Quantitative iron-neuromelanin MRI associates with motor severity in Parkinson's disease and matches radiological disease classification.

Background: Neuromelanin- and iron-sensitive MRI studies in Parkinson's disease (PD) are limited by small sample sizes and lack detailed clinical correlation. In a large case-control PD cohort, we evaluated the diagnostic accuracy of quantitative iron-neuromelanin MRI parameters from the substantia nigra (SN), their radiological utility, and clinical association.

Methods: PD patients and age-matched controls were prospectively recruited for motor assessment and midbrain neuromelanin- and iron-sensitive [quantitative susceptibility mapping (QSM) and susceptibility map-weighted imaging (SMWI)] MRI.

The Virological, Immunological, and Imaging Approaches for COVID-19 Diagnosis and Research.

In 2019, a novel coronavirus (SARS-CoV-2) was found to cause a highly contagious disease characterized by pneumonia. The disease (COVID-19) quickly spread around the globe, escalating to a global pandemic. In this review, we discuss the virological, immunological, and imaging approaches harnessed for COVID-19 diagnosis and research.

Cerebral white matter changes in deficit and non-deficit subtypes of schizophrenia.

The considerable clinical heterogeneity in schizophrenia makes elucidation of its neurobiology challenging. Subtyping the disorder is one way to reduce this heterogeneity and deficit status is one such categorization based on the prominence of negative symptoms. We aimed to utilize diffusion tensor imaging (DTI) to identify unique white matter cerebral changes in deficit schizophrenia (DS) compared with non-deficit schizophrenia (NDS) and healthy controls (HC) in an Asian sample.

Evaluation of phospho-histone H3 in Asian triple-negative breast cancer using multiplex immunofluorescence.

Purpose: We used multiplex immunofluorescence (mIF) to determine whether mitotic rate represents an independent prognostic marker in triple-negative breast cancer (TNBC). Secondary aims were to confirm the prognostic significance of immune cells in TNBC, and to investigate the relationship between immune cells and proliferating tumour cells.

Methods: A retrospective Asian cohort of 298 patients with TNBC diagnosed from 2003 to 2015 at the Singapore General Hospital was used in the present study.

The role of Ki-67 in Asian triple negative breast cancers: a novel combinatory panel approach.

The proliferation marker Ki-67 is frequently used to assess aggressiveness in the pathological evaluation of cancer, but its role remains uncertain in triple-negative breast cancer (TNBC). We aimed to quantify and localize Ki-67 expression in both epithelial and immune compartments in TNBC and investigate its association with clinicopathological parameters and survival outcomes. A total of 406 TNBC cases diagnosed between 2003 and 2015 at Singapore General Hospital were recruited.

Horizontal transfer of whole mitochondria restores tumorigenic potential in mitochondrial DNA-deficient cancer cells.

Recently, we showed that generation of tumours in syngeneic mice by cells devoid of mitochondrial (mt) DNA (ρ cells) is linked to the acquisition of the host mtDNA. However, the mechanism of mtDNA movement between cells remains unresolved. To determine whether the transfer of mtDNA involves whole mitochondria, we injected B16ρ mouse melanoma cells into syngeneic C57BL/6N mice that express red fluorescent protein in their mitochondria.

Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA.

We report that tumor cells without mitochondrial DNA (mtDNA) show delayed tumor growth, and that tumor formation is associated with acquisition of mtDNA from host cells. This leads to partial recovery of mitochondrial function in cells derived from primary tumors grown from cells without mtDNA and a shorter lag in tumor growth. Cell lines from circulating tumor cells showed further recovery of mitochondrial respiration and an intermediate lag to tumor growth, while cells from lung metastases exhibited full restoration of respiratory function and no lag in tumor growth.

The role of mitochondrial electron transport in tumorigenesis and metastasis.

Background: Tumor formation and spread via the circulatory and lymphatic drainage systems is associated with metabolic reprogramming that often includes increased glycolytic metabolism relative to mitochondrial energy production. However, cells within a tumor are not identical due to genetic change, clonal evolution and layers of epigenetic reprogramming. In addition, cell hierarchy impinges on metabolic status while tumor cell phenotype and metabolic status will be influenced by the local microenvironment including stromal cells, developing blood and lymphatic vessels and innate and adaptive immune cells.

Mitochondrial genome-knockout cells demonstrate a dual mechanism of action for the electron transport complex I inhibitor mycothiazole.

Mycothiazole, a polyketide metabolite isolated from the marine sponge Cacospongia mycofijiensis, is a potent inhibitor of metabolic activity and mitochondrial electron transport chain complex I in sensitive cells, but other cells are relatively insensitive to the drug. Sensitive cell lines (IC(50) 0.36-13.

