ADSL deficiency is a secondary mitochondrial disease affecting organelle homeostasis and ERK2/AKT signaling in a linear genotype-phenotype relation.

Adenylosuccinate lyase deficiency (ADSLd) is a rare autosomal recessive purine metabolism disorder with several clinical manifestations. While toxic substrate accumulation is a known hallmark, no additional molecular mechanisms have been established. Here, we show that ADSLd is associated with mitochondrial dysfunction, including increased fragmentation, impaired respiration, and reduced ATP production.

ATG conjugation-dependent/independent mechanisms underlie lysosomal stress-induced TFEB regulation.

TFEB, a master regulator of autophagy and lysosomal biogenesis, is activated by several cellular stresses including lysosomal damage, but its underlying mechanism is unclear. TFEB activation during lysosomal damage depends on the ATG conjugation system, which mediates lipidation of ATG8 proteins. Here, we newly identify ATG conjugation-independent TFEB regulation that precedes ATG conjugation-dependent regulation, designated Modes I and II, respectively.

Folliculin Deletion in the Mouse Kidney Results in Cystogenesis of the Loops of Henle via Aberrant TFEB Activation.

The mammalian kidney contains numerous nephrons connected to the collecting ducts, and each nephron consists of a glomerulus, a proximal tubule, the loop of Henle (LoH), and a distal tubule. Folliculin (FLCN) is a causative gene for Birt-Hogg-Dubé syndrome, which is characterized by a variety of manifestations, including renal cysts and cancer. Although deletion of Flcn in the mouse collecting duct and distal nephron leads to cyst formation, its precise role in the entire nephron remains unclear.

TFEB Orchestrates Stress Recovery and Paves the Way for Senescence Induction in Human Dermal Fibroblasts.

Cells experience oxidative stress and widespread cellular damage during stress-induced premature senescence (SIPS). Senescent cells show an increase in lysosomal content, which may contribute to mitigating cellular damage by promoting autophagy. This study investigates the dynamics of lysosomal quality control in human dermal fibroblasts (HDF), specifically examining lysosomal signaling pathways during oxidative stress-induced SIPS.

Folliculin depletion results in liver cell damage and cholangiocarcinoma through MiT/TFE activation.

Mutations in the tumor suppressor gene Folliculin (FLCN) are responsible for Birt-Hogg-Dube' (BHD) syndrome, a rare inherited condition that predisposes affected individuals to skin tumors, pulmonary cysts, and kidney tumors. FLCN regulates key cellular pathways, including TFEB, TFE3, and mTORC1, which are critical for maintaining cell homeostasis. Loss of FLCN leads to both hyperactivation of mTORC1 and constitutive activation of TFEB and TFE3, contributing to tumorigenesis.

Investigation of dynamic regulation of TFEB nuclear shuttling by microfluidics and quantitative modelling.

Transcription Factor EB (TFEB) controls lysosomal biogenesis and autophagy in response to nutritional status and other stress factors. Although its regulation by nuclear translocation is known to involve a complex network of well-studied regulatory processes, the precise contribution of each of these mechanisms is unclear. Using microfluidics technology and real-time imaging coupled with mathematical modelling, we explored the dynamic regulation of TFEB under different conditions.

Age-related TFEB downregulation in proximal tubules causes systemic metabolic disorders and occasional apolipoprotein A4-related amyloidosis.

With the aging of society, the incidence of chronic kidney disease (CKD), a common cause of death, has been increasing. Transcription factor EB (TFEB), the master transcriptional regulator of the autophagy/lysosomal pathway, is regarded as a promising candidate for preventing various age-related diseases. However, whether TFEB in the proximal tubules plays a significant role in elderly patients with CKD remains unknown.

Structural basis for growth factor and nutrient signal integration on the lysosomal membrane by mTORC1.

Mechanistic target of rapamycin complex 1 (mTORC1), which consists of mTOR, Raptor, and mLST8, receives signaling inputs from growth factor signals and nutrients. These signals are mediated by the Rheb and Rag small GTPases, respectively, which activate mTORC1 on the cytosolic face of the lysosome membrane. We biochemically reconstituted the activation of mTORC1 on membranes by physiological submicromolar concentrations of Rheb, Rags, and Ragulator.

Waste Material Classification Based on a Wavelength-Sensitive Ge-on-Si Photodetector.

Waste material classification is critical for efficient recycling and waste management. This study proposes a novel, low-cost material classification system based on a single, voltage-tunable Ge-on-Si photodetector operating across the visible and short-wave infrared (SWIR) spectral regions. Thanks to its tunability, the sensor is able to extract spectral information, and the system effectively distinguishes between seven different materials, including plastics, aluminum, glass, and paper.

