Glutamine Metabolism Heterogeneity in Glioblastoma Unveils an Innovative Combination Therapy Strategy.

Treatment of glioblastoma multiforme (GBM) remains challenging. Unraveling the orchestration of glutamine metabolism may provide a novel viewpoint on GBM therapy. The study presented a full and comprehensive comprehending of the glutamine metabolism atlas and heterogeneity in GBM for facilitating the development of a more effective therapeutic choice. Transcriptome data from large GBM cohorts were integrated in this study. A glutamine metabolism-based classification was established through consensus clustering approach, and a classifier by LASSO analysis was defined for differentiating the classification. Prognosis, signaling pathway activity, tumor microenvironment, and responses to immune checkpoint blockade (ICB) and small molecular drugs were characterized in each cluster. A combinational therapy of glutaminase inhibitor CB839 with dihydroartemisinin (DHA) was proposed, and the influence on glutamine metabolism, apoptosis, reactive oxygen species (ROS), and migration was measured in U251 and U373 cells. We discovered that GBM presented heterogeneous glutamine metabolism-based clusters, with unique survival outcomes, activity of signaling pathways, tumor microenvironment, and responses to ICB and small molecular compounds. In addition, the classifier could accurately differentiate the two clusters. Strikingly, the combinational therapy of CB839 with DHA synergistically attenuated glutamine metabolism, triggered apoptosis and ROS accumulation, and impaired migrative capacity in GBM cells, demonstrating the excellent preclinical efficacy. Altogether, our findings unveil the glutamine metabolism heterogeneity in GBM and propose an innovative combination therapy of CB839 with DHA for this malignant disease.

Matrix metalloproteinase-9 inhibition prevents aquaporin-4 depolarization-mediated glymphatic dysfunction in Parkinson's disease.

INTRODUCTION: The glymphatic system offers a perivascular pathway for the clearance of pathological proteins and metabolites to optimize neurological functions. Glymphatic dysfunction plays a pathogenic role in Parkinson's disease (PD); however, the molecular mechanism of glymphatic dysfunction in PD remains elusive. OBJECTIVE: To explore whether matrix metalloproteinase-9 (MMP-9)-mediated ß-dystroglycan (ß-DG) cleavage is involved in the regulation of aquaporin-4 (AQP4) polarity-mediated glymphatic system in PD. METHODS: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD and A53T mice were used in this study. The glymphatic function was evaluated using ex vivo imaging. TGN-020, an AQP4 antagonist, was administered to investigate the role of AQP4 in glymphatic dysfunction in PD. GM6001, an MMP-9 antagonist, was administered to investigate the role of the MMP-9/ß-DG pathway in regulating AQP4. The expression and distribution of AQP4, MMP-9, and ß-DG were assessed using western blotting, immunofluorescence, and co-immunoprecipitation. The ultrastructure of basement membrane (BM)-astrocyte endfeet was detected using transmission electron microscopy. Rotarod and open-field tests were performed to evaluate motor behavior. RESULTS: Perivascular influx and efflux of cerebral spinal fluid tracers were reduced in MPTP-induced PD mice with impaired AQP4 polarization. AQP4 inhibition aggravated reactive astrogliosis, glymphatic drainage restriction, and dopaminergic neuronal loss in MPTP-induced PD mice. MMP-9 and cleaved ß-DG were upregulated in both MPTP-induced PD and A53T mice, with reduced polarized localization of ß-DG and AQP4 to astrocyte endfeet. MMP-9 inhibition restored BM-astrocyte endfeet-AQP4 integrity and attenuated MPTP-induced metabolic perturbations and dopaminergic neuronal loss. CONCLUSION: AQP4 depolarization contributes to glymphatic dysfunction and aggravates PD pathologies, and MMP-9-mediated ß-DG cleavage regulates glymphatic function through AQP4 polarization in PD, which may provide novel insights into the pathogenesis of PD.

Comparative transcriptome analysis reveals growth and molecular pathway of body color regulation in turbot (Scophthalmus maximus) exposed to different light spectrum.

