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The immortal life of Henrietta Lacks
Documents the story of how scientists took cells from an unsuspecting descendant of freed slaves and created a human cell line that has been kept alive indefinitely, enabling discoveries in such areas as cancer research, in vitro fertilization, and gene mapping.
BOOK
Hydrodynamic stretching of single cells for large population mechanical phenotyping
Cell state is often assayed through measurement of biochemical and biophysical markers. Although biochemical markers have been widely used, intrinsic biophysical markers, such as the ability to mechanically deform under a load, are advantageous in that they do not require costly labeling or sample preparation. However, current techniques that assay cell mechanical properties have had limited adoption in clinical and cell biology research applications. Here, we demonstrate an automated microfluidic technology capable of probing single-cell deformability at approximately 2,000 cells/s. The method uses inertial focusing to uniformly deliver cells to a stretching extensional flow where cells are deformed at high strain rates, imaged with a high-speed camera, and computationally analyzed to extract quantitative parameters. This approach allows us to analyze cells at throughputs orders of magnitude faster than previously reported biophysical flow cytometers and single-cell mechanics tools, while creating easily observable larger strains and limiting user time commitment and bias through automation. Using this approach we rapidly assay the deformability of native populations of leukocytes and malignant cells in pleural effusions and accurately predict disease state in patients with cancer and immune activation with a sensitivity of 91% and a specificity of 86%. As a tool for biological research, we show the deformability we measure is an early biomarker for pluripotent stem cell differentiation and is likely linked to nuclear structural changes. Microfluidic deformability cytometry brings the statistical accuracy of traditional flow cytometric techniques to label-free biophysical biomarkers, enabling applications in clinical diagnostics, stem cell characterization, and single-cell biophysics.
Journal Article
A Molecular Fluorescent Probe for Targeted Visualization of Temperature at the Endoplasmic Reticulum
The dynamics of cellular heat production and propagation remains elusive at a subcellular level. Here we report the first small molecule fluorescent thermometer selectively targeting the endoplasmic reticulum (ER thermo yellow), with the highest sensitivity reported so far (3.9%/°C). Unlike nanoparticle thermometers, ER thermo yellow stains the target organelle evenly without the commonly encountered problem of aggregation and successfully demonstrates the ability to monitor intracellular temperature gradients generated by external heat sources in various cell types. We further confirm the ability of ER thermo yellow to monitor heat production by intracellular Ca
2+
changes in HeLa cells. Our thermometer anchored at nearly-zero distance from the ER, i.e. the heat source, allowed the detection of the heat as it readily dissipated and revealed the dynamics of heat production in real time at a subcellular level.
Journal Article
Glycolytic suppression dramatically changes the intracellular metabolic profile of multiple cancer cell lines in a mitochondrial metabolism-dependent manner
Most cancer cells rely on glycolysis to generate ATP, even when oxygen is available. However, merely inhibiting the glycolysis is insufficient for the eradication of cancer cells. One main reason for this is that cancer cells have the potential to adapt their metabolism to their environmental conditions. In this study, we investigated how cancer cells modify their intracellular metabolism when glycolysis is suppressed, using PANC-1 pancreatic cancer cells and two other solid tumor cell lines, A549 and HeLa. Our study revealed that glycolytically suppressed cells upregulated mitochondrial function and relied on oxidative phosphorylation (OXPHOS) to obtain the ATP necessary for their survival. Dynamic changes in intracellular metabolic profiles were also observed, reflected by the reduced levels of TCA cycle intermediates and elevated levels of most amino acids. Glutamine and glutamate were important for this metabolic reprogramming, as these were largely consumed by influx into the TCA cycle when the glycolytic pathway was suppressed. During the reprogramming process, activated autophagy was involved in modulating mitochondrial function. We conclude that upon glycolytic suppression in multiple types of tumor cells, intracellular energy metabolism is reprogrammed toward mitochondrial OXPHOS in an autophagy-dependent manner to ensure cellular survival.
