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"Tang, Rachel"
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Machine project : the platinum collection (live by special request)
New essays and images capture the quirky essence of Machine Project, where vacations for plants, concerts for dentists, and operas for dogs are a few of the typical offerings produced at the informal, non-profit, educational institution in Los Angeles. Designed in collaboration with Kimberly Varella, this book reflects on Machine Project's ongoing artistic practice, featuring an extensive selection of photographs of past projects and documentation of new performance projects at the Tang Museum by Haruko Tanaka, Krystal Krunch, Hana van der Kolk, Carmina Escobar, Kamau Patton, Dawn Kasper, Joshua Beckman, Asher Hartman, and Chris Kallmyer among others.
Book
ALKBH5 regulates anti–PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment
Although immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, many patients do not respond or develop resistance to ICB. N⁶-methylation of adenosine (m⁶A) in RNA regulates many pathophysiological processes. Here, we show that deletion of the m⁶A demethylase Alkbh5 sensitized tumors to cancer immunotherapy. Alkbh5 has effects on m⁶A density and splicing events in tumors during ICB. Alkbh5 modulates Mct4/Slc16a3 expression and lactate content of the tumor microenvironment and the composition of tumor-infiltrating Treg and myeloid-derived suppressor cells. Importantly, a small-molecule Alkbh5 inhibitor enhanced the efficacy of cancer immunotherapy. Notably, the ALKBH5 gene mutation and expression status of melanoma patients correlate with their response to immunotherapy. Our results suggest that m⁶A demethylases in tumor cells contribute to the efficacy of immunotherapy and identify ALKBH5 as a potential therapeutic target to enhance immunotherapy outcome in melanoma, colorectal, and potentially other cancers.
Journal Article
CLN3 is required for the clearance of glycerophosphodiesters from lysosomes
Lysosomes have many roles, including degrading macromolecules and signalling to the nucleus
1
. Lysosomal dysfunction occurs in various human conditions, such as common neurodegenerative diseases and monogenic lysosomal storage disorders (LSDs)
2
,
3
–
4
. For most LSDs, the causal genes have been identified but, in some, the function of the implicated gene is unknown, in part because lysosomes occupy a small fraction of the cellular volume so that changes in lysosomal contents are difficult to detect. Here we develop the LysoTag mouse for the tissue-specific isolation of intact lysosomes that are compatible with the multimodal profiling of their contents. We used the LysoTag mouse to study CLN3, a lysosomal transmembrane protein with an unknown function. In children, the loss of
CLN3
causes juvenile neuronal ceroid lipofuscinosis (Batten disease), a lethal neurodegenerative LSD. Untargeted metabolite profiling of lysosomes from the brains of mice lacking CLN3 revealed a massive accumulation of glycerophosphodiesters (GPDs)—the end products of glycerophospholipid catabolism. GPDs also accumulate in the lysosomes of CLN3-deficient cultured cells and we show that CLN3 is required for their lysosomal egress. Loss of CLN3 also disrupts glycerophospholipid catabolism in the lysosome. Finally, we found elevated levels of glycerophosphoinositol in the cerebrospinal fluid of patients with Batten disease, suggesting the potential use of glycerophosphoinositol as a disease biomarker. Our results show that CLN3 is required for the lysosomal clearance of GPDs and reveal Batten disease as a neurodegenerative LSD with a defect in glycerophospholipid metabolism.
The lysosomal transmembrane protein CLN3 is required for the lysosomal clearance of glycerophosphodiesters in mice and in human cells, suggesting that the loss of CLN3 causes Batten disease in children due to defects in glycerophospholipid metabolism.
Journal Article
Rab7a is an enhancer of TPC2 activity regulating melanoma progression through modulation of the GSK3β/β-Catenin/MITF-axis
Melanoma arising from pigment-producing melanocytes is the deadliest form of skin cancer. Extensive ultraviolet light exposure is a major cause of melanoma and individuals with low levels of melanin are at particular risk. Humans carrying gain-of-function polymorphisms in the melanosomal/endolysosomal two-pore cation channel TPC2 present with hypopigmentation, blond hair, and albinism. Loss of TPC2 is associated with decreased cancer/melanoma proliferation, migration, invasion, tumor growth and metastasis formation, and TPC2 depleted melanoma cells show increased levels of melanin. How TPC2 activity is controlled in melanoma and the downstream molecular effects of TPC2 activation on melanoma development remain largely elusive. Here we show that the small GTPase Rab7a strongly enhances the activity of TPC2 and that effects of TPC2 on melanoma hallmarks, in vitro and in vivo strongly depend on the presence of Rab7a, which controls TPC2 activity to modulate GSK3β, β-Catenin, and MITF, a major regulator of melanoma development and progression.