Fish body color changes play vital roles in adapting to ecological light environment and influencing market value. However, the initial mechanisms governing the changes remain unknown. Here, we scrutinized the impact of light spectrum on turbot (Scophthalmus maximus) body coloration, exposing them to red, blue, and full light spectra from embryo to 90 days post hatch. Transcriptome and quantitative real-time PCR (qRT-PCR) analyses were employed to elucidate underlying biological processes. The results showed that red light induced dimorphism in turbot juvenile skin pigmentation: some exhibited black coloration (Red_Black_Surface, R_B_S), while others displayed lighter skin (Red_White_Bottom, R_W_B), with red light leading to reduced skin lightness (L*) and body weight, particularly in R_B_S group. Transcriptomic and qRT-PCR analyses showcased upregulated gene expressions related to melanin synthesis in R_B_S individuals, notably tyrosinase (tyr), tyrosinase-related protein 1 (tyrp1), and dopachrome tautomerase (dct), alongside solute carrier family 24 member 5 (slc24a5) and oculocutaneous albinism type II (oca2) as pivotal regulators. Nervous system emerged as a critical mediator in spectral environment-driven color regulation. N-methyl d-aspartate (NMDA) glutamate receptor, and calcium signaling pathway emerged as pivotal links intertwining spectral conditions, neural signal transduction, and color regulation. The individual differences in NMDA glutamate receptor expression and subsequent neural excitability seemed responsible for dichromatic body coloration in red light-expose juveniles. This study provides new insights into the comprehending of fish adaptation to environment and methods for fish body color regulation and could potentially help enhance the economic benefit of fish farming industry.

Unveiling the Hidden Burden: Mapping the Landscape of Post-Intensive Care Syndrome Research. A Bibliometric Study and Visualization Analysis.

BACKGROUND Post-intensive care syndrome (PICS) has become a major concern for patients and their families due to the rising number of ICU admissions. We conducted a bibliometric analysis to identify hotspots and trends in PICS research. MATERIAL AND METHODS We searched for PICS-related publications in the Web of Science Core Collection up to May 1, 2022. We used CiteSpace, VOSviewer, and Scimago Graphica to analyze collaboration among countries, institutions, and authors, and to identify research hotspots and frontiers. RESULTS Our analysis included 294 research papers on PICS, with the United States leading the field with 146 published papers. Collaboration among institutions and authors was active mainly in the Americas, Europe, and Australia. Highly cited researchers were members of the Outcomes After Critical Illness and Surgery (OACIS) Group, with Ramona O Hopkins as the most published author. Research topics focused on septic shock, COVID-19, qualitative research, and rehabilitation, with publications primarily in critical care medicine journals. Keyword analysis revealed that the main research focus included stress disorders, quality of life, mechanical ventilation, acute lung injury, risk factors, and descriptive studies during hospitalization. CONCLUSIONS PICS research is limited, focusing primarily on short-term clinical effects and lacking long-term prognostic observations and multinational studies. Increased collaboration among countries and regions is necessary to advance research in this field. Hotspots in research focus on prognosis and an integrated approach to management.

Nuclear DJ-1 Regulates DNA Damage Repair via the Regulation of PARP1 Activity.

DNA damage and defective DNA repair are extensively linked to neurodegeneration in Parkinson's disease (PD), but the underlying molecular mechanisms remain poorly understood. Here, we determined that the PD-associated protein DJ-1 plays an essential role in modulating DNA double-strand break (DSB) repair. Specifically, DJ-1 is a DNA damage response (DDR) protein that can be recruited to DNA damage sites, where it promotes DSB repair through both homologous recombination and nonhomologous end joining. Mechanistically, DJ-1 interacts directly with PARP1, a nuclear enzyme essential for genomic stability, and stimulates its enzymatic activity during DNA repair. Importantly, cells from PD patients with the DJ-1 mutation also have defective PARP1 activity and impaired repair of DSBs. In summary, our findings uncover a novel function of nuclear DJ-1 in DNA repair and genome stability maintenance, and suggest that defective DNA repair may contribute to the pathogenesis of PD linked to DJ-1 mutations.

DNA Damage-Mediated Neurotoxicity in Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease around the world; however, its pathogenesis remains unclear so far. Recent advances have shown that DNA damage and repair deficiency play an important role in the pathophysiology of PD. There is growing evidence suggesting that DNA damage is involved in the propagation of cellular damage in PD, leading to neuropathology under different conditions. Here, we reviewed the current work on DNA damage repair in PD. First, we outlined the evidence and causes of DNA damage in PD. Second, we described the potential pathways by which DNA damage mediates neurotoxicity in PD and discussed the precise mechanisms that drive these processes by DNA damage. In addition, we looked ahead to the potential interventions targeting DNA damage and repair. Finally, based on the current status of research, key problems that need to be addressed in future research were proposed.

A bibliometric analysis of chronic obstructive pulmonary disease and COVID-19.