Oligodendroglial fatty acid metabolism as a central nervous system energy reserve.

Brain function requires a constant supply of glucose. However, the brain has no known energy stores, except for glycogen granules in astrocytes. In the present study, we report that continuous oligodendroglial lipid metabolism provides an energy reserve in white matter tracts.

TFEB activation hallmarks antigenic experience of B lymphocytes and directs germinal center fate decisions.

Ligation of the B cell antigen receptor (BCR) initiates humoral immunity. However, BCR signaling without appropriate co-stimulation commits B cells to death rather than to differentiation into immune effector cells. How BCR activation depletes potentially autoreactive B cells while simultaneously primes for receiving rescue and differentiation signals from cognate T lymphocytes remains unknown.

Neoadjuvant Chemotherapy in Breast Cancer: Evaluation of the Impact on Surgical Outcomes and Prognosis.

The correlation between TNM staging and histology variations in a sample of patients who underwent neoadjuvant chemotherapy demonstrates a positive impact on both increasing conservative surgery and achieving pCR, resulting in better outcomes in terms of disease-free survival (DFS) and the risk of relapse. Benefits have also been highlighted in terms of cosmetic outcomes, postoperative complications, and psychological benefits. However, the overall outcomes must be evaluated according to the subtype and individual characteristics of the patients.

Ragopathies and the rising influence of RagGTPases on human diseases.

RagGTPases (Rags) play an essential role in the regulation of cell metabolism by controlling the activities of both mechanistic target of rapamycin complex 1 (mTORC1) and Transcription factor EB (TFEB). Several diseases, herein named ragopathies, are associated to Rags dysfunction. These diseases may be caused by mutations either in genes encoding the Rags, or in their upstream regulators.

TFEB controls syncytiotrophoblast formation and hormone production in placenta.

TFEB, a bHLH-leucine zipper transcription factor belonging to the MiT/TFE family, globally modulates cell metabolism by regulating autophagy and lysosomal functions. Remarkably, loss of TFEB in mice causes embryonic lethality due to severe defects in placentation associated with aberrant vascularization and resulting hypoxia. However, the molecular mechanism underlying this phenotype has remained elusive.

RRAGD-Associated Autosomal Dominant Kidney Hypomagnesemia with Cardiomyopathy: A Review on the Clinical Manifestations and Therapeutic Options.

Background: A hereditary condition primarily affecting the kidneys and heart has newly been identified: the RRAGD-associated autosomal dominant kidney hypomagnesemia with cardiomyopathy (ADKH-RRAGD). This disorder is characterized by renal loss of magnesium and potassium, coupled with varying degrees of cardiac dysfunction. These range from arrhythmias to severe dilated cardiomyopathy, which may require heart transplantation.

Loss of the lysosomal protein CLN3 modifies the lipid content of the nuclear envelope leading to DNA damage and activation of YAP1 pro-apoptotic signaling.

Batten disease is characterized by early-onset blindness, juvenile dementia and death during the second decade of life. The most common genetic causes are mutations in the gene encoding a lysosomal protein. There are currently no therapies targeting the progression of the disease, mostly due to the lack of knowledge about the disease mechanisms.

High-throughput screening of novel TFEB agonists in protecting against acetaminophen-induced liver injury in mice.

Macroautophagy (referred to as autophagy hereafter) is a major intracellular lysosomal degradation pathway that is responsible for the degradation of misfolded/damaged proteins and organelles. Previous studies showed that autophagy protects against acetaminophen (APAP)-induced injury (AILI) selective removal of damaged mitochondria and APAP protein adducts. The lysosome is a critical organelle sitting at the end stage of autophagy for autophagic degradation fusion with autophagosomes.

Parity-conserving Cooper-pair transport and ideal superconducting diode in planar germanium.

Superconductor/semiconductor hybrid devices have attracted increasing interest in the past years. Superconducting electronics aims to complement semiconductor technology, while hybrid architectures are at the forefront of new ideas such as topological superconductivity and protected qubits. In this work, we engineer the induced superconductivity in two-dimensional germanium hole gas by varying the distance between the quantum well and the aluminum.

Dectin-1/CARD9 induction of the TFEB and TFE3 gene network is dispensable for phagocyte anti- activity in the lung.

Myeloid phagocytes of the respiratory immune system, such as neutrophils, monocytes, and alveolar macrophages, are essential for immunity to , the most common etiologic agent of mold pneumonia worldwide. Following the engulfment of conidia, fusion of the phagosome with the lysosome is a critical process for killing conidia. TFEB and TFE3 are transcription factors that regulate lysosomal biogenesis under stress and are activated by inflammatory stimuli in macrophages, but it is unknown whether TFEB and TFE3 contribute to anti- immunity during infection.