Metabolic flexibility and cell hierarchy in metastatic cancer.

Cancer is characterized by disturbed homeostasis of self-renewing cell populations, and their ability to seed and grow in multiple microenvironments. This overarching cellular property of metastatic cancer emerges from the contentious cancer stem cell hypothesis that underpins the more generic hallmarks of cancer (Hanahan and Weinberg, 2000) and its subsequent add-ons. An additional characteristic, metabolic flexibility, is related to concepts developed by Warburg and to subsequent work by mid 20th century biochemists who elucidated the bioenergetic workings of mitochondria.

Effects of mitochondrial gene deletion on tumorigenicity of metastatic melanoma: reassessing the Warburg effect.

Metabolic flexibility is a hallmark of cancer. Although many tumors preferentially use glycolysis in the presence of oxygen for bioenergetic purposes (Warburg effect), the effects of glycolytic metabolism on tumor metastasis have not been investigated. We have employed an extreme model of glycolytic metabolism to investigate the ability of metastatic B16 mouse melanoma cells to grow as primary subcutaneous tumors and to form lung tumors when injected intravenously into syngeneic and immunocompromised mice.

Evidence for NAD(P)H:quinone oxidoreductase 1 (NQO1)-mediated quinone-dependent redox cycling via plasma membrane electron transport: A sensitive cellular assay for NQO1.

2,3-Dimethoxy 1,4-naphthoquinone (DMNQ), which redox cycles via two-electron reduction, mediates reduction of the cell-impermeative tetrazolium dye WST-1 in kidney epithelial cells (MDCK), which express high levels of NQO1, but not in HL60 or CHO cells, which are NQO1 deficient. DMNQ-dependent WST-1 reduction by MDCK cells was strongly inhibited by low concentrations of the NQO1 inhibitor dicoumarol and was also inhibited by diphenyleneiodonium, capsaicin, and superoxide dismutase (SOD), but not by the uncoupler FCCP or the complex IV inhibitor cyanide. This suggests that DMNQ-dependent WST-1 reduction by MDCK cells is catalyzed by NQO1 via redox cycling and plasma membrane electron transport (PMET).

Differential effects of redox-cycling and arylating quinones on trans-plasma membrane electron transport.

Cytotoxicity of quinones has been attributed to free radical generation and to arylation of cellular nucleophiles. For redox-cycling quinones, cell injury is associated with mitochondrial permeability transition, whereas arylating quinones directly depolarise the mitochondrial membrane and deplete ATP. Like mitochondrial electron transport, plasma membrane electron transport (PMET), plays a multifaceted role in cellular redox homeostasis but the effects of quinones on PMET are unknown.

Tetrazolium dyes as tools in cell biology: new insights into their cellular reduction.

Tetrazolium salts have become some of the most widely used tools in cell biology for measuring the metabolic activity of cells ranging from mammalian to microbial origin. With mammalian cells, fractionation studies indicate that the reduced pyridine nucleotide cofactor, NADH, is responsible for most MTT reduction and this is supported by studies with whole cells. MTT reduction is associated not only with mitochondria, but also with the cytoplasm and with non-mitochondrial membranes including the endosome/lysosome compartment and the plasma membrane.

Distinct trans-plasma membrane redox pathways reduce cell-impermeable dyes in HeLa cells.

Trans-plasma membrane electron transport (tPMET) in mammalian cells has been demonstrated using artificial cell-impermeable dyes, but the extent to which reduction of these dyes involves distinct pathways remains unclear. Here we compare the properties of three commonly used dyes, WST-1, FeCN and DCIP. The presence of an intermediate electron carrier (mPMS or CoQ(1)) was obligatory for WST-1 reduction, whereas FeCN and DCIP were reduced directly.

Cell surface oxygen consumption by mitochondrial gene knockout cells.

Mitochondrial gene knockout (rho(0)) cells that depend on glycolysis for their energy requirements show an increased ability to reduce cell-impermeable tetrazolium dyes by electron transport across the plasma membrane. In this report, we show for the first time, that oxygen functions as a terminal electron acceptor for trans-plasma membrane electron transport (tPMET) in HL60rho(0) cells, and that this cell surface oxygen consumption is associated with oxygen-dependent cell growth in the absence of mitochondrial electron transport function. Non-mitochondrial oxygen consumption by HL60rho(0) cells was extensively inhibited by extracellular NADH and NADPH, but not by NAD(+), localizing this process at the cell surface.