The coronavirus disease 2019 (COVID-19) outbreak became the worst epidemic in decades. Since its inception, COVID-19 has had a dramatic impact on chronic obstructive pulmonary disease (COPD) patients. This study explores explore the current status, hot spots, and research frontiers of COVID-19 and COPD based on a bibliometric approach. The Web of Science Core Collection was used to search the literature related to COPD and COVID-19, and VOSviewer and CiteSpace software were applied to analyze the distribution characteristics, research hotspots, and research frontiers of literature in related fields and to map the scientific knowledge domains. A total of 816 valid publications were included, among which USA, China, and England are the core countries/regions publishing related literature, and the research institutions are concentrated in Huazhong University of Science and Technology (18 papers), University College London (17 papers), and Imperial College London (16 papers). Guan WJ is the most prolific author with the most articles. The journals with the most publications are PLOS ONE, JOURNAL OF CLINICAL MEDICINE, and FRONTIERS IN MEDICINE. The main research hotspots in this field are clinical features, disease management, and mechanism research. By constructing COPD and COVID-19 research network diagrams, we reveal the hot spots, frontiers, and development trends of relevant research fields, which provide a reference for subsequent researchers to quickly grasp the current status of related research fields.

The risk factors and predictive modeling of mortality in patients with mental disorders combined with severe pneumonia.

Background: We explored clinical characteristics and risk factors for mortality in patients with mental disorders combined with severe pneumonia and developed predictive models. Methods: We retrospectively analyzed the data of 161 patients with mental disorders combined with severe pneumonia in the intensive care unit (ICU) of a psychiatric hospital from May 2020 to February 2023, and divided them into two groups according to whether they died or not, and analyzed their basic characteristics, laboratory results and treatments, etc. We analyzed the risk factors of patients' deaths using logistics regression, established a prediction model, and drew a dynamic nomogram based on the results of the regression analysis. Based on the results of regression analysis, a prediction model was established and a dynamic nomogram was drawn. Results: The non-survivor group and the survivor group of patients with mental disorders combined with severe pneumonia were statistically different in terms of age, type of primary mental illness, whether or not they were intubated, whether or not they had been bedridden for a long period in the past, and the Montreal Cognitive Assessment (MoCA) scale, procalcitonin (PCT), albumin (ALB), hemoglobin (Hb), etc. Logistics regression analysis revealed the following: MoCA scale (OR = 0.932, 95% CI:0.872-0.997), age (OR = 1.077, 95%CI:1.029-1.128), PCT (OR = 1.078, 95% CI:10.006-10.155), ALB (OR = 0.971, 95%CI:0.893-1.056), Hb (OR = 0.971, 95% CI: 0.942-0.986) were statistically significant. The ROC curve showed that the model predicted patient death with an area under the curve (AUC) of 0.827 with a sensitivity of 73.4% and a specificity of 80.4%. Conclusion: Low MoCA score, age, PCT, and low Hb are independent risk factors for death in patients with mental disorders with severe pneumonia, and the prediction model constructed using these factors showed good predictive efficacy.

Association of Concurrent Olfactory Dysfunction and Probable Rapid Eye Movement Sleep Behavior Disorder with Early Parkinson's Disease Progression.

Background: Parkinson's disease (PD), with either rapid eye movement sleep behavior disorder (RBD) or olfactory dysfunction (OD), has been associated with disease progression. However, there is currently heterogeneity in predicting prognosis. Objectives: To identify whether the concurrent presence of OD and probable RBD (pRBD) in PD (Dual hit in PD, PD-DH) is associated with disease progression. Methods: We included 420 patients with de novo PD from the Parkinson's Progression Markers Initiative: 180 PD only (PD), 82 PD with OD (PD-OD), 94 PD with pRBD (PD-pRBD), and 64 PD with both OD and pRBD (PD-DH). Participants underwent motor and nonmotor evaluations, dopamine transporter imaging, and cerebrospinal fluid (CSF) assessment. Data were analyzed with generalized estimating equations and Cox proportional hazards analysis. Results: The PD-DH subtype was associated with higher scores and faster progression rates in Movement Disorder Society-Unified PD Rating Scale (MDS-UPDRS) Parts II and III. Also, patients in PD-DH group had faster deterioration in nonmotor symptoms, including MDS-UPDRS Part I score, Montreal Cognitive Assessment, Hopkins Verbal Learning Test-Revised, Wechsler Memory Scale-Third edition (WMS-III) Letter Number Sequencing score, Symbol Digit Modalities Test, and Scales for Outcomes in PD-Autonomic scores, with all P values <0.002. Moreover, the PD-DH subtype had a higher mild cognitive impairment risk (hazard ratio = 1.756, 95% confidence interval [CI] = 1.132-2.722; P = 0.012), faster decline in caudate standard uptake values (ß = -0.03, 95% CI = -0.06 to -0.008, P = 0.012), and CSF α-synuclein levels (ß = -77, 95% CI = -149 to -5, P = 0.034) than the PD group. Conclusion: Coexisting pRBD and OD in patients with PD may be associated with faster progressions in motor measurements and in cognitive and autonomic symptoms, indicating PD-DH as a more aggressive subtype for PD.

