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Targeted Therapy of CAR+ T-Cell Lymphoma after Anti-BCMA CAR T-Cell Therapy
Control of Golgi- V-ATPase through Sac1-dependent co-regulation of PI(4)P and cholesterol
Abstract Sac1 is a conserved phosphoinositide phosphatase, whose loss-of-function compromises cell and organism viability. Here, we employ acute auxin-inducible Sac1 degradation to identify its immediate downstream effectors in human cells. Most of Sac1 is degraded in ~1 h, paralleled by increased PI(4)P and decreased cholesterol in the trans- Golgi network (TGN) during the following hour, and superseded by Golgi fragmentation, impaired glycosylation, and selective degradation of TGN proteins by ~4 h. The TGN disintegration results from its acute deacidification caused by disassembly of the Golgi V-ATPase. Mechanistically, Sac1 mediated TGN membrane composition maintains an assembly-promoting conformation of the V 0 a2 subunit. Key phenotypes of acute Sac1 degradation are recapitulated in human differentiated trophoblasts, causing processing defects of chorionic gonadotropin, in line with loss-of-function intolerance of the human SACM1L gene. Collectively, our findings reveal that the assembly of the Golgi V-ATPase is controlled by the TGN membrane via Sac1 fuelled lipid exchange.
Regulating Private Equity in Health Care — The Massachusetts Model
In-situ synthesis of interfacial In-O-Mn lewis acid-base pairs for low-temperature photothermal CO2 hydrogenation to methanol
Elinzanetant for Vasomotor Symptoms from Endocrine Therapy for Breast Cancer
Deep learning prediction of noise-driven nonlinear instabilities in fibre optics
Abstract Machine learning is bringing revolutionary approaches into many fields of physics. Among those, photonics enables fast and scalable information processing. Photonics platforms further possess rich nonlinear dynamics that drive fundamental interest but also prove powerful for applications in computation, imaging, frequency conversion, source development and advanced signal processing. However, incoherent processes of nonlinear optics are hardly exploited in practice as the control of noise-driven dynamics remains challenging. Here, we exploit deep learning strategies and demonstrate that coherent optical seeding can effectively shape incoherent spectral broadening. We focus on the intricate interplay between weak coherent pulses and broadband noise, competing during nonlinear fibre propagation within an amplification process known as modulation instability. We demonstrate artificial neural networks’ capability to efficiently predict these complex incoherent dynamics, both numerically and experimentally. Our results show that input seed properties can be inferred from the incoherent output signal. Furthermore, our approach enables reliable prediction of output spectral fluctuations, paving the way to tailoring complex photonic signals with specific correlation features.
GM-CSF in Autoimmune Pulmonary Alveolar Proteinosis
Alien planet glimpsed in star’s ‘habitable zone’
Lanthanide cerium(III) complex with deep-red emission beyond 700 nm
The Consultant
A homochiral covalent organic framework membrane for the enantioseparation and fractionation of amino acids
Reforming the Prescription Drug User Fee Program
Prefrontal cortex astrocytes modulate distinct neuronal populations to control anxiety-like behavior
Overall Survival with Neoadjuvant Nivolumab plus Chemotherapy in Lung Cancer
Structural basis for the recognition and ubiquitylation of type-2 N-degron substrate by PRT1 plant N-recognin
Publisher Correction: NINJ1 regulates plasma membrane fragility under mechanical strain
FBXW7 regulates MYRF levels to control myelin capacity and homeostasis in the adult central nervous system
Patient-derived tumoroids from CIC::DUX4 rearranged sarcoma identify MCL1 as a therapeutic target
Abstract High-risk sarcomas, such as metastatic and relapsed Ewing and CIC-rearranged sarcoma, still have a poor prognosis despite intensive therapeutic regimens. Precision medicine approaches offer hope, and ex vivo drug response profiling of patient-derived tumor cells emerges as a promising tool to identify effective therapies for individual patients. Here, we establish ex vivo culture conditions to propagate Ewing sarcoma and CIC::DUX4 sarcoma as tumoroids. These models retain their original molecular and functional characteristics, including recurrent ARID1A mutations in CIC::DUX4 sarcoma, and serve as tumor avatars for large-scale drug testing. Screening a large drug library on a small living biobank of such tumors not only reveals distinct differences in drug response between the two entities, but also identifies a dependency of CIC::DUX4 sarcoma cells on MCL1. Mechanistically, MCL1 is identified as a direct transcriptional target of the CIC::DUX4 fusion oncogene. Genetic and pharmacological inhibition of MCL1 induces rapid apoptosis in CIC::DUX4 sarcoma cells and inhibits tumor growth in a xenograft model. Thus, MCL1 represents a potential therapeutic target for CIC::DUX4 sarcoma. Overall, our study highlights the feasibility of drug response profiling for individual sarcoma cases and suggests that further clinical assessments of its benefit are warranted.