Journal Article
Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12
Hereditary spastic paraplegias (HSPs) are a group of genetically heterogeneous neurodegenerative conditions. They are characterized by progressive spastic paralysis of the legs as a result of selective, length-dependent degeneration of the axons of the corticospinal tract. Mutations in 3 genes encoding proteins that work together to shape the ER into sheets and tubules - receptor accessory protein 1 (REEP1), atlastin-1 (ATL1), and spastin (SPAST) - have been found to underlie many cases of HSP in Northern Europe and North America. Applying Sanger and exome sequencing, we have now identified 3 mutations in reticulon 2 (RTN2), which encodes a member of the reticulon family of prototypic ER-shaping proteins, in families with spastic paraplegia 12 (SPG12). These autosomal dominant mutations included a complete deletion of RTN2 and a frameshift mutation predicted to produce a highly truncated protein. Wild-type reticulon 2, but not the truncated protein potentially encoded by the frameshift allele, localized to the ER. RTN2 interacted with spastin, and this interaction required a hydrophobic region in spastin that is involved in ER localization and that is predicted to form a curvature-inducing/sensing hairpin loop domain. Our results directly implicate a reticulon protein in axonopathy, show that this protein participates in a network of interactions among HSP proteins involved in ER shaping, and further support the hypothesis that abnormal ER morphogenesis is a pathogenic mechanism in HSP.
Journal Article
LC3 lipidation is essential for TFEB activation during the lysosomal damage response to kidney injury
Sensing and clearance of dysfunctional lysosomes is critical for cellular homeostasis. Here we show that transcription factor EB (TFEB)—a master transcriptional regulator of lysosomal biogenesis and autophagy—is activated during the lysosomal damage response, and its activation is dependent on the function of the ATG conjugation system, which mediates LC3 lipidation. In addition, lysosomal damage triggers LC3 recruitment on lysosomes, where lipidated LC3 interacts with the lysosomal calcium channel TRPML1, facilitating calcium efflux essential for TFEB activation. Furthermore, we demonstrate the presence and importance of this TFEB activation mechanism in kidneys in a mouse model of oxalate nephropathy accompanying lysosomal damage. A proximal tubule-specific TFEB-knockout mouse exhibited progression of kidney injury induced by oxalate crystals. Together, our results reveal unexpected mechanisms of TFEB activation by LC3 lipidation and their physiological relevance during the lysosomal damage response.Nakamura et al. find that the master transcriptional regulator of lysosomal biogenesis and autophagy TFEB is activated following LC3 lipidation during lysosomal damage and show the importance of this mechanism during kidney injury.
Journal Article
Nanotoxic Effects of Silver Nanoparticles on Normal HEK-293 Cells in Comparison to Cancerous HeLa Cell Line
Biomimetic approaches for the synthesis of silver nanoparticles (AgNPs) had created a substantial impression among the research community that focuses on nano-bio interactions. In this study, an eco-friendly method using
aqueous leaf extract as a reductant-rich hydrosol was followed to synthesize AgNPs and test its cytotoxicity.
To optimise the parameters for the synthesis of AgNPs, central composite design based on response surface methodology was used. The particles synthesized at a nano-scale were characterized in our previously published report. The present report further characterizes the nanoparticles by X-ray diffraction, SEM and TEM at varying sites and magnifications. The characterized AgNPs were tested for their cytotoxic effects on HEK-293 and HeLa cells.
The cytotoxicity on the cell lines was dose-dependent. At a concentration of 2.5 μL/mL of the AgNPs-containing hydrosol, 100% inhibition of HEK-293 cells and 75% inhibition of the HeLa cells were observed. The IC
value for AgNPs on HEK-293 was 0.622 µL/mL (12.135 ng), whereas, for HeLa cells, it was 1.98 µL/mL (38.629 ng).
The nanoparticles were three-fold toxic towards the HEK-293 cells in comparison to the HeLa cells. Therefore, the therapeutic index is low for
derived AgNPs on HeLa cells when tested in comparison with the HEK-293 cells. The nanotoxicity profile of the synthesized AgNPs seems more prominent than the nanotherapeutic index. According to our knowledge, this is the first-ever report on the optimization of synthesis of AgNPs using response surface methodology and identifying the therapeutic index of mangrove leaf-derived AgNPs.