Decoding the Role of Familial Parkinson's Disease-Related Genes in DNA Damage and Repair.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration of midbrain substantia nigra pars compacta dopaminergic neurons and the formation of Lewy bodies. Over the years, researchers have gained extensive knowledge about dopaminergic neuron degeneration from the perspective of the environmental and disease-causing genetic factors; however, there is still no disease-modifying therapy. Aging has long been recognized as a major risk factor for PD; however, little is known about how aging contributes to the disease development. Genome instability is the main driving force behind aging, and has been poorly studied in patients with PD. Here, we summarize the evidence for nuclear DNA damage in PD. We also discuss the molecular mechanisms of nuclear DNA damage and repair in PD, especially from the perspective of familial PD-related mutant genes. Understanding the significance of DNA damage and repair may provide new potential intervention targets for treating PD.

Quercetin Protects against MPP+/MPTP-Induced Dopaminergic Neuron Death in Parkinson's Disease by Inhibiting Ferroptosis.

Ferroptosis, a novel form of regulated cell death, is caused by accumulation of lipid peroxides and excessive iron deposition. This process has been linked to the death of dopaminergic neurons in substantia nigra compacta (SNc) of Parkinson's disease (PD) patients. Quercetin (QCT), a natural flavonoid, has multiple pharmacological activities. However, it has not been established whether QCT can protect against dopaminergic neuron death by inhibiting ferroptosis. In this study, we investigated the potential antiferroptotic effects of QCT in cellular models established using specific ferroptosis inducers (Erastin and RSL-3) and MPP+. The effects were also explored using MPTP-induced PD mouse models. The cell counting kit-8 (CCK-8) assay was performed to assess cell viability. Variations in mitochondrial morphology were evaluated by transmission electron microscopy (TEM) while the mitochondrial membrane potential, mass, and ROS were measured by fluorescent probes. Lipid peroxidation levels were assayed through measurement of lipid ROS, MDA, GSH, and SOD levels. The effects of QCT on MPTP-induced behavioral disorders were examined by rotarod and open field tests. In vitro and in vivo, QCT significantly inhibited ferroptosis by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) protein. Additionally, QCT ameliorated motor behavioral impairments and protected against the loss of dopaminergic neurons in MPTP-induced PD models. Interestingly, Nrf2 knockdown alleviated the protective effects of QCT against ferroptosis. In conclusion, these results demonstrate that ferroptosis is involved in MPP+/MPTP-induced PD, and QCT inhibits ferroptosis by activating the Nrf2 protein. Therefore, QCT is a potential agent for preventing the loss of dopaminergic neurons by targeting ferroptosis.

Apolipoprotein E Genotype Contributes to Motor Progression in Parkinson's Disease.

BACKGROUND: Emerging evidence indicates that the apolipoprotein E (APOE) ε4 exacerbates α-synuclein pathology. OBJECTIVE: To determine whether APOE ε4 contributes to motor progression in early Parkinson's disease (PD). METHODS: Longitudinal data were obtained from 384 patients with PD divided into APOE ε4 carriers (n = 85) and noncarriers (n = 299) in the Parkinson's Progression Marker Initiative. Participants underwent yearly motor assessments over a mean follow-up period of 78.9 months. Repeated measures and linear mixed models were used to test the effects of APOE ε4. RESULTS: The motor progression was significantly more rapid in patients with PD carrying APOE ε4 than in noncarriers (ß = 0.283, P = 0.026, 95% confidence interval: 0.033-0.532). Through subgroup analysis, we found that the effect of APOE ε4 was significant only in patients with high amyloid ß burden (ß = 0.761, P < 0.001, 95% confidence interval: 0.0356-1.167). CONCLUSIONS: APOE ε4 may be associated with rapid motor progression in PD. © 2021 International Parkinson and Movement Disorder Society.

[Runoff and sediment yielding processes on red soil engineering accumulation containing gravels by a simulated rainfall experiment].

