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Cancer cells rely on mitochondria for their bioenergetic supply and macromolecule synthesis. Central to mitochondrial function is the regulation of mitochondrial protein synthesis, which primarily depends on the cytoplasmic translation of nuclear-encoded mitochondrial mRNAs whose protein products are imported into mitochondria. Despite the growing evidence that mitochondrial protein synthesis contributes to the onset and progression of cancer, and can thus offer new opportunities for cancer therapy, knowledge of the underlying molecular mechanisms remains limited. Here, we show that RNA G-quadruplexes (RG4s) regulate mitochondrial function by modulating cytoplasmic mRNA translation of nuclear-encoded mitochondrial proteins. Our data support a model whereby the RG4 folding dynamics, under the control of oncogenic signaling and modulated by small molecule ligands or RG4-binding proteins, modifies mitochondria-localized cytoplasmic protein synthesis. Ultimately, this impairs mitochondrial functions, affecting energy metabolism and consequently cancer cell proliferation. Cancer cells rely on mitochondria for energy and macromolecule synthesis. Here, the authors show that RNA G-quadruplex dynamics, driven by oncogenic signals, regulate the translation of nuclear-encoded mitochondrial mRNAs, affecting mitochondrial function and promoting cancer cell growth.

RNA G-quadruplexes (RG4s) are four-stranded structures known to control mRNA translation of cancer relevant genes. RG4 formation is pervasive in vitro but not in cellulo, indicating the existence of poorly characterized molecular machinery that remodels RG4s and maintains them unfolded. Here, we performed a quantitative proteomic screen to identify cytosolic proteins that interact with a canonical RG4 in its folded and unfolded conformation. Our results identified hnRNP H/F as important components of the cytoplasmic machinery modulating the structural integrity of RG4s, revealed their function in RG4-mediated translation and uncovered the underlying molecular mechanism impacting the cellular stress response linked to the outcome of glioblastoma.

Deregulation of mRNA translation is a widespread characteristic of glioblastoma (GBM), aggressive malignant brain tumors that are resistant to conventional therapies. RNA-binding proteins (RBPs) play a critical role in translational regulation, yet the mechanisms and impact of these regulations on cancer development, progression and response to therapy remain to be fully understood. Here, we showed that hnRNP H/F RBPs are potent regulators of translation through several mechanisms that converge to modulate the expression and/or the activity of translation initiation factors. Among these, hnRNP H/F regulate the phosphorylation of eIF4E and its translational targets by controlling RNA splicing of the A-Raf kinase mRNA, which in turn modulates the MEK-ERK/MAPK signaling pathway. The underlying mechanism involves RNA G-quadruplex (RG4s), RNA structures whose modulation phenocopies hnRNP H/F translation regulation in GBM cells. Our results highlighted that hnRNP H/F are essential for key functional pathways regulating proliferation and survival of GBM, highlighting its targeting as a promising strategy for improving therapeutic outcomes.

Cancer cells rely on mitochondria for their bioenergetic supply and macromolecule synthesis. Central to mitochondrial function is the regulation of mitochondrial protein synthesis, which primarily depends on the cytoplasmic translation of nuclear-encoded mitochondrial mRNAs whose protein products are imported into mitochondria. Despite the growing evidence that mitochondrial protein synthesis contributes to the onset and progression of cancer, and can thus offer new opportunities for cancer therapy, knowledge of the underlying molecular mechanisms remains limited. Here, we show that RNA G-quadruplexes (RG4s) regulate mitochondrial function by modulating cytoplasmic mRNA translation of nuclear-encoded mitochondrial proteins. Our data support a model whereby the RG4 folding dynamics, under the control of oncogenic signaling and modulated by small molecule ligands or RG4-binding proteins, modifies mitochondria-localized cytoplasmic protein synthesis. Ultimately, this impairs mitochondrial functions, affecting energy metabolism and consequently cancer cell proliferation.Competing Interest StatementThe authors have declared no competing interest.

16p11.2 and 22q11.2 Copy Number Variants (CNVs) confer high risk for Autism Spectrum Disorder (ASD), schizophrenia (SZ), and Attention-Deficit-Hyperactivity-Disorder (ADHD), but their impact on functional connectivity (FC) remains unclear. Here we report an analysis of resting-state FC using magnetic resonance imaging data from 101 CNV carriers, 755 individuals with idiopathic ASD, SZ, or ADHD and 1,072 controls. We characterize CNV FC-signatures and use them to identify dimensions contributing to complex idiopathic conditions. CNVs have large mirror effects on FC at the global and regional level. Thalamus, somatomotor, and posterior insula regions play a critical role in dysconnectivity shared across deletions, duplications, idiopathic ASD, SZ but not ADHD. Individuals with higher similarity to deletion FC-signatures exhibit worse cognitive and behavioral symptoms. Deletion similarities identified at the connectivity level could be related to the redundant associations observed genome-wide between gene expression spatial patterns and FC-signatures. Results may explain why many CNVs affect a similar range of neuropsychiatric symptoms. The impact of neurodevelopmental mutations on functional brain connectivity is poorly understood. Here the authors identify thalamo-sensorimotor dysconnectivity dimensions shared across 16p11.2 and 22q11.2 copy number variants, autism and schizophrenia, but not ADHD.

