Performance enhancement of a closed-loop accelerometer tuned close to its instability regime

International audienceA closed-loop micro-accelerometer is presented where its instability regime is used in order to enhance its static gain. Sensitivity functions are decreased in low frequencies and therefore any acceleration applied on the proof mass is better rejected than in conventional closed-loop approach. To design a robust controller, an identification procedure of the instable structure is presented as well. Finally the signal reconstruction of the applied acceleration is made trough a Kalman filter. Simulation results are given and demonstrate the efficiency of the proposed approach

Diarrhées des jeunes agneaux‎ : étude descriptive dans vingt élevages ovins laitiers des Pyrénées Atlantiques

Les éleveurs ovins laitiers sont de plus en plus préoccupés par les diarrhées néonatales des agneaux, qui occasionnent des pertes économiques importantes. L’objectif principal de cette étude était de mieux décrire les circonstances d’apparition des diarrhées ainsi que certains facteurs de risque liés aux agneaux et aux brebis, au microbisme, au logement et à la conduite d’élevage dans 20 élevages des Pyrénées Atlantiques suivis pendant un mois lors des agnelages du premier lot de reproduction. Dans la majorité des élevages suivis, les diarrhées sont apparues dès la première semaine d’agnelages avec une morbidité n’excédant pas 25% et une mortalité toujours inférieure à 8%. Cryptosporidium parvum a été fréquemment retrouvé mais dans la majorité des prélèvements effectués, aucun agent pathogène n’a été identifié. Les résultats indiquent par ailleurs que les défauts de transfert d’immunité passive sont fréquents et que le statut parasitaire défavorable des brebis, leur état corporel insuffisant à l’agnelage, et la composition du lait dans la phase d’allaitement pourraient être impliqués dans les troubles de santé. L’ensemble de ces résultats, obtenus sur un faible effectif d’élevages, mérite d’être confirmé sur un échantillon plus large

Diagnosis and treatment of osteoporosis in spinal cord injury patients: A literature review

AbstractObjectiveTo present an up-to-date literature review of osteoporosis in spinal cord injury (SCI) patients, in view of the seriousness of this complication (with a high risk of fractures) and the complexity of its diagnosis, evaluation and treatment.MethodsA Medline search with the following keywords: immobilization osteoporosis, spinal cord injury, bone loss, dual energy X-ray absorptiometry (DEXA), bisphosphonate.ResultsOur analysis of the literature noted a bone metabolism imbalance in SCI patients, with accelerated early bone resorption (particularly during the first 6months post-injury). Although dual energy X-ray absorptiometry constitutes the “gold standard” diagnostic method, the decrease in bone mineral density only becomes significant 12months after the injury. Bisphosphonate therapy has proven efficacy. Despite the frequent use of various physical therapies, these methods have not been found to be effective.ConclusionAlthough our literature review did not identify any guidelines on the strategy for diagnosing and treating osteoporosis in SCI patients, several findings provide guidance on procedures for early diagnosis and preventive treatment

Adenovirus type 5 E4 Orf3 protein targets promyelocytic leukaemia (PML) protein nuclear domains for disruption via a sequence in PML isoform II that is predicted as a protein interaction site by bioinformatic analysis

Human adenovirus type 5 infection causes the disruption of structures in the cell nucleus termed promyelocytic leukaemia (PML) protein nuclear domains or ND10, which contain the PML protein as a critical component. This disruption is achieved through the action of the viral E4 Orf3 protein, which forms track-like nuclear structures that associate with the PML protein. This association is mediated by a direct interaction of Orf3 with a specific PML isoform, PMLII. We show here that the Orf3 interaction properties of PMLII are conferred by a 40 aa residue segment of the unique C-terminal domain of the protein. This segment was sufficient to confer interaction on a heterologous protein. The analysis was informed by prior application of a bioinformatic tool for the prediction of potential protein interaction sites within unstructured protein sequences (predictors of naturally disordered region analysis; PONDR). This tool predicted three potential molecular recognition elements (MoRE) within the C-terminal domain of PMLII, one of which was found to form the core of the Orf3 interaction site, thus demonstrating the utility of this approach. The sequence of the mapped Orf3-binding site on PML protein was found to be relatively poorly conserved across other species; however, the overall organization of MoREs within unstructured sequence was retained, suggesting the potential for conservation of functional interactions

