitochondrial network in a healthy state. Should defects of the organelle occur, a variety of reactions would ensue at the cellular level, including disrupted mitochondrial respiratory network and perturbed calcium homeostasis, possibly resulting in cellular death. Meanwhile, α-syn is a presynaptic protein that helps regulate synaptic vesicle transportation and endocytosis. Its misfolding into oligomeric sheets and fibrillation is toxic to the mitochondria and neurons. Increased cellular oxidative stress leads to α-syn accumulation, causing mitochondrial dysfunction. The proteasome and endo-lysosomal systems function to regulate damage and unwanted waste management within the cell while facilitating the quality control of mitochondria and α-syn. This review will analyze the biological functions and interactions between mitochondria, α-syn, and the endo-lysosomal system in the pathogenesis of PD.

Several models have tentatively associated improving attention-deficit/hyperactivity disorder (ADHD) symptoms with arousal and external environmental stimulation. In order to further clarify the relationships between ADHD symptoms, arousal, and external stimulation, this study focused on exploring the “simultaneous” effects of white noise on intrinsic attentional performance and extrinsic on-task behaviors in preschoolers with and without ADHD. By using the computerized task (K-CPT 2), 104 preschoolers, including 52 ADHD children and 52 typically developing (TD) children, were tested and analyzed for their intrinsic attention (such as detectability, omission errors, commission errors, and reaction time). Simultaneously, these preschoolers’ external on-task behaviors were recorded for analysis through systematic observation. This study showed that white noise could effectively improve attention performance, including enhancing the ability to differentiate non-targets from targets and decreasing omission errors. It could also reduce the extrinsic hyperactive behaviors of preschoolers with ADHD. The findings of this study highlighted that white noise stimulation is a beneficial non-pharmacological treatment for preschoolers with ADHD. In contrast, for TD preschoolers, the results of this study showed that the external white noise stimuli were not only unhelpful but also a burden.

Background The inner membrane mitochondrial protein (IMMT) is a central unit of the mitochondrial contact site and cristae organizing system (MICOS). While researchers continue to demonstrate the physiological function of IMMT in regulating mitochondrial dynamics and preserving mitochondrial structural integrity, the roles of IMMT in clinicopathology, the tumor immune microenvironment (TIME), and precision oncology in breast cancer (BC) remain unclear. Methods Multi-omics analysis was used here to evaluate the diagnostic and prognostic value of IMMT. Web applications aimed at analyzing the whole tumor tissue, single cells, and spatial transcriptomics were used to examine the relationship of IMMT with TIME. Gene set enrichment analysis (GSEA) was employed to determine the primary biological impact of IMMT. Experimental verification using siRNA knockdown and clinical specimens of BC patients confirmed the mechanisms behind IMMT on BC cells and the clinical significance, respectively. Potent drugs were identified by accessing the data repositories of CRISPR-based drug screenings. Results High IMMT expression served as an independent diagnostic biomarker, correlated with advanced clinical status, and indicated a poor relapse-free survival (RFS) rate for patients with BC. Although, the contents of Th1, Th2, MSC, macrophages, basophil, CD4 + T cell and B cell, and TMB levels counteracted the prognostic significance. Single-cell level and whole-tissue level analyses revealed that high IMMT was associated with an immunosuppressive TIME. GSEA identified IMMT perturbation as involved in cell cycle progression and mitochondrial antioxidant defenses. Experimental knockdown of IMMT impeded the migration and viability of BC cells, arrested the cell cycle, disturbed mitochondrial function, and increased the ROS level and lipid peroxidation. The clinical values of IMMT were amenable to ethnic Chinese BC patients, and can be extrapolated to some other cancer types. Furthermore, we discovered that pyridostatin acted as a potent drug candidate in BC cells harboring an elevated IMMT expression. Conclusion This study combined a multi-omics survey with experimental verification to reveal the novel clinical significance of IMMT in BC, demonstrating its role in TIME, cancer cell growth and mitochondrial fitness, and identified pyridostatin as a promising drug candidate for the development of precision medicine.

Thermal infrared imagery provides temperature information on target objects, and has been widely applied in non-destructive testing. However, thermal infrared imagery is not always able to display detailed textures of inspected objects, which hampers the understanding of geometric entities consisting of temperature information. Although some commercial software has been developed for 3D thermal model displays, the software requires the use of expensive specific thermal infrared sensors. This study proposes a cost-effective method for 3D thermal model reconstruction based on image-based modeling. Two smart phones and a low-cost thermal infrared camera are employed to acquire visible images and thermal images, respectively, that are fused for 3D thermal model reconstruction. The experiment results demonstrate that the proposed method is able to effectively reconstruct a 3D thermal model which extremely approximates its corresponding entity. The total computational time for the 3D thermal model reconstruction is intensive while generating dense points required for the creation of a geometric entity. Future work will improve the efficiency of the proposed method in order to expand its potential applications to in-time monitoring.