Sundowner winds are downslope gusty winds often observed on the southern slopes of the Santa Ynez Mountains (SYM) in coastal Santa Barbara (SB), California. They typically peak near sunset and exhibit characteristics of downslope windstorms through the evening. They are SB’s most critical fire weather in all seasons and represent a major hazard for aviation. The Sundowner Winds Experiment Pilot Study was designed to evaluate vertical profiles of winds, temperature, humidity, and stability leeward of the SYM during a Sundowner event. This was accomplished by launching 3-hourly radiosondes during a significant Sundowner event on 28–29 April 2018. This study showed that winds in the lee of the SYM exhibit complex spatial and temporal patterns. Vertical profiles showed a transition from humid onshore winds from morning to midafternoon to very pronounced offshore winds during the evening after sunset. These winds accompanied mountain waves and a northerly nocturnal lee jet with variable temporal behavior. Around sunset, the jet was characterized by strong wind speeds enhanced by mountain-wave breaking. Winds weakened considerably at 2300 PDT 29 April but enhanced dramatically at 0200 PDT 29 April at much lower elevations. These transitions were accompanied by changes in stability profiles and in the Richardson number. A simulation with the Weather Research and Forecasting (WRF) Model at 1-km grid spacing was examined to evaluate the skill of the model in capturing the observed winds and stability profiles and to assess mesoscale processes associated with this event. These results advanced understanding on Sundowner’s spatiotemporal characteristics and driving mechanisms.

Antibiotic prophylaxis for patients with cancer remains a controversial issue and is not broadly recommended for hematological malignancies. The venetoclax (VEN) and azacitidine (AZA) combination allows for high rates of complete remission in acute myeloid leukemia (AML) but enhances the incidence of febrile neutropenia (FN) compared to AZA alone, making primary antibiotic prophylaxis a relevant question. Patients with AML who received VEN-AZA were selected from the DATAML registry to investigate the use of levofloxacin (LEVO) prophylaxis, administered at 500 mg/day from day 10 following the first course of VEN-AZA, until neutrophil recovery (>0.5 × 10 /L). A cohort of 258 patients was identified (median age 69.8 years, interquartile range 20.4-87.4), with 72 having received LEVO and 186 treated with standard of care (SOC). VEN-AZA was used for newly diagnosed AML in 52.7% of cases. FN occurred in 33.3% of LEVO patients versus 37.1% of SOC patients ( = .572). Time from day 10 VEN-AZA to FN was significantly delayed in LEVO patients (12.5 days vs 8 in SOC; = .037). Pulmonary infections were considerably reduced by LEVO (10.2% vs 1.4%, = .018) as well as those involving Enterobacterales (9.1% vs 1.4%; = .029). No early increase in fluoroquinolone resistance was detected ( = .142). Levofloxacin as primary prophylaxis in patients with AML treated with VEN-AZA seems to decrease the rate of documented infections even if the incidence of FN was not significantly decreased. This prophylaxis shaped a different clinical and microbiological landscape without significant increase of antibiotic resistance.

16p11.2 and 22q11.2 Copy Number Variants (CNVs) confer high risk for Autism Spectrum Disorder (ASD), schizophrenia (SZ), and Attention-Deficit-Hyperactivity-Disorder (ADHD), but their impact on functional connectivity (FC) remains unclear. We analyzed resting-state functional magnetic resonance imaging data from 101 CNV carriers, 755 individuals with idiopathic ASD, SZ, or ADHD and 1,072 controls. We used CNV FC-signatures to identify dimensions contributing to complex idiopathic conditions. CNVs had large mirror effects on FC at the global and regional level. Thalamus, somatomotor, and posterior insula regions played a critical role in dysconnectivity shared across deletions, duplications, idiopathic ASD, SZ but not ADHD. Individuals with higher similarity to deletion FC-signatures exhibited worse cognitive and behavioural symptoms. Deletion similarities identified at the connectivity level could be related to the redundant associations observed genome-wide between gene expression spatial patterns and FC-signatures. Results may explain why many CNVs affect a similar range of neuropsychiatric symptoms. Competing Interest Statement The authors have declared no competing interest. Footnotes * Extensive efforts have, in particular, been directed towards 1) Demonstrating the robustness of the results by using novel data, performing an array of sensitivity analyses, and systematic comparison with previously published results in autism and schizophrenia 2) Fully reshaping the last section of the manuscript on gene expression. This included analyzing expression data genome-wide and performing a new array of methods that generated results of significant interest. * https://github.com/surchs/Neuropsychiatric_CNV_code_supplement