PML isoforms in response to arsenic: high-resolution analysis of PML body structure and degradation

Arsenic is a clinically effective treatment for acute promyelocytic leukaemia (APL) in which the promyelocytic leukaemia (PML) protein is fused to retinoic receptor alpha (RARα). PML-RARα is degraded by the proteasome by a SUMO-dependent, ubiquitin-mediated pathway in response to arsenic treatment, curing the disease. Six major PML isoforms are expressed as a result of alternative splicing, each of which encodes a unique C-terminal region. Using a system in which only a single EYFP-linked PML isoform is expressed, we demonstrate that PMLI, PMLII and PMLVI accumulate in the cytoplasm following arsenic treatment, whereas PMLIII, PMLIV and PMLV do not. 3D structured illumination was used to obtain super-resolution images of PML bodies, revealing spherical shells of PML along with associated SUMO. Arsenic treatment results in dramatic isoform-specific changes to PML body ultrastructure. After extended arsenic treatment most PML isoforms are degraded, leaving SUMO at the core of the nuclear bodies. A high-content imaging assay identifies PMLV as the isoform most readily degraded following arsenic treatment, and PMLIV as relatively resistant to degradation. Immunoprecipitation analysis demonstrates that all PML isoforms are modified by SUMO and ubiquitin after arsenic treatment, and by using siRNA, we demonstrate that arsenic-induced degradation of all PML isoforms is dependent on the ubiquitin E3 ligase RNF4. Intriguingly, depletion of RNF4 results in marked accumulation of PMLV, suggesting that this isoform is an optimal substrate for RNF4. Thus the variable C-terminal domain influences the rate and location of degradation of PML isoforms following arsenic treatment

The helicase HAGE prevents interferon-a-induced PML expression in ABCB5+ malignant melanoma-initiating cells by promoting the expression of SOCS1

The tumour suppressor PML (promyelocytic leukaemia protein) regulates several cellular pathways involving cell growth, apoptosis, differentiation and senescence. PML also has an important role in the regulation of stem cell proliferation and differentiation. Here, we show the involvement of the helicase HAGE in the transcriptional repression of PML expression in ABCB5 + malignant melanoma-initiating cells (ABCB5 + MMICs), a population of cancer stem cells which are responsible for melanoma growth, progression and resistance to drug-based therapy. HAGE prevents PML gene expression by inhibiting the activation of the JAK-STAT (janus kinase-signal transducers and activators of transcription) pathway in a mechanism which implicates the suppressor of cytokine signalling 1 (SOCS1). Knockdown of HAGE led to a significant decrease in SOCS1 protein expression, activation of the JAK-STAT signalling cascade and a consequent increase of PML expression. To confirm that the reduction in SOCS1 expression was dependent on the HAGE helicase activity, we showed that SOCS1, effectively silenced by small interfering RNA, could be rescued by re-introduction of HAGE into cells lacking HAGE. Furthermore, we provide a mechanism by which HAGE promotes SOCS1 mRNA unwinding and protein expression in vitro

Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control

DNA replication stress is a source of genomic instability. Here we identify ​changed mutation rate 1 (​Cmr1) as a factor involved in the response to DNA replication stress in Saccharomyces cerevisiae and show that ​Cmr1—together with ​Mrc1/​Claspin, ​Pph3, the chaperonin containing ​TCP1 (CCT) and 25 other proteins—define a novel intranuclear quality control compartment (INQ) that sequesters misfolded, ubiquitylated and sumoylated proteins in response to genotoxic stress. The diversity of proteins that localize to INQ indicates that other biological processes such as cell cycle progression, chromatin and mitotic spindle organization may also be regulated through INQ. Similar to ​Cmr1, its human orthologue ​WDR76 responds to proteasome inhibition and DNA damage by relocalizing to nuclear foci and physically associating with CCT, suggesting an evolutionarily conserved biological function. We propose that ​Cmr1/​WDR76 plays a role in the recovery from genotoxic stress through regulation of the turnover of sumoylated and phosphorylated proteins

