The Influence of ALS-associated MATR3 Toxicity on Cell Size in the Yeast Model

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease1. The pathology of ALS is described as the progressive degeneration of motor neurons that initially leads to atrophy of the voluntary muscles followed by the involuntary muscles1,2. Ultimately, the cause of death is pulmonary distress due to loss of function of the diaphragm2. Life expectancy after diagnosis is usually one year, and there are currently no cures or effective treatments for this fatal disease3. Approximately 90% of all ALS cases are sporadic meaning that the disease is developed randomly, while around 10% of the cases are familial meaning that the disease is passed down within a family3,4. Over 30 years, many genes have been identified and linked to the development of familial ALS. One of these genes is MATR3 which codes for Matrin-3, a nuclear matrix protein that binds to DNA and RNA with various roles in the nucleus5. Matrin-3 is normally found in the nucleus; however, when the gene is mutated, Matrin-3 is depleted from the nucleus and accumulates in clusters in the cytoplasm6. Matrin-3 associated toxicity is hypothesized to be either due to the loss of function of the protein in the nucleus or a gain of toxicity function in the cytoplasm leading to neuronal cell death. Furthermore, with increasing MATR3 toxicity in yeast, an increase in cell size was observed

Hierarchical speaker representation for target speaker extraction

Target speaker extraction aims to isolate a specific speaker's voice from a composite of multiple sound sources, guided by an enrollment utterance or called anchor. Current methods predominantly derive speaker embeddings from the anchor and integrate them into the separation network to separate the voice of the target speaker. However, the representation of the speaker embedding is too simplistic, often being merely a 1*1024 vector. This dense information makes it difficult for the separation network to harness effectively. To address this limitation, we introduce a pioneering methodology called Hierarchical Representation (HR) that seamlessly fuses anchor data across granular and overarching 5 layers of the separation network, enhancing the precision of target extraction. HR amplifies the efficacy of anchors to improve target speaker isolation. On the Libri-2talker dataset, HR substantially outperforms state-of-the-art time-frequency domain techniques. Further demonstrating HR's capabilities, we achieved first place in the prestigious ICASSP 2023 Deep Noise Suppression Challenge. The proposed HR methodology shows great promise for advancing target speaker extraction through enhanced anchor utilization.Comment: Accepted to ICASSP 202

MC-SpEx: Towards Effective Speaker Extraction with Multi-Scale Interfusion and Conditional Speaker Modulation

The previous SpEx+ has yielded outstanding performance in speaker extraction and attracted much attention. However, it still encounters inadequate utilization of multi-scale information and speaker embedding. To this end, this paper proposes a new effective speaker extraction system with multi-scale interfusion and conditional speaker modulation (ConSM), which is called MC-SpEx. First of all, we design the weight-share multi-scale fusers (ScaleFusers) for efficiently leveraging multi-scale information as well as ensuring consistency of the model's feature space. Then, to consider different scale information while generating masks, the multi-scale interactive mask generator (ScaleInterMG) is presented. Moreover, we introduce ConSM module to fully exploit speaker embedding in the speech extractor. Experimental results on the Libri2Mix dataset demonstrate the effectiveness of our improvements and the state-of-the-art performance of our proposed MC-SpEx.Comment: Accepted by InterSpeech 202

TEA-PSE 3.0: Tencent-Ethereal-Audio-Lab Personalized Speech Enhancement System For ICASSP 2023 DNS Challenge

This paper introduces the Unbeatable Team's submission to the ICASSP 2023 Deep Noise Suppression (DNS) Challenge. We expand our previous work, TEA-PSE, to its upgraded version -- TEA-PSE 3.0. Specifically, TEA-PSE 3.0 incorporates a residual LSTM after squeezed temporal convolution network (S-TCN) to enhance sequence modeling capabilities. Additionally, the local-global representation (LGR) structure is introduced to boost speaker information extraction, and multi-STFT resolution loss is used to effectively capture the time-frequency characteristics of the speech signals. Moreover, retraining methods are employed based on the freeze training strategy to fine-tune the system. According to the official results, TEA-PSE 3.0 ranks 1st in both ICASSP 2023 DNS-Challenge track 1 and track 2.Comment: Accepted by ICASSP 202

Caspase-1 causes truncation and aggregation of the Parkinson's disease-associated protein α-synuclein

The aggregation of α-synuclein (aSyn) leading to the formation of Lewy bodies is the defining pathological hallmark of Parkinson's disease (PD). Rare familial PD-associated mutations in aSyn render it aggregation-prone; however, PD patients carrying wild type (WT) aSyn also have aggregated aSyn in Lewy bodies. The mechanisms by which WT aSyn aggregates are unclear. Here, we report that inflammation can play a role in causing the aggregation of WT aSyn. We show that activation of the inflammasome with known stimuli results in the aggregation of aSyn in a neuronal cell model of PD. The insoluble aggregates are enriched with truncated aSyn as found in Lewy bodies of the PD brain. Inhibition of the inflammasome enzyme caspase-1 by chemical inhibition or genetic knockdown with shRNA abated aSyn truncation. In vitro characterization confirmed that caspase-1 directly cleaves aSyn, generating a highly aggregation-prone species. The truncation-induced aggregation of aSyn is toxic to neuronal culture, and inhibition of caspase-1 by shRNA or a specific chemical inhibitor improved the survival of a neuronal PD cell model. This study provides a molecular link for the role of inflammation in aSyn aggregation, and perhaps in the pathogenesis of sporadic PD as well