Engineering accumulation formed in production and construction projects is characterized by unique structure and complex material composition. Characteristics of soil erosion on the engineering accumulation significantly differ from those on farmland. An artificially simulated rainfall experiment was carried out to investigate the effects of rainfall intensity on the processes of runoff and sediment yielding on the engineering accumulation of different gravel contents (0%, 10%, 20% and 30%) in red soil regions. Results showed that the initial time of runoff generation decreased with increases in rainfall intensity and gravel content, the decreased amplitudes being about 48.5%-77.9% and 4.2%-34.2%, respectively. The initial time was found to be a power function of rainfall intensity. Both runoff velocity and runoff rate manifested a trend of first rising and then in a steady state with runoff duration. Rainfall intensity was found to be the main factor influencing runoff velocity and runoff rate, whereas the influence of gravel content was not significant. About 10% of gravel content was determined to be a critical value in the influence of gravel content on runoff volume. For the underlying surface of 10% gravel content, the runoff volume was least at rainfall intensity of 1.0 mm · min(-1) and maximum at rainfall intensity of greater than 1.0 mm · min(-1). The runoff volume in- creased 10%-60% with increase in rainfall intensity. Sediment concentration showed a sharp decline in first 6 min and then in a stable state in rest of time. Influence of rainfall intensity on sediment concentration decreased as gravel content increased. Gravels could reduce sediment yield significantly at rainfall intensity of greater than 1.0 mm · min(-1). Sediment yield was found to be a linear function of rainfall intensity and gravel content.

Evaluation of a new optical biometry device for measurements of ocular components and its comparison with IOLMaster.

OBJECTIVE: To assess the reliability of ocular component measurements with a new optical biometry device (AL-Scan; Nidek) and compare these measurements with those of the IOLMaster (Carl Zeiss Meditec) in patients with cataract. METHODS: Sixty-eight cataractous eyes of 68 patients were included in the prospective study. To assess AL-Scan repeatability and reproducibility, central corneal thickness, anterior chamber depth (ACD), keratometry (K) over 2.4 mm and 3.3 mm diameter, axial length (AL), white to white (WTW), and pupil distance (PD) values were measured by two operators. ACD, K, AL and WTW were also measured with the IOLMaster to investigate the level of agreement. Calculations of intraocular lens (IOL) power were compared between the two devices. RESULTS: AL-Scan measurements were highly repeatable and reproducible, except for WTW and PD. Bland-Altman analysis showed good agreement between devices for AL, ACD and most K values. Compared with the IOLMaster, AL-Scan-derived K values using a diameter of 2.4 mm showed a narrower 95% limit of agreement (LoA) than those obtained with a diameter of 3.3 mm. However, poor agreement of WTW measurements was found. The 95% LoAs between devices for IOL calculations were smaller when based on AL-Scan K measurements using a diameter of 2.4 mm rather than 3.3 mm. CONCLUSIONS: The repeatability and reproducibility of AL-Scan was excellent for all parameters, except WTW and PD. Excluding WTW, good agreement was found between the AL-Scan and IOLMaster. The 2.4-mm diameter K value may be the most reliable choice for calculation of IOL power with the AL-Scan.

Distribution and location of Daxx in cervical epithelial cells with high risk human papillomavirus positive.

AIMS: To provide the basis for further exploring the effect and its mechanism of Death domain associated protein (Daxx) on the progress of cervical carcinoma induced by human papillomavirus (HPV), the distribution and location of Daxx in cervical carcinoma with high risk HPV(HR-HPV) positive was analyzed. METHODS: The samples of normal cervical epithelial cells, cervical intraepithelial neoplasia grade I (CINI), CINII CINIII and cervical cancers were collected. Immunohistochemistry assay was used to analyze the distributions and locations of Daxx in the cervical tissue. Indirect immunoinfluorescence test was utilized to observe the locations of Daxx in Caski cells with HPV16 positive. RESULTS: Under the light microscopy, the brown signals of Daxx distributed in the nuclei of normal cervical epithelial cells; Daxx mainly distributed in nuclear membrane and there were a small amount of Daxx in the nuclei in CINI. Daxx intensively distributed in the cytoplasm and cell membrane in CINII, CINIII and cervical cancer. Under fluorescent microscopy, the distribution and location of Daxx in Caski cells was similarly to that in cervical cells of CINII, CINIII and cervical cancer. CONCLUSION: In the progress of the cervical cancer, Daxx gradually translocates from nucleus into nuclear membrane, cytoplasm and cell membrane. Daxx locates in the cytoplasm and cell membrane in CINII, CINIII and cervical cancer. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/4671548951113870.