Towards a Quantitative Modeling of the Synthesis of the Pectate Lyases, Essential Virulence Factors in Dickeya Dadantii

A dynamic mathematical model has been developed and validated to describe the synthesis of pectate lyases (Pels), the major virulence factors in Dickeya dadantii. This work focuses on the simultaneous modeling of the metabolic degradation of pectin by Pel enzymes and the genetic regulation of pel genes by 2-keto-3-deoxygluconate (KDG), a catabolite product of pectin which inactivates KdgR, one of the main repressors of pel genes. This modeling scheme takes into account the fact that the system is composed of two time-varying compartments: the extracellular medium, where Pel enzymes cleave pectin into oligomers, and the bacterial cytoplasm where, after internalization, oligomers are converted to KDG. Using the quasi-stationary state approximations, the model consists of some nonlinear differential equations for which most of the parameters could be estimated from the literature or from independent experiments. The few remaining unknown parameters were obtained by fitting the model equations against a set of Pel activity data. Model predictions were verified by measuring the time courses of bacterial growth, Pel production, pel mRNA accumulation and pectin consumption under various growth conditions. This work reveals that pectin is almost totally consumed before the burst of Pel production. This paradoxical behaviour can be interpreted as an evolutionary strategy to control the diffusion process so that as soon as a small amount of pectin is detected by the bacteria in its surroundings it anticipates more pectin to come. The model also predicts the possibility of bistable steady states in the presence of constant pectin compounds.Comment: 21 pages, 11 figures, Journal of Biological Chemistry (In press

Subcellular distribution of nuclear import-defective isoforms of the promyelocytic leukemia protein

<p>Abstract</p> <p>Background</p> <p>The promyelocytic leukemia (PML) protein participates in a number of cellular processes, including transcription regulation, apoptosis, differentiation, virus defense and genome maintenance. This protein is structurally organized into a tripartite motif (TRIM) at its N-terminus, a nuclear localization signal (NLS) at its central region and a C-terminus that varies between alternatively spliced isoforms. Most PML splice variants target the nucleus where they define sub-nuclear compartments termed PML nuclear bodies (PML NBs). However, PML variants that lack the NLS are also expressed, suggesting the existence of PML isoforms with cytoplasmic functions. In the present study we expressed PML isoforms with a mutated NLS in U2OS cells to identify potential cytoplasmic compartments targeted by this protein.</p> <p>Results</p> <p>Expression of NLS mutated PML isoforms in U2OS cells revealed that PML I targets early endosomes, PML II targets the inner nuclear membrane (partially due to an extra NLS at its C-terminus), and PML III, IV and V target late endosomes/lysosomes. Clustering of PML at all of these subcellular locations depended on a functional TRIM domain.</p> <p>Conclusions</p> <p>This study demonstrates the capacity of PML to form macromolecular protein assemblies at several different subcellular sites. Further, it emphasizes a role of the variable C-terminus in subcellular target selection and a general role of the N-terminal TRIM domain in promoting protein clustering.</p

Biomphalaria pfeifferi Snails and Intestinal Schistosomiasis, Lake Malawi, Africa, 2017-2018

Two surveys conducted in 2017 and 2018 demonstrated Biomphalaria pfeifferi snails in Lake Malawi in Africa. Epidemiologic examination of 175 local children at 3 primary schools confirmed emergence of intestinal schistosomiasis. These findings highlight autochthonous transmission of Schistosoma mansoni flukes in Lake Malawi and the need to revise international travel advice