A Pan-cancer analysis reveals high-frequency genetic alterations in mediators of signaling by the tgf-β superfamily

We present an integromic analysis of gene alterations that modulate transforming growth factor β (TGF-β)-Smad-mediated signaling in 9,125 tumor samples across 33 cancer types in The Cancer Genome Atlas (TCGA). Focusing on genes that encode mediators and regulators of TGF-β signaling, we found at least one genomic alteration (mutation, homozygous deletion, or amplification) in 39% of samples, with highest frequencies in gastrointestinal cancers. We identified mutation hotspots in genes that encode TGF-β ligands (BMP5), receptors (TGFBR2, AVCR2A, and BMPR2), and Smads (SMAD2 and SMAD4). Alterations in the TGF-β superfamily correlated positively with expression of metastasis-associated genes and with decreased survival. Correlation analyses showed the contributions of mutation, amplification, deletion, DNA methylation, and miRNA expression to transcriptional activity of TGF-β signaling in each cancer type. This study provides a broad molecular perspective relevant for future functional and therapeutic studies of the diverse cancer pathways mediated by the TGF-β superfamily

A Yeast Model of FUS/TLS-Dependent Cytotoxicity

FUS/TLS is a nucleic acid binding protein that, when mutated, can cause a subset of familial amyotrophic lateral sclerosis (fALS). Although FUS/TLS is normally located predominantly in the nucleus, the pathogenic mutant forms of FUS/TLS traffic to, and form inclusions in, the cytoplasm of affected spinal motor neurons or glia. Here we report a yeast model of human FUS/TLS expression that recapitulates multiple salient features of the pathology of the disease-causing mutant proteins, including nuclear to cytoplasmic translocation, inclusion formation, and cytotoxicity. Protein domain analysis indicates that the carboxyl-terminus of FUS/TLS, where most of the ALS-associated mutations are clustered, is required but not sufficient for the toxicity of the protein. A genome-wide genetic screen using a yeast over-expression library identified five yeast DNA/RNA binding proteins, encoded by the yeast genes ECM32, NAM8, SBP1, SKO1, and VHR1, that rescue the toxicity of human FUS/TLS without changing its expression level, cytoplasmic translocation, or inclusion formation. Furthermore, hUPF1, a human homologue of ECM32, also rescues the toxicity of FUS/TLS in this model, validating the yeast model and implicating a possible insufficiency in RNA processing or the RNA quality control machinery in the mechanism of FUS/TLS mediated toxicity. Examination of the effect of FUS/TLS expression on the decay of selected mRNAs in yeast indicates that the nonsense-mediated decay pathway is probably not the major determinant of either toxicity or suppression.Fidelity Biosciences (Firm)Fidelity Biosciences (Firm) (Research Inititative)ALS Therapy AllianceNational Institutes of Health (U.S.) (NIH 1RC1NS06839)National Institutes of Health (U.S.) (NIH U01NS05225-03)National Institutes of Health (U.S.) (NIH R01NS050557-05)National Institutes of Health (U.S.) (NIH 1RC2NS070342-01)Pierre L. de Bourgknecht ALS Research FoundationNational Science Foundation (U.S.) (NS614192

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

China's system and vision of innovation: analysis of the national medium- and long-term science and technology development plan (2006-2020)

Presented at the GLOBELICS 6th International Conference 2008 22-24 September, Mexico City, Mexico.China has been characterised by extremely high rates of economic growth for the last several decades. This growth originates from a transformation of the institutional set up giving more room for regional initiative, private ownership and use of market mechanisms. Regional political resources have been aligned to globally oriented market resources and this alignment has established a very specific and unique mechanism of capital accumulation resulting in extremely high savings and investment rates. The downside of this growth model is its intensive exploitation of human and natural resources. While the rate of capital accumulation is extremely high (40-50% of GNP takes the form of gross savings and investment) non reproducible natural and social capital are suffering in the process of growth. Social and regional inequality has reached critical levels and so have ecological imbalances. The central leadership of China are aware of these problems and recent policy documents put strong emphasis on ‘harmonious development’ and ‘independent innovation’ (Gu and Lundvall 2006). In China the transformation of the national innovation system is now regarded as a major step toward a necessary renewal of the growth model. This paper presents a general framework for the analysis of national innovation system, a historical overview over the development of China’s production and innovation system and ends up with a discussion of the National Medium- and Long-term Science and Technology Development Plan (2006-2020). We conclude that the plan represents steps forward in important respects. This is true for the emphasis on need driven innovation policy with focus on energy and environment, the stronger role for enterprises as hosts of R&D-efforts and innovation, a more active role for public procurement and a more realistic understanding of the limits of science as source of innovation. But the plan has some weaknesses and needs to be complemented with other initiatives. There is exaggerated technology optimism and the need for institutional and organisational change at the level of the enterprise is underestimated. In some cases the policy instruments and tools seem to be inadequate when related to the very ambitious targets set by the plan. Especially problematic is the absence of an explicit analysis of the regional dimension and the need to upgrade working life in terms of skills and organisation. The fact that a knowledge based strategy, if left to itself, leads to further social and regional polarisation is not taken into account. Finally how the idea of ‘indigenous innovation’ will be implemented is crucial both for the success of the plan and for China’s relationships with the rest of the world