Global well-posedness and asymptotic behavior in Besov-Morrey spaces for chemotaxis-Navier-Stokes fluids

In this work we consider the Keller-Segel system coupled with Navier-Stokes equations in $\mathbb{R}^{N}$ for $N\geq2$. We prove the global well-posedness with small initial data in Besov-Morrey spaces. Our initial data class extends previous ones found in the literature such as that obtained by Kozono-Miura-Sugiyama (J. Funct. Anal. 2016). It allows to consider initial cell density and fluid velocity concentrated on smooth curves or at points depending on the spatial dimension. Self-similar solutions are obtained depending on the homogeneity of the initial data and considering the case of chemical attractant without degradation rate. Moreover, we analyze the asymptotic stability of solutions at infinity and obtain a class of asymptotically self-similar ones.Comment: 22 pages. Some typos have been corrected. Some references have been updated/correcte

Deep Cross-Modal Correlation Learning for Audio and Lyrics in Music Retrieval

Deep cross-modal learning has successfully demonstrated excellent performance in cross-modal multimedia retrieval, with the aim of learning joint representations between different data modalities. Unfortunately, little research focuses on cross-modal correlation learning where temporal structures of different data modalities such as audio and lyrics should be taken into account. Stemming from the characteristic of temporal structures of music in nature, we are motivated to learn the deep sequential correlation between audio and lyrics. In this work, we propose a deep cross-modal correlation learning architecture involving two-branch deep neural networks for audio modality and text modality (lyrics). Data in different modalities are converted to the same canonical space where inter modal canonical correlation analysis is utilized as an objective function to calculate the similarity of temporal structures. This is the first study that uses deep architectures for learning the temporal correlation between audio and lyrics. A pre-trained Doc2Vec model followed by fully-connected layers is used to represent lyrics. Two significant contributions are made in the audio branch, as follows: i) We propose an end-to-end network to learn cross-modal correlation between audio and lyrics, where feature extraction and correlation learning are simultaneously performed and joint representation is learned by considering temporal structures. ii) As for feature extraction, we further represent an audio signal by a short sequence of local summaries (VGG16 features) and apply a recurrent neural network to compute a compact feature that better learns temporal structures of music audio. Experimental results, using audio to retrieve lyrics or using lyrics to retrieve audio, verify the effectiveness of the proposed deep correlation learning architectures in cross-modal music retrieval

Links between electrophilic stress and antifungal resistance in pathogenic Candida species

Collectively, Candida species are the most prevalent cause of both superficial and invasive fungal infections worldwide. Invasive Candida infections have a high mortality rate and predominantly affect individuals with underlying diseases, such as diabetes, HIV, or cancer. Unfortunately, many invasive Candida infections are recalcitrant to antifungal treatment, while intrinsically multidrug-resistant pathogens, like Candida auris, are increasing in prevalence. Although the canonical mechanisms of antifungal resistance in Candida species are well established, i.e., overexpression of efflux pumps and overexpression of or mutations in genes encoding drug targets, factors affecting the natural evolution and regulation of resistance mechanisms remain poorly understood. One cause of antifungal resistance in Candida species is the acquisition of gain-of-function mutations in the transcription factor Mrr1, resulting in overexpression of the multidrug transporter Mdr1. However, little is known about the functions of other genes regulated by Mrr1 or how Mrr1 activity is modulated in vivo. In this work, we demonstrate in Candida lusitaniae and in C. auris that Mrr1 contributes to resistance against methylglyoxal (MG), a toxic, electrophilic dicarbonyl derived from natural metabolic processes, and that Mrr1-mediated MG resistance is driven in part by expression of the methylglyoxal reductase genes MGD1 and MGD2 in C. lusitaniae and MGD1 in C. auris. Furthermore, we show that a sublethal concentration of MG induces expression of MDR1 and MG reductase genes in C. lusitaniae and C. auris, and consequently increases fluconazole (FLZ) resistance in C. lusitaniae. Finally, we characterize the complete Mrr1- dependent and independent transcriptional response of C. auris to MG and to the known inducer of Mrr1-regulated gene expression, benomyl, and show that both compounds cause the differential expression of a multitude of genes involved in metabolism and stress response, which could contribute to pathogen survival while colonizing and infecting a mammalian host. Together, the work presented herein provides valuable insight into a potential mechanism for the regulation of Mrr1-dependent transcription in vivo as well as a possible selective pressure for gain-of-function mutations in the MRR1 gene. This is particularly noteworthy because MG is elevated in many of the same human diseases that are considered risk factors for Candida infection, and MG is also produced by activated phagocytes in response to pathogens. Thus, it is conceivable that Candida would encounter biologically significant levels of MG in the context of infection. We propose that MG-mediated induction of Mrr1-dependent transcription in Candida species is one factor that plays a role in antifungal treatment failure