Direct interaction between the small GTPase Rab7a and the cation channel TPC2 has been reported but the functional regulation is less clear. Here, the authors show that Rab7a enhances the activity of TPC2 to promote melanoma progression through the GSK3β/β-Catenin/MITF axis.
Journal Article
Polymethoxyflavones from Kaempferia parviflora stimulate melanogenesis by blocking the TPC2 channel
Kaempferia parviflora
, well-known as Thai ginseng (Krachaidum), has been used as a medicinal plant and food source for centuries. Its rhizome contains several flavonoids, particularly poly-
O
-methylated flavones (also known as polymethoxyflavones). We previously found that
K. parviflora
extract had a strong stimulatory effect on melanogenesis in B16F10 mouse melanoma cells. The aim of this study was to investigate the melanogenic stimulation exerted by various
O
-methylated flavonoids from
K. parviflora
in human melanoma cells and elucidate the mechanism of action of the most active compound. MNT-1 cells were used to screen for the most potent
O
-methylated flavonoid, and its effects on some key steps in melanin biosynthesis would subsequently be investigated. The poly-
O
-methylated flavone 3,5,7,3′,4′-pentamethoxyflavone (PMF) exhibited the strongest melanogenesis-stimulating activity among the 13
O
-methylated flavones isolated from
K. parviflora
. It was shown to enhance tyrosinase (TYR) activity by upregulating the levels of TYR and TYR-related protein 1 (TRP-1) via its inhibitory effect on two-pore channel 2 (TPC2). In conclusion, poly-
O
-methylated flavones, especially PMF, were suggested as a potential group of flavonoids that could stimulate melanin production by inhibiting the activity of the TPC2 channel, leading to increased TYR and TRP-1 activities.
Journal Article
Estradiol analogs attenuate autophagy, cell migration and invasion by direct and selective inhibition of TRPML1, independent of estrogen receptors
The cation channel TRPML1 is an important regulator of lysosomal function and autophagy. Loss of TRPML1 is associated with neurodegeneration and lysosomal storage disease, while temporary inhibition of this ion channel has been proposed to be beneficial in cancer therapy. Currently available TRPML1 channel inhibitors are not TRPML isoform selective and block at least two of the three human isoforms. We have now identified the first highly potent and isoform-selective TRPML1 antagonist, the steroid 17β-estradiol methyl ether (EDME). Two analogs of EDME, PRU-10 and PRU-12, characterized by their reduced activity at the estrogen receptor, have been identified through systematic chemical modification of the lead structure. EDME and its analogs, besides being promising new small molecule tool compounds for the investigation of TRPML1, selectively affect key features of TRPML1 function: autophagy induction and transcription factor EB (TFEB) translocation. In addition, they act as inhibitors of triple-negative breast cancer cell migration and invasion.
Journal Article
Flavonoids increase melanin production and reduce proliferation, migration and invasion of melanoma cells by blocking endolysosomal/melanosomal TPC2
Two-pore channel 2 (TPC2) resides in endolysosomal membranes but also in lysosome-related organelles such as the melanin producing melanosomes. Gain-of-function polymorphisms in hTPC2 are associated with decreased melanin production and blond hair color. Vice versa genetic ablation of TPC2 increases melanin production. We show here an inverse correlation between melanin production and melanoma proliferation, migration, and invasion due to the dual activity of TPC2 in endolysosomes and melanosomes. Our results are supported by both genetic ablation and pharmacological inhibition of TPC2. Mechanistically, our data show that loss/block of TPC2 results in reduced protein levels of MITF, a major regulator of melanoma progression, but an increased activity of the melanin-generating enzyme tyrosinase. TPC2 inhibition thus provides a twofold benefit in melanoma prevention and treatment by increasing, through interference with tyrosinase activity, the synthesis of UV blocking melanin in melanosomes and by decreasing MITF-driven melanoma progression by increased GSK3β-mediated MITF degradation.
