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  1. Book ; Online: Transformers without Tears

    Nguyen, Toan Q. / Salazar, Julian

    Improving the Normalization of Self-Attention

    2019  

    Abstract: We evaluate three simple, normalization-centric changes to improve Transformer training. First, we show that pre-norm residual connections (PreNorm) and smaller initializations enable warmup-free, validation-based training with large learning rates. ... ...

    Abstract We evaluate three simple, normalization-centric changes to improve Transformer training. First, we show that pre-norm residual connections (PreNorm) and smaller initializations enable warmup-free, validation-based training with large learning rates. Second, we propose $\ell_2$ normalization with a single scale parameter (ScaleNorm) for faster training and better performance. Finally, we reaffirm the effectiveness of normalizing word embeddings to a fixed length (FixNorm). On five low-resource translation pairs from TED Talks-based corpora, these changes always converge, giving an average +1.1 BLEU over state-of-the-art bilingual baselines and a new 32.8 BLEU on IWSLT'15 English-Vietnamese. We observe sharper performance curves, more consistent gradient norms, and a linear relationship between activation scaling and decoder depth. Surprisingly, in the high-resource setting (WMT'14 English-German), ScaleNorm and FixNorm remain competitive but PreNorm degrades performance.

    Comment: Accepted to IWSLT 2019 (oral); code is available at https://github.com/tnq177/transformers_without_tears
    Keywords Computer Science - Computation and Language ; Computer Science - Machine Learning ; Statistics - Machine Learning
    Subject code 006
    Publishing date 2019-10-13
    Publishing country us
    Document type Book ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Book ; Online: Data Augmentation by Concatenation for Low-Resource Translation

    Nguyen, Toan Q. / Murray, Kenton / Chiang, David

    A Mystery and a Solution

    2021  

    Abstract: In this paper, we investigate the driving factors behind concatenation, a simple but effective data augmentation method for low-resource neural machine translation. Our experiments suggest that discourse context is unlikely the cause for the improvement ... ...

    Abstract In this paper, we investigate the driving factors behind concatenation, a simple but effective data augmentation method for low-resource neural machine translation. Our experiments suggest that discourse context is unlikely the cause for the improvement of about +1 BLEU across four language pairs. Instead, we demonstrate that the improvement comes from three other factors unrelated to discourse: context diversity, length diversity, and (to a lesser extent) position shifting.
    Keywords Computer Science - Computation and Language
    Publishing date 2021-05-04
    Publishing country us
    Document type Book ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Mfsd7b facilitates choline transport and missense mutations affect choline transport function.

    Ha, Hoa Thi Thuy / Sukumar, Viresh Krishnan / Chua, Jonathan Wei Bao / Nguyen, Dat T / Nguyen, Toan Q / Lim, Lina Hsiu Kim / Cazenave-Gassiot, Amaury / Nguyen, Long N

    Cellular and molecular life sciences : CMLS

    2023  Volume 81, Issue 1, Page(s) 3

    Abstract: MFSD7b belongs to the Major Facilitator Superfamily of transporters that transport small molecules. Two isoforms of MFSD7b have been identified and they are reported to be heme exporters that play a crucial role in maintaining the cytosolic and ... ...

    Abstract MFSD7b belongs to the Major Facilitator Superfamily of transporters that transport small molecules. Two isoforms of MFSD7b have been identified and they are reported to be heme exporters that play a crucial role in maintaining the cytosolic and mitochondrial heme levels, respectively. Mutations of MFSD7b (also known as FLVCR1) have been linked to retinitis pigmentosa, posterior column ataxia, and hereditary sensory and autonomic neuropathy. Although MFSD7b functions have been linked to heme detoxification by exporting excess heme from erythroid cells, it is ubiquitously expressed with a high level in the kidney, gastrointestinal tract, lungs, liver, and brain. Here, we showed that MFSD7b functions as a facilitative choline transporter. Expression of MFSD7b slightly but significantly increased choline import, while its knockdown reduced choline influx in mammalian cells. The influx of choline transported by MFSD7b is dependent on the expression of choline metabolizing enzymes such as choline kinase (CHKA) and intracellular choline levels, but it is independent of gradient of cations. Additionally, we showed that choline transport function of Mfsd7b is conserved from fly to man. Employing our transport assays, we showed that missense mutations of MFSD7b caused reduced choline transport functions. Our results show that MFSD7b functions as a facilitative choline transporter in mammalian cells.
    MeSH term(s) Animals ; Humans ; Choline/metabolism ; Heme ; Mammals ; Mutation, Missense ; Membrane Transport Proteins/genetics
    Chemical Substances Choline (N91BDP6H0X) ; Heme (42VZT0U6YR) ; FLVCR1 protein, human ; Membrane Transport Proteins
    Language English
    Publishing date 2023-12-06
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1358415-7
    ISSN 1420-9071 ; 1420-682X
    ISSN (online) 1420-9071
    ISSN 1420-682X
    DOI 10.1007/s00018-023-05048-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Lack of SPNS1 results in accumulation of lysolipids and lysosomal storage disease in mouse models.

