Twist1 Controls Lung Vascular Permeability and Endotoxin-Induced Pulmonary Edema by Altering Tie2 Expression

Tight regulation of vascular permeability is necessary for normal development and deregulated vascular barrier function contributes to the pathogenesis of various diseases, including acute respiratory distress syndrome, cancer and inflammation. The angiopoietin (Ang)-Tie2 pathway is known to control vascular permeability. However, the mechanism by which the expression of Tie2 is regulated to control vascular permeability has not been fully elucidated. Here we show that transcription factor Twist1 modulates pulmonary vascular leakage by altering the expression of Tie2 in a context-dependent way. Twist1 knockdown in cultured human lung microvascular endothelial cells decreases Tie2 expression and phosphorylation and increases RhoA activity, which disrupts cell-cell junctional integrity and increases vascular permeability in vitro. In physiological conditions, where Ang1 is dominant, pulmonary vascular permeability is elevated in the Tie2-specific Twist1 knockout mice. However, depletion of Twist1 and resultant suppression of Tie2 expression prevent increase in vascular permeability in an endotoxin-induced lung injury model, where the balance of Angs shifts toward Ang2. These results suggest that Twist1-Tie2-Angs signaling is important for controlling vascular permeability and modulation of this mechanism may lead to the development of new therapeutic approaches for pulmonary edema and other diseases caused by abnormal vascular permeability

Chromosome-scale assembly of the Moringa oleifera Lam. genome uncovers polyploid history and evolution of secondary metabolism pathways through tandem duplication

The African Orphan Crops Consortium (AOCC) selected the highly nutritious, fast growing and drought tolerant tree crop moringa (Moringa oleifera Lam.) as one of the first of 101 plant species to have its genome sequenced and a first draft assembly was published in 2019. Given the extensive uses and culture of moringa, often referred to as the multipurpose tree, we generated a significantly improved new version of the genome based on long-read sequencing into 14 pseudochromosomes equivalent to n = 14 haploid chromosomes. We leveraged this nearly complete version of the moringa genome to investigate main drivers of gene family and genome evolution that may be at the origin of relevant biological innovations including agronomical favorable traits. Our results reveal that moringa has not undergone any additional whole-genome duplication (WGD) or polyploidy event beyond the gamma WGD shared by all core eudicots. Moringa duplicates retained following that ancient gamma events are also enriched for functions commonly considered as dosage balance sensitive. Furthermore, tandem duplications seem to have played a prominent role in the evolution of specific secondary metabolism pathways including those involved in the biosynthesis of bioactive glucosinolate, flavonoid, and alkaloid compounds as well as of defense response pathways and might, at least partially, explain the outstanding phenotypic plasticity attributed to this species. This study provides a genetic roadmap to guide future breeding programs in moringa, especially those aimed at improving secondary metabolism related traits.https://wileyonlinelibrary.com/journal/tpg2dm2022BiochemistryGeneticsMicrobiology and Plant Patholog

Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein.

The discovery of the causative gene for Huntington's disease (HD) has promoted numerous efforts to uncover cellular pathways that lower levels of mutant huntingtin protein (mHtt) and potentially forestall the appearance of HD-related neurological defects. Using a cell-based model of pathogenic huntingtin expression, we identified a class of compounds that protect cells through selective inhibition of a lipid kinase, PIP4Kγ. Pharmacological inhibition or knock-down of PIP4Kγ modulates the equilibrium between phosphatidylinositide (PI) species within the cell and increases basal autophagy, reducing the total amount of mHtt protein in human patient fibroblasts and aggregates in neurons. In two Drosophila models of Huntington's disease, genetic knockdown of PIP4K ameliorated neuronal dysfunction and degeneration as assessed using motor performance and retinal degeneration assays respectively. Together, these results suggest that PIP4Kγ is a druggable target whose inhibition enhances productive autophagy and mHtt proteolysis, revealing a useful pharmacological point of intervention for the treatment of Huntington's disease, and potentially for other neurodegenerative disorders

