Lysosomal reduced thiols are essential for mouse embryonic development.

While it has been appreciated for decades that lysosomes can import cysteine, its for organismal physiology is unclear. Recently, the MFSD12 transmembrane protein was shown to be necessary to import cysteine into lysosomes (and melanosomes), enabling the study of these processes using genetic tools. Here, we find that mice lacking die between embryonic days 10.

Technologies for Decoding Cancer Metabolism with Spatial Resolution.

It is increasingly appreciated that cancer cells adapt their metabolic pathways to support rapid growth and proliferation as well as survival, often even under the poor nutrient conditions that characterize some tumors. Cancer cells can also rewire their metabolism to circumvent chemotherapeutics that inhibit core metabolic pathways, such as nucleotide synthesis. A critical approach to the study of cancer metabolism is metabolite profiling (metabolomics), the set of technologies, usually based on mass spectrometry, that allow for the detection and quantification of metabolites in cancer cells and their environments.

Reach-dependent reorientation of rotational dynamics in motor cortex.

During reaching, neurons in motor cortex exhibit complex, time-varying activity patterns. Though single-neuron activity correlates with movement parameters, movement correlations explain neural activity only partially. Neural responses also reflect population-level dynamics thought to generate outputs.

Ergothioneine boosts mitochondrial respiration and exercise performance via direct activation of MPST.

Ergothioneine (EGT) is a diet-derived, atypical amino acid that accumulates to high levels in human tissues. Reduced EGT levels have been linked to age-related disorders, including neurodegenerative and cardiovascular diseases, while EGT supplementation is protective in a broad range of disease and aging models in mice. Despite these promising data, the direct and physiologically relevant molecular target of EGT has remained elusive.

An evolutionary mechanism to assimilate new nutrient sensors into the mTORC1 pathway.

Animals sense and respond to nutrient availability in their environments, a task coordinated in part by the mTOR complex 1 (mTORC1) pathway. mTORC1 regulates growth in response to nutrients and, in mammals, senses specific amino acids through specialized sensors that bind the GATOR1/2 signaling hub. Given that animals can occupy diverse niches, we hypothesized that the pathway might evolve distinct sensors in different metazoan phyla.

Not all information is informative: An exploration of educational content on recycled potable water knowledge and acceptance.

As drought and water shortages threaten access to safe water supplies globally, finding ways to increase public acceptance of recycled water has become increasingly important. Educational interventions have often been explored as a potential method to help overcome public distaste for recycled water. However, in past research, the effects of educational interventions have tended to be modest, leading to some skepticism over the ability of public information campaigns to truly increase acceptance.

An evolutionary mechanism to assimilate new nutrient sensors into the mTORC1 pathway.

Animals must sense and respond to nutrient availability in their local niche. This task is coordinated in part by the mTOR complex 1 (mTORC1) pathway, which regulates growth and metabolism in response to nutrients. In mammals, mTORC1 senses specific amino acids through specialized sensors that act through the upstream GATOR1/2 signaling hub.

Collateral deletion of the mitochondrial AAA+ ATPase ATAD1 sensitizes cancer cells to proteasome dysfunction.

The tumor suppressor gene is the second most commonly deleted gene in cancer. Such deletions often include portions of the chromosome 10q23 locus beyond the bounds of itself, which frequently disrupts adjacent genes. Coincidental loss of -adjacent genes might impose vulnerabilities that could either affect patient outcome basally or be exploited therapeutically.

CLN3 is required for the clearance of glycerophosphodiesters from lysosomes.

Lysosomes have many roles, including degrading macromolecules and signalling to the nucleus. Lysosomal dysfunction occurs in various human conditions, such as common neurodegenerative diseases and monogenic lysosomal storage disorders (LSDs). 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.

Sestrin mediates detection of and adaptation to low-leucine diets in Drosophila.

Mechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth and metabolism in response to multiple nutrients, including the essential amino acid leucine. Recent work in cultured mammalian cells established the Sestrins as leucine-binding proteins that inhibit mTORC1 signalling during leucine deprivation, but their role in the organismal response to dietary leucine remains elusive. Here we find that Sestrin-null flies (Sesn) fail to inhibit mTORC1 or activate autophagy after acute leucine starvation and have impaired development and a shortened lifespan on a low-leucine diet.