    Ha, Hoa Tt / Liu, SiYi / Nguyen, Xuan Ta / Vo, Linh K / Leong, Nancy Cp / Nguyen, Dat T / Balamurugan, Shivaranjani / Lim, Pei Yen / Wu, YaJun / Seong, Eunju / Nguyen, Toan Q / Oh, Jeongah / Wenk, Markus R / Cazenave-Gassiot, Amaury / Yapici, Zuhal / Ong, Wei-Yi / Burmeister, Margit / Nguyen, Long N

    JCI insight

    2024  Volume 9, Issue 8

    Abstract: Accumulation of sphingolipids, especially sphingosines, in the lysosomes is a key driver of several lysosomal storage diseases. The transport mechanism for sphingolipids from the lysosome remains unclear. Here, we identified SPNS1, which shares the ... ...

    Abstract Accumulation of sphingolipids, especially sphingosines, in the lysosomes is a key driver of several lysosomal storage diseases. The transport mechanism for sphingolipids from the lysosome remains unclear. Here, we identified SPNS1, which shares the highest homology to SPNS2, a sphingosine-1-phosphate (S1P) transporter, functions as a transporter for lysolipids from the lysosome. We generated Spns1-KO cells and mice and employed lipidomic and metabolomic approaches to reveal SPNS1 ligand identity. Global KO of Spns1 caused embryonic lethality between E12.5 and E13.5 and an accumulation of sphingosine, lysophosphatidylcholines (LPC), and lysophosphatidylethanolamines (LPE) in the fetal livers. Similarly, metabolomic analysis of livers from postnatal Spns1-KO mice presented an accumulation of sphingosines and lysoglycerophospholipids including LPC and LPE. Subsequently, biochemical assays showed that SPNS1 is required for LPC and sphingosine release from lysosomes. The accumulation of these lysolipids in the lysosomes of Spns1-KO mice affected liver functions and altered the PI3K/AKT signaling pathway. Furthermore, we identified 3 human siblings with a homozygous variant in the SPNS1 gene. These patients suffer from developmental delay, neurological impairment, intellectual disability, and cerebellar hypoplasia. These results reveal a critical role of SPNS1 as a promiscuous lysolipid transporter in the lysosomes and link its physiological functions with lysosomal storage diseases.
    MeSH term(s) Animals ; Female ; Humans ; Male ; Mice ; Disease Models, Animal ; Liver/metabolism ; Lysophospholipids/metabolism ; Lysosomal Storage Diseases/metabolism ; Lysosomal Storage Diseases/genetics ; Lysosomal Storage Diseases/pathology ; Lysosomes/metabolism ; Mice, Knockout ; Sphingolipids/metabolism ; Sphingosine/analogs & derivatives ; Sphingosine/metabolism
    Chemical Substances Lysophospholipids ; Sphingolipids ; Sphingosine (NGZ37HRE42) ; Spns1 protein, mouse
    Language English
    Publishing date 2024-03-07
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2379-3708
    ISSN (online) 2379-3708
    DOI 10.1172/jci.insight.175462
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Postnatal deletion of Spns2 prevents neuroinflammation without compromising blood vascular functions.

    Hasan, Zafrul / Nguyen, Toan Q / Lam, Brenda Wan Shing / Wong, Jovi Hui Xin / Wong, Caleb Cheng Yi / Tan, Clarissa Kai Hui / Yu, Jiabo / Thiam, Chung Hwee / Zhang, Yongliang / Angeli, Veronique / Nguyen, Long N

    Cellular and molecular life sciences : CMLS

    2022  Volume 79, Issue 11, Page(s) 541

    Abstract: Protein Spinster homolog 2 (Spns2) is a sphingosine-1-phosphate (S1P) transporter that releases S1P to regulate lymphocyte egress and trafficking. Global deletion of Spns2 ( ... ...