SeamlessM4T-Massively Multilingual & Multimodal Machine Translation

What does it take to create the Babel Fish, a tool that can help individuals translate speech between any two languages? While recent breakthroughs in text-based models have pushed machine translation coverage beyond 200 languages, unified speech-to-speech translation models have yet to achieve similar strides. More specifically, conventional speech-to-speech translation systems rely on cascaded systems that perform translation progressively, putting high-performing unified systems out of reach. To address these gaps, we introduce SeamlessM4T, a single model that supports speech-to-speech translation, speech-to-text translation, text-to-speech translation, text-to-text translation, and automatic speech recognition for up to 100 languages. To build this, we used 1 million hours of open speech audio data to learn self-supervised speech representations with w2v-BERT 2.0. Subsequently, we created a multimodal corpus of automatically aligned speech translations. Filtered and combined with human-labeled and pseudo-labeled data, we developed the first multilingual system capable of translating from and into English for both speech and text. On FLEURS, SeamlessM4T sets a new standard for translations into multiple target languages, achieving an improvement of 20% BLEU over the previous SOTA in direct speech-to-text translation. Compared to strong cascaded models, SeamlessM4T improves the quality of into-English translation by 1.3 BLEU points in speech-to-text and by 2.6 ASR-BLEU points in speech-to-speech. Tested for robustness, our system performs better against background noises and speaker variations in speech-to-text tasks compared to the current SOTA model. Critically, we evaluated SeamlessM4T on gender bias and added toxicity to assess translation safety. Finally, all contributions in this work are open-sourced and accessible at https://github.com/facebookresearch/seamless_communicatio

Estimated Glomerular Filtration Rate, Albuminuria, and Adverse Outcomes. An Individual-Participant Data Meta-Analysis

IMPORTANCE: Chronic kidney disease (low estimated glomerular filtration rate [eGFR] or albuminuria) affects approximately 14% of adults in the US. OBJECTIVE: To evaluate associations of lower eGFR based on creatinine alone, lower eGFR based on creatinine combined with cystatin C, and more severe albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes. DESIGN, SETTING, AND PARTICIPANTS: Individual-participant data meta-analysis of 27 503 140 individuals from 114 global cohorts (eGFR based on creatinine alone) and 720 736 individuals from 20 cohorts (eGFR based on creatinine and cystatin C) and 9 067 753 individuals from 114 cohorts (albuminuria) from 1980 to 2021. EXPOSURES: The Chronic Kidney Disease Epidemiology Collaboration 2021 equations for eGFR based on creatinine alone and eGFR based on creatinine and cystatin C; and albuminuria estimated as urine albumin to creatinine ratio (UACR). MAIN OUTCOMES AND MEASURES: The risk of kidney failure requiring replacement therapy, all-cause mortality, cardiovascular mortality, acute kidney injury, any hospitalization, coronary heart disease, stroke, heart failure, atrial fibrillation, and peripheral artery disease. The analyses were performed within each cohort and summarized with random-effects meta-analyses. RESULTS: Within the population using eGFR based on creatinine alone (mean age, 54 years [SD, 17 years]; 51% were women; mean follow-up time, 4.8 years [SD, 3.3 years]), the mean eGFR was 90 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 11 mg/g (IQR, 8-16 mg/g). Within the population using eGFR based on creatinine and cystatin C (mean age, 59 years [SD, 12 years]; 53% were women; mean follow-up time, 10.8 years [SD, 4.1 years]), the mean eGFR was 88 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 9 mg/g (IQR, 6-18 mg/g). Lower eGFR (whether based on creatinine alone or based on creatinine and cystatin C) and higher UACR were each significantly associated with higher risk for each of the 10 adverse outcomes, including those in the mildest categories of chronic kidney disease. For example, among people with a UACR less than 10 mg/g, an eGFR of 45 to 59 mL/min/1.73 m2 based on creatinine alone was associated with significantly higher hospitalization rates compared with an eGFR of 90 to 104 mL/min/1.73 m2 (adjusted hazard ratio, 1.3 [95% CI, 1.2-1.3]; 161 vs 79 events per 1000 person-years; excess absolute risk, 22 events per 1000 person-years [95% CI, 19-25 events per 1000 person-years]). CONCLUSIONS AND RELEVANCE: In this retrospective analysis of 114 cohorts, lower eGFR based on creatinine alone, lower eGFR based on creatinine and cystatin C, and more severe UACR were each associated with increased rates of 10 adverse outcomes, including adverse kidney outcomes, cardiovascular diseases, and hospitalizations

Dynamics of magnetization at infinite temperature in a Heisenberg spin chain

Understanding universal aspects of quantum dynamics is an unresolved problem in statistical mechanics. In particular, the spin dynamics of the 1D Heisenberg model were conjectured to belong to the Kardar-Parisi-Zhang (KPZ) universality class based on the scaling of the infinite-temperature spin-spin correlation function. In a chain of 46 superconducting qubits, we study the probability distribution, $P(\mathcal{M})$, of the magnetization transferred across the chain's center. The first two moments of $P(\mathcal{M})$ show superdiffusive behavior, a hallmark of KPZ universality. However, the third and fourth moments rule out the KPZ conjecture and allow for evaluating other theories. Our results highlight the importance of studying higher moments in determining dynamic universality classes and provide key insights into universal behavior in quantum systems