Local null controllability of a two-dimensional fluid-structure interaction problem

In this paper, we prove a controllability result for a fluid-structure interaction problem. In dimension two, a rigid structure moves into an incompressible fluid governed by Navier-Stokes equations. The control acts on a fixed subset of the fluid domain. We prove that, for small initial data, this system is null controllable, that is, for a given T > 0, the system can be driven at rest and the structure to its reference configuration at time T. To show this result, we first consider a linearized system. Thanks to an observability inequality obtained from a Carleman inequality, we prove an optimal controllability result with a regular control. Next, with the help of Kakutani's fixed point theorem and a regularity result, we pass to the nonlinear problem

Class switching and meiotic defects in mice lacking the E3 ubiquitin ligase RNF8

53BP1 is a well-known mediator of the cellular response to DNA damage. Two alternative mechanisms have been proposed to explain 53BP1’s interaction with DNA double-strand breaks (DSBs), one by binding to methylated histones and the other via an RNF8 E3 ligase–dependent ubiquitylation pathway. The formation of RNF8 and 53BP1 irradiation-induced foci are both dependent on histone H2AX. To evaluate the contribution of the RNF8-dependent pathway to 53BP1 function, we generated RNF8 knockout mice. We report that RNF8 deficiency results in defective class switch recombination (CSR) and accumulation of unresolved immunoglobulin heavy chain–associated DSBs. The CSR DSB repair defect is milder than that observed in the absence of 53BP1 but similar to that found in H2AX−/− mice. Moreover, similar to H2AX but different from 53BP1 deficiency, RNF8−/− males are sterile, and this is associated with defective ubiquitylation of the XY chromatin. Combined loss of H2AX and RNF8 does not cause further impairment in CSR, demonstrating that the two genes function epistatically. Importantly, although 53BP1 foci formation is RNF8 dependent, its binding to chromatin is preserved in the absence of RNF8. This suggests a two-step mechanism for 53BP1 association with chromatin in which constitutive loading is dependent on interactions with methylated histones, whereas DNA damage–inducible RNF8-dependent ubiquitylation allows its accumulation at damaged chromatin

Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis

OBJECTIVES: We used a screening strategy of global serum microRNA (miRNA) profiling, followed by a second stage of independent replication and exploration of liver expression of selected miRNAs to study: (1) the circulating miRNA signature associated with non-alcoholic fatty liver disease (NAFLD) progression and predictive power, (2) the role of miRNAs in disease biology and (3) the association between circulating miRNAs and features of the metabolic syndrome. METHODS: The study used a case-control design and included patients with NAFLD proven through biopsy and healthy controls. RESULTS: Among 84 circulating miRNAs analysed, miR-122, miR-192, miR-19a and miR-19b, miR-125b, and miR-375 were upregulated >2-fold (p<0.05) either in simple steatosis (SS) or non-alcoholic steatohepatitis (NASH). The most dramatic and significant fold changes were observed in the serum levels of miR-122 (7.2-fold change in NASH vs controls and 3.1-fold change in NASH vs SS) and miR-192 (4.4-fold change in NASH vs controls); these results were replicated in the validation set. The majority of serum miR-122 circulate in argonaute2-free forms. Circulating miR-19a/b and miR-125b were correlated with biomarkers of atherosclerosis. Liver miR-122 expression was 10-fold (p<0.03) downregulated in NASH compared with SS and was preferentially expressed at the edge of lipid-laden hepatocytes. In vitro exploration showed that overexpression of miR-122 enhances alanine aminotransferase activity. CONCLUSIONS: miR-122 plays a role of physiological significance in the biology of NAFLD; circulating miRNAs mirror the histological and molecular events occurring in the liver. NAFLD has a distinguishing circulating miRNA profile associated with a global dysmetabolic disease state and cardiovascular risk.Fil: Pirola, Carlos Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Fernandez Gianotti, Tomas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Castaño, Gustavo Osvaldo. Gobierno de la Ciudad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Mallardi, Pablo. Hospital Diego Thompson; ArgentinaFil: San Martino, Julio. Hospital Diego Thompson; ArgentinaFil: González López Ledesma, María Mora. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Flichman, Diego Martin. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Virología; ArgentinaFil: Mirshahi, Faridodin. Virginia Commonwealth University; Estados UnidosFil: Sanyal, Arun J.. Virginia Commonwealth University; ArgentinaFil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital "Dr. Abel Zubizarreta"; Argentin