    Abstract Protein Spinster homolog 2 (Spns2) is a sphingosine-1-phosphate (S1P) transporter that releases S1P to regulate lymphocyte egress and trafficking. Global deletion of Spns2 (Spns2
    MeSH term(s) Animals ; Anion Transport Proteins/metabolism ; Lymphocytes/metabolism ; Lysophospholipids/metabolism ; Mice ; Mice, Knockout ; Neuroinflammatory Diseases ; Sphingosine/metabolism
    Chemical Substances Anion Transport Proteins ; Lysophospholipids ; Spns2 protein, mouse ; Sphingosine (NGZ37HRE42)
    Language English
    Publishing date 2022-10-05
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1358415-7
    ISSN 1420-9071 ; 1420-682X
    ISSN (online) 1420-9071
    ISSN 1420-682X
    DOI 10.1007/s00018-022-04573-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Postnatal deletion of Spns2 prevents neuroinflammation without compromising blood vascular functions

    Hasan, Zafrul / Nguyen, Toan Q. / Lam, Brenda Wan Shing / Wong, Jovi Hui Xin / Wong, Caleb Cheng Yi / Tan, Clarissa Kai Hui / Yu, Jiabo / Thiam, Chung Hwee / Zhang, Yongliang / Angeli, Veronique / Nguyen, Long N.

    Cell. Mol. Life Sci.. 2022 Nov., v. 79, no. 11 p.541-541

    2022  

    Abstract: Protein Spinster homolog 2 (Spns2) is a sphingosine-1-phosphate (S1P) transporter that releases S1P to regulate lymphocyte egress and trafficking. Global deletion of Spns2 (Spns2⁻/⁻) has been shown to reduce disease severity in several autoimmune disease ...

    Abstract Protein Spinster homolog 2 (Spns2) is a sphingosine-1-phosphate (S1P) transporter that releases S1P to regulate lymphocyte egress and trafficking. Global deletion of Spns2 (Spns2⁻/⁻) has been shown to reduce disease severity in several autoimmune disease models. To examine whether Spns2 could be exploited as a drug target, we generated and characterized the mice with postnatal knockout of Spns2 (Spns2-Mx1Cre). Our results showed that Spns2-Mx1Cre mice had significantly low number of lymphocytes in blood and lymphoid organs similar to Spns2⁻/⁻ mice. Lymph but not plasma S1P levels were significantly reduced in both groups of knockout mice. Our lipidomic results also showed that Spns2 releases different S1P species into lymph. Interestingly, lymphatic vessels in the lymph nodes (LNs) of Spns2⁻/⁻ and Spns2-Mx1Cre mice exhibited morphological defects. The structures of high endothelial venules (HEV) in the LNs of Spns2-Mx1Cre mice were disorganized. These results indicate that lack of Spns2 affects both S1P secretion and LN vasculatures. Nevertheless, blood vasculature of these Spns2 deficient mice was not different to controls under homeostasis and vascular insults. Importantly, Spns2-Mx1Cre mice were resistant to multiple sclerosis in experimental autoimmune encephalomyelitis (EAE) models with significant reduction of pathogenic Th17 cells in the central nervous system (CNS). This study suggests that pharmacological inhibition of Spns2 may be exploited for therapeutic applications in treatment of neuroinflammation.
    Keywords autoimmune diseases ; blood ; central nervous system ; disease severity ; drugs ; encephalitis ; homeostasis ; lipidomics ; lymph ; sclerosis ; secretion ; therapeutics
    Language English
    Dates of publication 2022-11
    Size p. 541.
    Publishing place Springer International Publishing
    Document type Article ; Online
    ZDB-ID 1358415-7
    ISSN 1420-9071 ; 1420-682X
    ISSN (online) 1420-9071
    ISSN 1420-682X
    DOI 10.1007/s00018-022-04573-y
    Database NAL-Catalogue (AGRICOLA)

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  7. Book ; Online: Masked Language Model Scoring

    Salazar, Julian / Liang, Davis / Nguyen, Toan Q. / Kirchhoff, Katrin

    2019  

    Abstract: Pretrained masked language models (MLMs) require finetuning for most NLP tasks. Instead, we evaluate MLMs out of the box via their pseudo-log-likelihood scores (PLLs), which are computed by masking tokens one by one. We show that PLLs outperform scores ... ...