Kidney renal clear cell carcinoma (KIRC) accounts for approximately 75% of all renal cancers. The prognosis for patients with metastatic KIRC is poor, with less than 10% surviving five years after diagnosis. Inner membrane mitochondrial protein (IMMT) plays a crucial role in shaping the inner mitochondrial membrane (IMM), regulation of metabolism and innate immunity. However, the clinical relevance of IMMT in KIRC is not yet fully understood, and its role in shaping the tumor immune microenvironment (TIME) remains unclear. This study aimed to investigate the clinical significance of IMMT in KIRC using a combination of supervised learning and multi-omics integration. The supervised learning principle was applied to analyze a TCGA dataset, which was downloaded and split into training and test datasets. The training dataset was used to train the prediction model, while the test and the entire TCGA dataset were used to evaluate its performance. Based on the risk score, the cutoff between the low and high IMMT group was set at median value. A Kaplan-Meier curve, receiver operating characteristic (ROC) curve, principal component analysis (PCA) and Spearman’s correlation were conducted to evaluate the prediction ability of the model. Gene Set Enrichment Analysis (GSEA) was used to investigate the critical biological pathways. Immunogenicity, immunological landscape and single-cell analysis were performed to examine the TIME. Databases including Gene Expression Omnibus (GEO), Human Protein Atlas (HPA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) were employed for inter-database verification. Pharmacogenetic prediction was analyzed via single-guide RNA (sgRNA)-based drug sensitivity screening using Q-omics v.1.30. Low expressions of IMMT in tumor predicted dismal prognosis in KIRC patients and correlated with KIRC progression. GSEA revealed that low expressions of IMMT were implicated in mitochondrial inhibition and angiogenetic activation. In addition, low IMMT expressions had associations with reduced immunogenicity and an immunosuppressive TIME. Inter-database verification corroborated the correlation between low IMMT expressions, KIRC tumors and the immunosuppressive TIME. Pharmacogenetic prediction identified lestaurtinib as a potent drug for KIRC in the context of low IMMT expressions. This study highlights the potential of IMMT as a novel biomarker, prognostic predictor and pharmacogenetic predictor to inform the development of more personalized and effective cancer treatments. Additionally, it provides important insights into the role of IMMT in the mechanism underlying mitochondrial activity and angiogenesis development in KIRC, which suggests IMMT as a promising target for the development of new therapies.

MicroRNA-29 (miR-29) has been shown to play a critical role in reducing inflammation and fibrosis following liver injury. Non-alcoholic fatty liver disease (NAFLD) occurs when fat is deposited (steatosis) in the liver due to causes other than excessive alcohol use and is associated with liver fibrosis. In this study, we asked whether miR-29a could reduce experimental high fat diet (HFD)-induced obesity and liver fibrosis in mice. We performed systematical expression analyses of miR-29a transgenic mice (miR-29aTg mice) and wild-type littermates subjected to HFD-induced NAFLD. The results demonstrated that increased miR-29a not only alleviated HFD-induced body weight gain but also subcutaneous, visceral, and intestinal fat accumulation and hepatocellular steatosis in mice. Furthermore, hepatic tissue in the miR-29aTg mice displayed a weak fibrotic matrix concomitant with low fibrotic collagen1α1 expression within the affected tissues compared to the wild-type (WT) mice fed the HFD diet. Increased miR-29a signaling also resulted in the downregulation of expression of the epithelial mesenchymal transition-executing transcription factor snail, mesenchymal markers vimentin, and such pro-inflammation markers as il6 and mcp1 within the liver tissue. Meanwhile, miR-29aTg-HFD mice exhibited significantly lower levels of peroxisome proliferator-activated receptor γ (PPARγ), mitochondrial transcription factor A TFAM, and mitochondria DNA content in the liver than the WT-HFD mice. An in vitro luciferase reporter assay further confirmed that miR-29a mimic transfection reduced fatty acid translocase CD36 expression in HepG2 cells. Conclusion: Our data provide new insights that miR-29a can improve HDF-induced obesity, hepatocellular steatosis, and fibrosis, as well as highlight the role of miR-29a in regulation of NAFLD.

Parkinson disease (PD) is the second-most common neurodegenerative disease. The characteristic pathology of progressive dopaminergic neuronal loss in people with PD is associated with iron accumulation and is suggested to be driven in part by the novel cell death pathway, ferroptosis. A unique modality of cell death, ferroptosis is mediated by iron-dependent phospholipid peroxidation. The mechanisms of ferroptosis inhibitors enhance antioxidative capacity to counter the oxidative stress from lipid peroxidation, such as through the system xc−/glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis and the coenzyme Q10 (CoQ10)/FSP1 pathway. Another means to reduce ferroptosis is with iron chelators. To date, there is no disease-modifying therapy to cure or slow PD progression, and a recent topic of research seeks to intervene with the development of PD via regulation of ferroptosis. In this review, we provide a discussion of different cell death pathways, the molecular mechanisms of ferroptosis, the role of ferroptosis in blood–brain barrier damage, updates on PD studies in ferroptosis, and the latest progress of pharmacological agents targeting ferroptosis for the intervention of PD in clinical trials.