Spatial Analysis of Digital Imagery of Weeds in a Maize Crop

Modern photographic imaging of agricultural crops can pin-point individual weeds, the patterns of which can be analyzed statistically to reveal how they are affected by variation in soil, by competition from other species and by agricultural operations. This contrasts with previous research on the patchiness of weeds that has generally used grid sampling and ignored processes operating at a fine scale. Nevertheless, an understanding of the interaction of biology, environment and management at all scales will be required to underpin robust precise control of weeds. We studied the spatial distributions of six common weed species in a maize field in central Spain. We obtained digital imagery of a rectangular plot 41.0 m by 10.5 m (= 430.5 m2) and from it recorded the exact coordinates of every seedling: more than 82,000 individuals in all. We analyzed the resulting body of data using three techniques: an aggregation analysis of the punctual distributions, a geostatistical analysis of quadrat counts and wavelet analysis of quadrat counts. We found that all species were aggregated with average distances across patches ranging from 3 cm–18 cm. Species with small seeds tended to occur in larger patches than those with large seeds. Several species had aggregation patterns that repeated periodically at right angles to the direction of the crop rows. Wheel tracks favoured some species (e.g., thornapple), whereas other species (e.g., johnsongrass) were denser elsewhere. Interactions between species at finer scales (<1 m) were negligible, although a negative correlation between thornapple and cocklebur was evident. We infer that the spatial distributions of weeds at the fine scales are products both of their biology and local environment caused by cultivation, with interactions between species playing a minor role. Spatial analysis of such high-resolution imagery can reveal patterns that are not immediately evident from sampling at coarser scales and aid our understanding of how and why weeds aggregate in patches

Neutrophil Function in Elderly Patients Hospitalized with Community- Acquired Pneumonia

Background: Advanced age is associated with immunosenescence as well as increased risk for poor outcomes during episodes of community-acquired pneumonia (CAP). Data on neutrophil function in hospitalized elderly patients with CAP is lacking. In this study we compared neutrophil function in elderly and non-elderly hospitalized patients with CAP. Methods: Prospective study of healthy controls (HC) and patients hospitalized with CAP nonelderly (NE-CAP) and elderly (E-CAP). Blood samples were obtained on the day of hospitalization. The following neutrophil functional assays were performed: degranulation of secretory vesicles (CD35), degranulation of specific granules (CD66b), phagocytosis, and hydrogen peroxide (H2O2) production. The Mann-Whitney U-test was used to compare differences in neutrophil function. Results: A total of 12 HC, 28 NE-CAP, and 12 E-CAP were evaluated. There were no significant differences between NE-CAP and E-CAP patients in regard to CD35 expression (p=0.465), CD66b expression (p=0.601), phagocytosis (p=0.654), or H2O2 production (p=0.541) Conclusions: We failed to demonstrate any significant difference in neutrophil function in nonelderly versus elderly patients hospitalized with CAP in relation to membrane expression of CD35 and CD66b, phagocytosis, and respiratory burst. Abnormal neutrophil function is unlikely to be an important component of the immunosenescence described in elderly patients with CAP

Critical COPD respiratory illness is linked to increased transcriptomic activity of neutrophil proteases genes

BACKGROUND: Gene expression profiling (GEP) in cells obtained from peripheral blood has shown that this is a very useful approach for biomarker discovery and for studying molecular pathogenesis of prevalent diseases. While there is limited literature available on gene expression markers associated with Chronic Obstructive Pulmonary Disease (COPD), the transcriptomic picture associated with critical respiratory illness in this disease is not known at the present moment. FINDINGS: By using Agilent microarray chips, we have profiled gene expression signatures in the whole blood of 28 COPD patients hospitalized with different degrees of respiratory compromise.12 of them needed of admission to the ICU, whilst 16 were admitted to the Respiratory Medicine Service. GeneSpring GX 11.0 software was used for performing statistical comparisons of transcript levels between ICU and non-ICU patients. Ingenuity pathway analysis 8.5 (IPA) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to select, annotate and visualize genes by function and pathway (gene ontology). T-test showed evidence of 1501 genes differentially expressed between ICU and non-ICU patients. IPA and KEGG analysis of the most representative biological functions revealed that ICU patients had increased levels of neutrophil gene transcripts, being [cathepsin G (CTSG)], [elastase, neutrophil expressed (ELANE)], [proteinase 3 (PRTN3)], [myeloperoxidase (MPO)], [cathepsin D (CTSD)], [defensin, alpha 3, neutrophil-specific (DEFA3)], azurocidin 1 (AZU1)], and [bactericidal/permeability-increasing protein (BPI)] the most representative ones. Proteins codified by these genes form part of the azurophilic granules of neutrophils and are involved in both antimicrobial defence and tissue damage. This “neutrophil signature” was paralleled by the necessity of advanced respiratory and vital support, and the presence of bacterial infection. CONCLUSION: Study of transcriptomic signatures in blood suggests an essential role of neutrophil proteases in COPD patients with critical respiratory illness. Measurement and modulation of the expression of these genes could present an option for clinical monitoring and treatment of severe COPD exacerbations

Genomic Instability, Defective Spermatogenesis, Immunodeficiency, and Cancer in a Mouse Model of the RIDDLE Syndrome