Journal Article
GC-MS Metabolites of Duku (Lansium domesticum) Leaves and Bark Extract as Anticancer against MCF-7, Hela Cancer Cell, and Molecular Docking Revealed its Potential
Lansium domesticum (L. domesticum) is a tropical fruit widely cultivated in Indonesia, with its leaves and bark known to contain bioactive compounds. However, their biological activities remain largely unexplored. This study aimed to evaluate the antioxidant activity and cytotoxic potential of ethanol extracts from L. domesticum leaves and bark against breast cancer (MCF-7) and cervical cancer (HeLa) cells in vitro. Antioxidant activity was assessed using the DPPH radical scavenging assay, while cytotoxicity was determined using the MTT assay. The results revealed that the leaf extract exhibited stronger antioxidant activity than the bark extract. Cytotoxicity analysis demonstrated that both extracts were toxic to MCF-7 and HeLa cells, with the bark extract exhibiting higher potency. The IC₅₀ values for the leaf extract were 71.77 µg/mL against MCF-7 cells and 37.45 µg/mL against HeLa cells, while the bark extract showed IC₅₀ values of 58.65 µg/mL and 17.54 µg/mL against MCF-7 and HeLa cells, respectively. Furthermore, molecular docking analysis revealed that allo-aromadendrene exhibited the strongest binding affinity to both the MCF-7 (3ERT) and HeLa (5DXU) receptors, with the lowest Gibbs free energy values and inhibition constant. Ɛ-muurolene also demonstrated a notable interaction with the HeLa receptor. These findings suggest that L. domesticum bark extract, particularly due to the presence of allo-aromadendrene and Ɛ-muurolene, has significant cytotoxic potential and could serve as a promising candidate for the development of natural anticancer agents, particularly against cervical cancer. Further studies are warranted to explore its mechanisms of action and potential therapeutic applications
Journal Article
YTHDF3 facilitates translation and decay of N 6 -methyladenosine-modified RNA
N
-methyladenosine (m
A) is the most abundant internal modification in eukaryotic messenger RNAs (mRNAs), and plays important roles in cell differentiation and tissue development. It regulates multiple steps throughout the RNA life cycle including RNA processing, translation, and decay, via the recognition by selective binding proteins. In the cytoplasm, m
A binding protein YTHDF1 facilitates translation of m
A-modified mRNAs, and YTHDF2 accelerates the decay of m
A-modified transcripts. The biological function of YTHDF3, another cytoplasmic m
A binder of the YTH (YT521-B homology) domain family, remains unknown. Here, we report that YTHDF3 promotes protein synthesis in synergy with YTHDF1, and affects methylated mRNA decay mediated through YTHDF2. Cells deficient in all three YTHDF proteins experience the most dramatic accumulation of m
A-modified transcripts. These results indicate that together with YTHDF1 and YTHDF2, YTHDF3 plays critical roles to accelerate metabolism of m
A-modified mRNAs in the cytoplasm. All three YTHDF proteins may act in an integrated and cooperative manner to impact fundamental biological processes related to m
A RNA methylation.
Journal Article
Anticancer Activity Test Of 70% Alcohol Extract of Sembung Leaves ( Blumea Balsamifera ) Against Cervical Cancer Cells In-Vitro
Cervical cancer is one of the most common cancers among Indonesian women, second only to breast cancer. Several anticancer medications cause minor to severe adverse effects such as fever, nausea, vomiting, hair loss, and other diseases. Because of the negative side effects suffered by patients, numerous researchs have been done to investigate herbal medicines as alternative cancer therapies with less side effects and more efficacy. The purpose of this study is to assess the efficacy of a 70% alcohol extract of Blumea Balsamifera (Sembung leaf) against cervical cancer cells. This study used a true experimental design with a quantitative methodology. The study used a 70% alcohol extract of Blumea Balsamifera leaves with concentrations of 15.625, 31.75, 62.5, 125, and 250 mg/ml, as well as HeLa cell cultures. Absorbance values were determined using the MTT assay and an ELISA Reader. Significant differences were discovered at concentrations of 125 and 250 mg/ml, while no significant differences were seen at concentrations of 15.625 and 31.25 mg/ml (p > 0.05). The study found that a concentration of 21.62 μg/ml of the extract reduces cell viability by up to 50%.
Journal Article