Structure of the nutrient-sensing hub GATOR2.

Mechanistic target of rapamycin complex 1 (mTORC1) controls growth by regulating anabolic and catabolic processes in response to environmental cues, including nutrients. Amino acids signal to mTORC1 through the Rag GTPases, which are regulated by several protein complexes, including GATOR1 and GATOR2. GATOR2, which has five components (WDR24, MIOS, WDR59, SEH1L and SEC13), is required for amino acids to activate mTORC1 and interacts with the leucine and arginine sensors SESN2 and CASTOR1, respectively.

Zonated leucine sensing by Sestrin-mTORC1 in the liver controls the response to dietary leucine.

The mechanistic target of rapamycin complex 1 (mTORC1) kinase controls growth in response to nutrients, including the amino acid leucine. In cultured cells, mTORC1 senses leucine through the leucine-binding Sestrin proteins, but the physiological functions and distribution of Sestrin-mediated leucine sensing in mammals are unknown. We find that mice lacking Sestrin1 and Sestrin2 cannot inhibit mTORC1 upon dietary leucine deprivation and suffer a rapid loss of white adipose tissue (WAT) and muscle.

Sustainable groundwater treatment technologies for underserved rural communities in emerging economies.

Worldwide, about one out of two people depend on groundwater resources to satisfy their drinking water needs. While groundwater typically is of higher quality than surface water, pollution and geologic conditions may require treating groundwater to meet safe water quality criteria. Herein, a critical overview is presented of water treatment technologies for rural and underserved communities in emerging economies that depend on groundwater.

Fumarate is a terminal electron acceptor in the mammalian electron transport chain.

For electrons to continuously enter and flow through the mitochondrial electron transport chain (ETC), they must ultimately land on a terminal electron acceptor (TEA), which is known to be oxygen in mammals. Paradoxically, we find that complex I and dihydroorotate dehydrogenase (DHODH) can still deposit electrons into the ETC when oxygen reduction is impeded. Cells lacking oxygen reduction accumulate ubiquinol, driving the succinate dehydrogenase (SDH) complex in reverse to enable electron deposition onto fumarate.

GCN2 adapts protein synthesis to scavenging-dependent growth.

Pancreatic cancer cells with limited access to free amino acids can grow by scavenging extracellular protein. In a murine model of pancreatic cancer, we performed a genome-wide CRISPR screen for genes required for scavenging-dependent growth. The screen identified key mediators of macropinocytosis, peripheral lysosome positioning, endosome-lysosome fusion, lysosomal protein catabolism, and translational control.

mTOR-Activating Mutations in Are Causative for Kidney Tubulopathy and Cardiomyopathy.

Background: Over the last decade, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, approximately 20% of all patients with tubulopathy lack a genetic diagnosis.

Methods: We performed whole-exome and -genome sequencing of a patient cohort with a novel, inherited, salt-losing tubulopathy; hypomagnesemia; and dilated cardiomyopathy.

Limited survival and impaired hepatic fasting metabolism in mice with constitutive Rag GTPase signaling.

The mechanistic target of rapamycin complex 1 (mTORC1) integrates cellular nutrient signaling and hormonal cues to control metabolism. We have previously shown that constitutive nutrient signaling to mTORC1 by means of genetic activation of RagA (expression of GTP-locked RagA, or RagA) in mice resulted in a fatal energetic crisis at birth. Herein, we rescue neonatal lethality in RagA mice and find morphometric and metabolic alterations that span glucose, lipid, ketone, bile acid and amino acid homeostasis in adults, and a median lifespan of nine months.

Phosphorus recovery and recycling from model animal wastewaters using materials prepared from rice straw and corn cobs.

Anthropogenic loss of phosphorus to surface waters not only causes environmental problems but depletes valuable phosphorus reserves. In this study, magnesium amended biochars and magnesium silicate, synthesized from corn cobs and rice straw, respectively, were evaluated for phosphorus uptake including the effects of pH and alkalinity. The overall goal was to close the phosphorus loop by recovering phosphorus from animal waste and reusing it as fertilizer.