The impairment of the ovarian response in in vitro fertilization (IVF) cycles after salpingectomy remains contentious. Therefore, we investigated whether a history of salpingectomy affects the number of oocytes retrieved in women undergoing IVF in comparison with the number in women without underlying tubal disease. Case-control study (Canadian Task Force Classification II-2). A tertiary hospital-affiliated fertility center. Fifty-four women aged <35 years with a history of salpingectomy and 59 age-matched women without tubal disease. Gonadotropin-releasing hormone antagonist protocol for controlled ovarian stimulation and transvaginal oocyte retrieval. The antral follicle count (AFC), anti-Müllerian hormone (AMH) levels, and the number of retrieved oocytes were significantly lower in women with prior salpingectomy than in women without tubal disease. Day-3 follicle-stimulating hormone (FSH) levels, total gonadotropin dosage, and stimulation days did not significantly differ between the groups. The indications of salpingectomy (i.e., hydrosalpinx and ectopic pregnancy) did not differ significantly in terms of ovarian response or reserve among women with salpingectomy history. A history of salpingectomy and other factors related to ovarian response in IVF, such as age, AMH, AFC, day-3 FSH, and total gonadotropin dose, were significantly correlated with the number of oocytes retrieved by univariate regression analysis. In the multivariate-adjusted model after controlling all the above-mentioned variables, only AFC and AMH levels continued to exhibit significant associations with the number of retrieved oocytes. In a subgroup analysis, the negative impact of prior salpingectomy on the number of retrieved oocytes was especially significant in women with suboptimal ovarian reserves (defined as AMH < 4 ng/mL), regardless of the indication of salpingectomy or whether salpingectomy was bilateral or unilateral. A negative effect on the number of retrieved oocytes in the subsequent IVF cycle after salpingectomy is more likely in women aged <35 years with suboptimal ovarian reserve. Nevertheless, postsurgical AMH and AFC levels still possess a more direct predictive value on ovarian response than the history of salpingectomy.

Deep sequencing of T-cell receptor (TCR) genes is powerful at profiling immune repertoire. To prepare a TCR sequencing library, multiplex polymerase chain reaction (mPCR) is widely applied and is highly efficient. That is, most mPCR products contain the region critical for antigen recognition, which also indicates regular V(D)J recombination. Multiplex PCR, however, may suffer from primer bias. A promising alternative is 5’-RACE, which avoids primer bias by applying only one primer pair. In 5’-RACE data, however, non-regular V(D)J recombination (e.g., TCR sequences without a V gene segment) has been observed and the frequency varies (30–80%) between studies. This suggests that the cause of or how to reduce non-regular TCR sequences is not yet well known by the science community. Although it is possible to speculate the cause by comparing the 5’-RACE protocols, careful experimental confirmation is needed and such a systematic study is still not available. Here, we examined the 5’-RACE protocol of a commercial kit and demonstrated how a modification increased the fraction of regular TCR-β sequences to >85%. We also found a strong linear correlation between the fraction of short DNA fragments and the percentage of non-regular TCR-β sequences, indicating that the presence of short DNA fragments in the library was the main cause of non-regular TCR-β sequences. Therefore, thorough removal of short DNA fragments from a 5’-RACE library is the key to high data efficiency. We highly recommend conducting a fragment length analysis before sequencing, and the fraction of short DNA fragments can be used to estimate the percentage of non-regular TCR sequences. As deep sequencing of TCR genes is still relatively expensive, good quality control should be valuable.

Mounting evidence suggests that ferroptosis is not just a consequence but also a fundamental contributor to the development and progression of Parkinson’s disease (PD). Ferroptosis is characterized as iron-dependent regulated cell death caused by excessive lipid peroxidation, leading to plasma membrane rupture, release of damage-associated molecular patterns, and neuroinflammation. Due to the crucial role of intracellular iron in mediating the production of reactive oxygen species and the formation of lipid peroxides, ferroptosis is intimately controlled by regulators involved in many aspects of iron metabolism, including iron uptake, storage and export, and by pathways constituting the antioxidant systems. Translational and transcriptional regulation of iron homeostasis and redox status provide an integrated network to determine the sensitivity of ferroptosis. We herein review recent advances related to ferroptosis, ranging from fundamental mechanistic discoveries and cutting-edge preclinical animal studies, to clinical trials in PD and the regulation of neuroinflammation via ferroptosis pathways. Elucidating the roles of ferroptosis in the survival of dopaminergic neurons and microglial activity can enhance our understanding of the pathogenesis of PD and provide opportunities for the development of novel prevention and treatment strategies.