    Abstract Pretrained masked language models (MLMs) require finetuning for most NLP tasks. Instead, we evaluate MLMs out of the box via their pseudo-log-likelihood scores (PLLs), which are computed by masking tokens one by one. We show that PLLs outperform scores from autoregressive language models like GPT-2 in a variety of tasks. By rescoring ASR and NMT hypotheses, RoBERTa reduces an end-to-end LibriSpeech model's WER by 30% relative and adds up to +1.7 BLEU on state-of-the-art baselines for low-resource translation pairs, with further gains from domain adaptation. We attribute this success to PLL's unsupervised expression of linguistic acceptability without a left-to-right bias, greatly improving on scores from GPT-2 (+10 points on island effects, NPI licensing in BLiMP). One can finetune MLMs to give scores without masking, enabling computation in a single inference pass. In all, PLLs and their associated pseudo-perplexities (PPPLs) enable plug-and-play use of the growing number of pretrained MLMs; e.g., we use a single cross-lingual model to rescore translations in multiple languages. We release our library for language model scoring at https://github.com/awslabs/mlm-scoring.

    Comment: ACL 2020 camera-ready (presented July 2020)
    Keywords Computer Science - Computation and Language ; Computer Science - Machine Learning ; Electrical Engineering and Systems Science - Audio and Speech Processing ; Statistics - Machine Learning
    Subject code 410
    Publishing date 2019-10-31
    Publishing country us
    Document type Book ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Mfsd2b and Spns2 are essential for maintenance of blood vessels during development and in anaphylactic shock.

    Le, Thanh Nha Uyen / Nguyen, Toan Q / Kalailingam, Pazhanichamy / Nguyen, Yen Thi Kim / Sukumar, Viresh Krishnan / Tan, Clarissa Kai Hui / Tukijan, Farhana / Couty, Ludovic / Hasan, Zafrul / Del Gaudio, Ilaria / Wenk, Markus R / Cazenave-Gassiot, Amaury / Camerer, Eric / Nguyen, Long N

    Cell reports

    2022  Volume 40, Issue 7, Page(s) 111208

    Abstract: Sphingosine-1-phosphate (S1P) is a potent lipid mediator that is secreted by several cell types. We recently showed that Mfsd2b is an S1P transporter from hematopoietic cells that contributes approximately 50% plasma S1P. Here we report the ... ...

    Abstract Sphingosine-1-phosphate (S1P) is a potent lipid mediator that is secreted by several cell types. We recently showed that Mfsd2b is an S1P transporter from hematopoietic cells that contributes approximately 50% plasma S1P. Here we report the characterization of compound deletion of Mfsd2b and Spns2, another S1P transporter active primarily in endothelial cells. Global deletion of Mfsd2b and Spns2 (global double knockout [gDKO]) results in embryonic lethality beyond embryonic day 14.5 (E14.5), with severe hemorrhage accompanied by defects of tight junction proteins, indicating that Mfsd2b and Spns2 provide S1P for signaling, which is essential for blood vessel integrity. Compound postnatal deletion of Mfsd2b and Spns2 using Mx1Cre (ctDKO-Mx1Cre) results in maximal 80% reduction of plasma S1P. ctDKO-Mx1Cre mice exhibit severe susceptibility to anaphylaxis, indicating that S1P from Mfsd2b and Spns2 is indispensable for vascular homeostasis. Our results show that S1P export from Mfsd2b and Spns2 is essential for developing and mature vasculature.
    MeSH term(s) Anaphylaxis/metabolism ; Animals ; Anion Transport Proteins/metabolism ; Biological Transport ; Endothelial Cells/metabolism ; Homeostasis ; Lysophospholipids/metabolism ; Membrane Proteins/metabolism ; Mice ; Sphingosine/metabolism
    Chemical Substances Anion Transport Proteins ; Lysophospholipids ; Membrane Proteins ; Mfsd2b protein, mouse ; Spns2 protein, mouse ; Sphingosine (NGZ37HRE42)
    Language English
    Publishing date 2022-07-31
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2022.111208
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Erythrocytes efficiently utilize exogenous sphingosines for S1P synthesis and export via Mfsd2b.

