ORCID Profile
0000-0001-5278-0668
Current Organisations
French governmental CNRS
,
King Abdullah University of Science and Technology (KAUST)
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Publisher: Cold Spring Harbor Laboratory
Date: 09-09-2020
DOI: 10.1101/2020.09.07.285692
Abstract: Estimates of marine plastic stocks, a major threat to marine life (1), are far lower than expected from exponentially-increasing litter inputs, suggesting important loss factors (2, 3). These may involve microbial degradation, as the plastic-degrading polyethylene terephthalate enzyme (PETase) has been reported in marine microbial communities (4). An assessment of 416 metagenomes of planktonic communities across the global ocean identifies 68 oceanic PETase variants (oPETase) that evolved from ancestral enzymes degrading polycyclic aromatic hydrocarbons. Twenty oPETases show predicted efficiencies comparable to those of laboratory-optimized PETases, suggesting strong selective pressures directing the evolution of these enzymes. We found oPETases in 90.1% of s les across all oceans and depths, particularly abundant at 1,000 m depth, with a strong dominance of Pseudomonadales containing putative highly-efficient oPETase variants in the dark ocean. Enzymatic degradation may be removing plastic from the marine environment while providing a carbon source for bathypelagic microbial communities.
Publisher: Wiley
Date: 28-07-2022
Abstract: Conventional biosensors rely on the diffusion‐dominated transport of the target analyte to the sensor surface. Consequently, they require an incubation step that may take several hours to allow for the capture of analyte molecules by sensor biorecognition sites. This incubation step is a primary cause of long s le‐to‐result times. Here, alternating current electrothermal flow (ACET) is integrated in an organic electrochemical transistor (OECT)‐based sensor to accelerate the device operation. ACET is applied to the gate electrode functionalized with nanobody–SpyCatcher fusion proteins. Using the SARS‐CoV‐2 spike protein in human saliva as an ex le target, it is shown that ACET enables protein recognition within only 2 min of s le exposure, supporting its use in clinical practice. The ACET integrated sensor exhibits better selectivity, higher sensitivity, and lower limit of detection than the equivalent sensor with diffusion‐dominated operation. The performance of ACET integrated sensors is compared with two types of organic semiconductors in the channel and grounds for device‐to‐device variations are investigated. The results provide guidelines for the channel material choice in OECT‐based biochemical sensors, and demonstrate that ACET integration substantially decreases the detection speed while increasing the sensitivity and selectivity of transistor‐based sensors.
Publisher: Springer Science and Business Media LLC
Date: 08-02-2017
DOI: 10.1038/NATURE21370
Abstract: Chenopodium quinoa (quinoa) is a highly nutritious grain identified as an important crop to improve world food security. Unfortunately, few resources are available to facilitate its genetic improvement. Here we report the assembly of a high-quality, chromosome-scale reference genome sequence for quinoa, which was produced using single-molecule real-time sequencing in combination with optical, chromosome-contact and genetic maps. We also report the sequencing of two diploids from the ancestral gene pools of quinoa, which enables the identification of sub-genomes in quinoa, and reduced-coverage genome sequences for 22 other s les of the allotetraploid goosefoot complex. The genome sequence facilitated the identification of the transcription factor likely to control the production of anti-nutritional triterpenoid saponins found in quinoa seeds, including a mutation that appears to cause alternative splicing and a premature stop codon in sweet quinoa strains. These genomic resources are an important first step towards the genetic improvement of quinoa.
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.CELREP.2018.07.075
Abstract: The human protein arginine methyltransferase NDUFAF7 controls the assembly of the ∼1-MDa mitochondrial complex I (CI the NADH ubiquinone oxidoreductase) by methylating its subunit NDUFS2. We determined crystal structures of MidA, the Dictyostelium ortholog of NDUFAF7. The MidA catalytic core domain resembles other eukaryotic methyltransferases. However, three large core loops assemble into a regulatory domain that is likely to control ligand selection. Binding of MidA to NDUFS2 is weakened by methylation, suggesting a mechanism for methylation-controlled substrate release. Structural and bioinformatic analyses support that MidA and NDUFAF7 and their role in CI assembly are conserved from bacteria to humans, implying that protein methylation already existed in proteobacteria. In vivo studies confirmed the critical role of the MidA methyltransferase activity for CI assembly, growth, and phototaxis of Dictyostelium. Collectively, our data elucidate the origin of protein arginine methylation and its use by MidA/NDUFAF7 to regulate CI assembly.
Publisher: Elsevier BV
Date: 02-2009
DOI: 10.1016/J.JMB.2008.12.010
Abstract: The association between novel Src homology 2-containing protein (NSP) and Crk-associated substrate (Cas) family members contributes to integrin and receptor tyrosine kinase signalling and is involved in conferring anti-oestrogen resistance to human breast carcinomas. The precise role of this association in tumorigenesis remains controversial, and the molecular basis for the complex NSP and Cas protein form is unknown. Here we present a pluridisciplinary approach, including small-angle X-ray scattering, that provides first insights into the structure of the complex formed between breast cancer anti-oestrogen resistance 3 (BCAR3, an NSP family member) and human enhancer of filamentation 1 (HEF1, also named NEDD9 or Cas-L, a Cas family protein). Our analysis corroborates a four-helix bundle structure for the NSP-binding domain of HEF1 and a Cdc25-like guanine nucleotide exchange factor (GEF) fold for the Cas-binding domain of BCAR3. Using residues located on helix 2 of the four-helix bundle, HEF1 binds very tightly to a site on BCAR3 that is remote from the putative guanosine triphosphatase binding site of the GEF domain, but similar to a site implicated in allosteric regulation of the homologous SOS (Son of Sevenless) GEF domain. Thus, the association between NSP and Cas proteins might not only create a very stable link between these molecules, co-localising their cellular functions, but also modulate the function of the NSP GEF domains. Such modulation may explain, at least in part, the controversial results published for NSP GEF function.