Journal Article
Segregated cation flux by TPC2 biases Ca2+ signaling through lysosomes
Two-pore channels are endo-lysosomal cation channels with malleable selectivity filters that drive endocytic ion flux and membrane traffic. Here we show that TPC2 can differentially regulate its cation permeability when co-activated by its endogenous ligands, NAADP and PI(3,5)P
2
. Whereas NAADP rendered the channel Ca
2+
-permeable and PI(3,5)P
2
rendered the channel Na
+
-selective, a combination of the two increased Ca
2+
but not Na
+
flux. Mechanistically, this was due to an increase in Ca
2+
permeability independent of changes in ion selectivity. Functionally, we show that cell permeable NAADP and PI(3,5)P
2
mimetics synergistically activate native TPC2 channels in live cells, globalizing cytosolic Ca
2+
signals and regulating lysosomal pH and motility. Our data reveal that flux of different ions through the same pore can be independently controlled and identify TPC2 as a likely coincidence detector that optimizes lysosomal Ca
2+
signaling.
TPC2 is a lysosomal ion channel permeable to both calcium and sodium ions. Here, the authors show that TPC2 can selectively increase its calcium permeability when simultaneously challenged by both its natural activators- NAADP and PI(3,5)P
2
.
Journal Article
Access to ultrasound imaging: A qualitative study in two northern, remote, Indigenous communities in Canada
Ultrasound imaging is an essential component of healthcare services. This study sought to explore perceptions of access, and factors which shape access, to ultrasound imaging in two northern, remote, Indigenous communities in Canada. Using interpretive description as a methodological approach and a multi-dimensional conceptualisation of access to care as a theoretical framework, 15 semi-structured interviews were conducted in the northern Canadian communities of Stony Rapids and Black Lake, Saskatchewan. All participants had an obstetrical or non-obstetrical ultrasound exam performed in the past 10 years. Interviews were audio recorded and interview transcripts were analysed using constant comparative analysis. Geographic isolation from imaging facilities was a central barrier to participants accessing ultrasound imaging. Other barriers became apparent when participants had to travel for ultrasound, including fear of air travel, isolation from family, financial means, and unfamiliarity with larger cities. Barriers such as family and work responsibilities were exacerbated by the barrier of geography. Participants overcame these barriers as they were motivated by potential diagnostic benefits of ultrasound imaging. This study highlights disparities in access to ultrasound for northern, remote, Indigenous populations. Future efforts to improve access to imaging should consider barriers of distance to imaging facilities and strategies to bridge these barriers.
Journal Article
Where does physical activity fit into preschool postpandemic? A qualitative exploration with parents, teachers and administrators
ObjectivesDuring the preschool years, children depend on adult caregivers to provide opportunities for physical activity (PA). Research has focused on measuring PA in preschool, as well as barriers and facilitators to children’s PA but caregiver perceptions remain largely unknown especially in light of the COVID-19 pandemic. This study aims to understand the value of PA in preschool following the pandemic from three types of adult caregivers, parents of a young child (n=7), preschool teachers (n=7) and preschool administrators (n=7).MethodsIn-depth qualitative interviews were conducted to explore the following research questions: (a) how do caregivers describe the importance of PA in preschool postpandemic? (b) how do caregivers support and prioritise PA in preschool postpandemic and what challenges do they face in doing so? and (c) how do caregivers interact with one another to promote PA? Qualitative answers were coded using a codebook developed to answer the research questions of interest.ResultsParents, teachers and administrators all described valuing PA for preschoolers, but each caregiver type described a different way of promoting it. All the caregivers listed barriers that inhibit their ability to prioritise and promote PA, some heightened postpandemic. Lastly, there were limited caregiver interactions when it came to promoting PA, with the burden largely falling on teachers.ConclusionOur findings indicate that one particularly important area for intervention is supporting parents, teachers and preschool administrators in creating a shared understanding of the importance of PA for young children and ways to collaborate to promote it.
Journal Article