    Nguyen, Toan Q / Vu, Thiet Minh / Tukijan, Farhana / Muralidharan, Sneha / Foo, Juat Chin / Li Chin, Jasmine Fei / Hasan, Zafrul / Torta, Federico / Nguyen, Long N

    The Journal of biological chemistry

    2021  Volume 296, Page(s) 100201

    Abstract: Sphingosine-1-phosphate (S1P) is a potent lipid mediator that exerts its activity via activation of five different G protein-coupled receptors, designated as S1P1-5. This potent lipid mediator is synthesized from the sphingosine precursor by two ... ...

    Abstract Sphingosine-1-phosphate (S1P) is a potent lipid mediator that exerts its activity via activation of five different G protein-coupled receptors, designated as S1P1-5. This potent lipid mediator is synthesized from the sphingosine precursor by two sphingosine kinases (SphK1 and 2) and must be exported to exert extracellular signaling functions. We recently identified Mfsd2b as the S1P transporter in the hematopoietic system. However, the sources of sphingosine for S1P synthesis and the transport mechanism of Mfsd2b in erythrocytes remain to be determined. Here, we show that erythrocytes efficiently take up exogenous sphingosine and that a de novo synthesis pathway in part provides sphingosines to erythrocytes. The uptake of sphingosine in erythrocytes is facilitated by the activity of SphK1. By converting sphingosine into S1P, SphK1 indirectly increases the influx of sphingosine, a process that is irreversible in erythrocytes. Our results explain for the abnormally high amount of sphingosine accumulation in Mfsd2b knockout erythrocytes. Furthermore, we show that Mfsd2b utilizes a proton gradient to facilitate the release of S1P. The negatively charged residues D95 and T157 are essential for Mfsd2b transport activity. Of interest, we also discovered an S1P analog that inhibits S1P export from erythrocytes, providing evidence that sphingosine analogs can be used to inhibit S1P export by Mfsd2b. Collectively, our results highlight that erythrocytes are efficient in sphingosine uptake for S1P production and the release of S1P is dependent on Mfsd2b functions.
    MeSH term(s) Animals ; Biological Transport ; Biosynthetic Pathways ; Erythrocytes/metabolism ; Lysophospholipids/metabolism ; Membrane Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Models, Molecular ; Sphingosine/analogs & derivatives ; Sphingosine/metabolism
    Chemical Substances Lysophospholipids ; Membrane Proteins ; Mfsd2b protein, mouse ; sphingosine 1-phosphate (26993-30-6) ; Sphingosine (NGZ37HRE42)
    Language English
    Publishing date 2021-01-23
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.RA120.012941
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: MFSD7c functions as a transporter of choline at the blood-brain barrier.

    Nguyen, Xuan Thi Anh / Le, Thanh Nha Uyen / Nguyen, Toan Q / Thi Thuy Ha, Hoa / Artati, Anna / Leong, Nancy C P / Nguyen, Dat T / Lim, Pei Yen / Susanto, Adelia Vicanatalita / Huang, Qianhui / Fam, Ling / Leong, Lo Ngah / Bonne, Isabelle / Lee, Angela / Granadillo, Jorge L / Gooch, Catherine / Yu, Dejie / Huang, Hua / Soong, Tuck Wah /
    Chang, Matthew Wook / Wenk, Markus R / Adamski, Jerzy / Cazenave-Gassiot, Amaury / Nguyen, Long N

    Cell research

    2024  Volume 34, Issue 3, Page(s) 245–257

    Abstract: Mutations in the orphan transporter MFSD7c (also known as Flvcr2), are linked to Fowler syndrome. Here, we used Mfsd7c knockout ( ... ...

    Abstract Mutations in the orphan transporter MFSD7c (also known as Flvcr2), are linked to Fowler syndrome. Here, we used Mfsd7c knockout (Mfsd7c
    MeSH term(s) Animals ; Humans ; Mice ; Biological Transport ; Blood-Brain Barrier ; Brain ; Choline ; Endothelial Cells ; Polycystic Ovary Syndrome ; Urination Disorders
    Chemical Substances Choline (N91BDP6H0X) ; FLVCR2 protein, human
    Language English
    Publishing date 2024-02-02
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1319303-x
    ISSN 1748-7838 ; 1001-0602
    ISSN (online) 1748-7838
    ISSN 1001-0602
    DOI 10.1038/s41422-023-00923-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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