Publisher: Springer Science and Business Media LLC
Date: 04-12-2015
DOI: 10.1038/NCOMMS10013
Abstract: Wilms tumour is an embryonal tumour of childhood that closely resembles the developing kidney. Genomic changes responsible for the development of the majority of Wilms tumours remain largely unknown. Here we identify recurrent mutations within Wilms tumours that involve the highly conserved YEATS domain of MLLT1 (ENL), a gene known to be involved in transcriptional elongation during early development. The mutant MLLT1 protein shows altered binding to acetylated histone tails. Moreover, MLLT1 -mutant tumours show an increase in MYC gene expression and HOX dysregulation. Patients with MLLT1 -mutant tumours present at a younger age and have a high prevalence of precursor intralobar nephrogenic rests. These data support a model whereby activating MLLT1 mutations early in renal development result in the development of Wilms tumour.
Publisher: Cold Spring Harbor Laboratory
Date: 21-02-2020
DOI: 10.1101/2020.02.17.952895
Abstract: The spread of the novel coronavirus (SARS-CoV-2) has triggered a global emergency, that demands urgent solutions for detection and therapy to prevent escalating health, social and economic impacts. The spike protein (S) of this virus enables binding to the human receptor ACE2, and hence presents a prime target for vaccines preventing viral entry into host cells 1 . The S proteins from SARS-CoV-1 and SARS-CoV-2 are similar 2 , but structural differences in the receptor binding domain (RBD) preclude the use of SARS-CoV-1–specific neutralizing antibodies to inhibit SARS-CoV-2 3 . Here we used comparative pangenomic analysis of all sequenced Betacoronaviruses to reveal that, among all core gene clusters present in these viruses, the envelope protein E shows a variant shared by SARS and SARS-Cov2 with two completely-conserved key functional features, an ion-channel and a PDZ-binding Motif (PBM). These features trigger a cytokine storm that activates the inflammasome, leading to increased edema in lungs causing the acute respiratory distress syndrome (ARDS) 4-6 , the leading cause of death in SARS-CoV-1 and SARS-CoV-2 infection 7,8 . However, three drugs approved for human use may inhibit SARS-CoV-1 and SARS-CoV-2 Protein E, either acting upon the ion channel (Amantadine and Hexamethylene amiloride 9,10 ) or the PBM (SB203580 5 ), thereby potentially increasing the survival of the host, as already demonstrated for SARS-CoV-1in animal models. Hence, blocking the SARS protein E inhibits development of ARDS in vivo . Given that our results demonstrate that the protein E subcluster for the SARS clade is quasi -identical for the key functional regions of SARS-CoV-1 and SARS-CoV-2, we conclude that use of approved drugs shown to act as SARS E protein inhibitors can help prevent further casualties from COVID-2019 while vaccines and other preventive measures are being developed.
Publisher: Springer Science and Business Media LLC
Date: 24-05-2021
Publisher: IEEE
Date: 06-03-2022
Publisher: Elsevier BV
Date: 05-2001
Publisher: Springer Science and Business Media LLC
Date: 21-08-2017
DOI: 10.1038/NG.3940
Publisher: IEEE
Date: 10-07-2022
Publisher: Cold Spring Harbor Laboratory
Date: 13-11-2020
DOI: 10.1101/2020.11.12.20228874
Abstract: The COVID-19 pandemic highlights the need for rapid protein detection and quantification at the single-molecule level in a format that is simple and robust enough for widespread point-of-care applications. We here introduce a modular nanobody-organic electrochemical transistor architecture that enables the fast and specific detection and quantification of single-molecule to nanomolar protein antigen concentrations in complex bodily fluids. The sensor combines a new solution-processable organic semiconductor material in the transistor channel with the high-density and orientation-controlled bioconjugation of nanobody fusion proteins on disposable gate electrodes. It provides results after a 10 minutes exposure to 5 µL of unprocessed s les, maintains high specificity and single-molecule sensitivity in human saliva or serum, and is rapidly reprogrammed towards any protein target for which nanobodies exist. We demonstrate the use of this highly modular platform for the detection of green fluorescent protein, SARS-CoV-1/2, and MERS-CoV spike proteins and validate the sensor for COVID-19 screening in unprocessed clinical nasopharyngeal swab and saliva s les.
Publisher: Springer Science and Business Media LLC
Date: 22-09-2017
DOI: 10.1007/S00439-017-1843-2
Abstract: Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 68 families (105 patients) all with novel ID-related variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease-gene links following previous reports (TRAK1, GTF3C3, SPTBN4 and NKX6-2), some of which were based on single families. Furthermore, we describe novel variants in 14 genes that we propose as novel candidates (ANKHD1, ASTN2, ATP13A1, FMO4, MADD, MFSD11, NCKAP1, NFASC, PCDHGA10, PPP1R21, SLC12A2, SLK, STK32C and ZFAT). We highlight MADD and PCDHGA10 as particularly compelling candidates in which we identified biallelic likely deleterious variants in two independent ID families each. We also highlight NCKAP1 as another compelling candidate in a large family with autosomal dominant mild intellectual disability that fully segregates with a heterozygous truncating variant. The candidacy of NCKAP1 is further supported by its biological function, and our demonstration of relevant expression in human brain. Our study expands the locus and allelic heterogeneity of ID and demonstrates the power of positional mapping to reveal unusual mutational mechanisms.
Location: Saudi Arabia
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Stefan T Arold.