Eukaryotic cells have evolved to use complex pathways for DNA damage signaling and repair to maintain genomic integrity. RNF168 is a novel E3 ligase that functions downstream of ATM,γ-H2A.X, MDC1, and RNF8. It has been shown to ubiquitylate histone H2A and to facilitate the recruitment of other DNA damage response proteins, including 53BP1, to sites of DNA break. In addition, RNF168 mutations have been causally linked to the human RIDDLE syndrome. In this study, we report that Rnf168−/− mice are immunodeficient and exhibit increased radiosensitivity. Rnf168−/− males suffer from impaired spermatogenesis in an age-dependent manner. Interestingly, in contrast to H2a.x−/−, Mdc1−/−, and Rnf8−/− cells, transient recruitment of 53bp1 to DNA double-strand breaks was abolished in Rnf168−/− cells. Remarkably, similar to 53bp1 inactivation, but different from H2a.x deficiency, inactivation of Rnf168 impairs long-range V(D)J recombination in thymocytes and results in long insertions at the class-switch junctions of B-cells. Loss of Rnf168 increases genomic instability and synergizes with p53 inactivation in promoting tumorigenesis. Our data reveal the important physiological functions of Rnf168 and support its role in both γ-H2a.x-Mdc1-Rnf8-dependent and -independent signaling pathways of DNA double-strand breaks. These results highlight a central role for RNF168 in the hierarchical network of DNA break signaling that maintains genomic integrity and suppresses cancer development in mammals

CAR density influences antitumoral efficacy of BCMA CAR T cells and correlates with clinical outcome

Identification of new markers associated with long-term efficacy in patients treated with CAR T cells is a current medical need, particularly in diseases such as multiple myeloma. In this study, we address the impact of CAR density on the functionality of BCMA CAR T cells. Functional and transcriptional studies demonstrate that CAR T cells with high expression of the CAR construct show an increased tonic signaling with up-regulation of exhaustion markers and increased in vitro cytotoxicity but a decrease in in vivo BM infiltration. Characterization of gene regulatory networks using scRNA-seq identified regulons associated to activation and exhaustion up-regulated in CARHigh T cells, providing mechanistic insights behind differential functionality of these cells. Last, we demonstrate that patients treated with CAR T cell products enriched in CARHigh T cells show a significantly worse clinical response in several hematological malignancies. In summary, our work demonstrates that CAR density plays an important role in CAR T activity with notable impact on clinical response

Response to Novel Drugs before and after Allogeneic Stem Cell Transplantation in Patients with Relapsed Multiple Myeloma

Multiple myeloma (MM) remains as an incurable disease and, although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative approach, most patients ultimately relapse, and their treatment remains challenging. Because allo-HSCT can modify not only the biology of the disease, but also the immune system and the microenvironment, it can potentially enhance the response to rescue therapies. Information on the efficacy and safety of novel drugs in patients relapsing after allo-HSCT is lacking, however. The objectives of this study were to evaluate the efficacy and toxicity of rescue therapies in patients with MM who relapsed after allo-HSCT, as well as to compare their efficacy before and after allo-HSCT. This retrospective multicenter study included 126 consecutive patients with MM who underwent allo-HSCT between 2000 and 2013 at 8 Spanish centers. All patients engrafted. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 47%, and nonrelapse mortality within the first 100 days post-transplantation was 13%. After a median follow-up of 92 months, overall survival (OS) was 51% at 2 years and 43% at 5 years. The median progression-free survival after allo-HSCT was 7 months, whereas the median OS after relapse was 33 months. Patients relapsing in the first 6 months after transplantation had a dismal prognosis compared with those who relapsed later (median OS, 11 months versus 120 months; P <.001). The absence of chronic GVHD was associated with reduced OS after relapse (hazard ratio, 3.44; P <.001). Most patients responded to rescue therapies, including proteasome inhibitors (PIs; 62%) and immunomodulatory drugs (IMiDs; 77%), with a good toxicity profile. An in-depth evaluation, including the type and intensity of PI- and IMiD-based combinations used before and after allo-HSCT, showed that the overall response rate and duration of response after allo-HSCT were similar to those seen in the pretransplantation period. Patients with MM who relapse after allo-HSCT should be considered candidates for therapy with new drugs, which can achieve similar response rates with similar durability as seen in the pretransplantation period. This pattern does not follow the usual course of the disease outside the transplantation setting, where response rates and time to progression decreases with each consecutive line of treatment

Non-productive angiogenesis disassembles Aß plaque-associated blood vessels

The human Alzheimer’s disease (AD) brain accumulates angiogenic markers but paradoxically, the cerebral microvasculature is reduced around Aß plaques. Here we demonstrate that angiogenesis is started near Aß plaques in both AD mouse models and human AD samples. However, endothelial cells express the molecular signature of non-productive angiogenesis (NPA) and accumulate, around Aß plaques, a tip cell marker and IB4 reactive vascular anomalies with reduced NOTCH activity. Notably, NPA induction by endothelial loss of presenilin, whose mutations cause familial AD and which activity has been shown to decrease with age, produced a similar vascular phenotype in the absence of Aß pathology. We also show that Aß plaque-associated NPA locally disassembles blood vessels, leaving behind vascular scars, and that microglial phagocytosis contributes to the local loss of endothelial cells. These results define the role of NPA and microglia in local blood vessel disassembly and highlight the vascular component of presenilin loss of function in AD