Genetic diversity and pathogenicity of the grey mould fungus Botrytis

Genetic diversity and pathogenicity of the grey mould fungus Botrytis Botrytis spp., causes pre- and postharvest decay on strawberry crops. Botrytis spp. isolates from several German strawberry-growing fields, which received several fungicide treatments against Botrytis per season, were analyzed to determine their sensitivity against botryticides.Universidad de Malaga. Campus de Excelencia Internacional Andalucia Tec

Proof of the Refined Alternating Sign Matrix Conjecture

Mills, Robbins, and Rumsey conjectured, and Zeilberger proved, that the number of alternating sign matrices of order $n$ equals $A(n):={{1!4!7! ... (3n-2)!} \over {n!(n+1)! ... (2n-1)!}}$. Mills, Robbins, and Rumsey also made the stronger conjecture that the number of such matrices whose (unique) `1' of the first row is at the $r^{th}$ column, equals $A(n) {{n+r-2} \choose {n-1}}{{2n-1-r} \choose {n-1}}/ {{3n-2} \choose {n-1}}$. Standing on the shoulders of A.G. Izergin, V. E. Korepin, and G. Kuperberg, and using in addition orthogonal polynomials and $q$-calculus, this stronger conjecture is proved.Comment: Plain Te

Comparative Genomics for the Elucidation of Multidrug Resistance in Candida lusitaniae

Multidrug resistance (MDR) has emerged in hospitals due to the use of several agents administered in combination or sequentially to the same individual. We reported earlier MDR in Candida lusitaniae during therapy with amphotericin B (AmB), azoles, and candins. Here, we used comparative genomic approaches between the initial susceptible isolate and 4 other isolates with different MDR profiles. From a total of 18 nonsynonymous single nucleotide polymorphisms (NSS) in genome comparisons with the initial isolate, six could be associated with MDR. One of the single nucleotide polymorphisms (SNPs) occurred in a putative transcriptional activator (MRR1) resulting in a V668G substitution in isolates resistant to azoles and 5-fluorocytosine (5-FC). We demonstrated by genome editing that MRR1 acted by upregulation of MFS7 (a multidrug transporter) in the presence of the V668G substitution. MFS7 itself mediated not only azole resistance but also 5-FC resistance, which represents a novel resistance mechanism for this drug class. Three other distinct NSS occurred in FKS1 (a glucan synthase gene that is targeted by candins) in three candin-resistant isolates. Last, two other NSS in ERG3 and ERG4 (ergosterol biosynthesis) resulting in nonsense mutations were revealed in AmB-resistant isolates, one of which accumulated the two ERG NSS. AmB-resistant isolates lacked ergosterol and exhibited sterol profiles, consistent with ERG3 and ERG4 defects. In conclusion, this genome analysis combined with genetics and metabolomics helped decipher the resistance profiles identified in this clinical case. MDR isolates accumulated six different mutations conferring resistance to all antifungal agents used in medicine. This case study illustrates the capacity of C. lusitaniae to rapidly adapt under drug pressure within the host.IMPORTANCE Antifungal resistance is an inevitable phenomenon when fungal pathogens are exposed to antifungal drugs. These drugs can be grouped in four distinct classes (azoles, candins, polyenes, and pyrimidine analogs) and are used in different clinical settings. Failures in therapy implicate the sequential or combined use of these different drug classes, which can result in some cases in the development of multidrug resistance (MDR). MDR is particularly challenging in the clinic since it drastically reduces possible treatment alternatives. In this study, we report the rapid development of MDR in Candida lusitaniae in a patient, which became resistant to all known antifungal agents used until now in medicine. To understand how MDR developed in C. lusitaniae, whole-genome sequencing followed by comparative genome analysis was undertaken in sequential MDR isolates. This helped to detect all specific mutations linked to drug resistance and explained the different MDR patterns exhibited by the clinical isolates

The Transcription Factor Mrr1p Controls Expression of the MDR1 Efflux Pump and Mediates Multidrug Resistance in Candida albicans

Constitutive overexpression of the MDR1 (multidrug resistance) gene, which encodes a multidrug efflux pump of the major facilitator superfamily, is a frequent cause of resistance to fluconazole and other toxic compounds in clinical Candida albicans strains, but the mechanism of MDR1 upregulation has not been resolved. By genome-wide gene expression analysis we have identified a zinc cluster transcription factor, designated as MRR1 (multidrug resistance regulator), that was coordinately upregulated with MDR1 in drug-resistant, clinical C. albicans isolates. Inactivation of MRR1 in two such drug-resistant isolates abolished both MDR1 expression and multidrug resistance. Sequence analysis of the MRR1 alleles of two matched drug-sensitive and drug-resistant C. albicans isolate pairs showed that the resistant isolates had become homozygous for MRR1 alleles that contained single nucleotide substitutions, resulting in a P683S exchange in one isolate and a G997V substitution in the other isolate. Introduction of these mutated alleles into a drug-susceptible C. albicans strain resulted in constitutive MDR1 overexpression and multidrug resistance. By comparing the transcriptional profiles of drug-resistant C. albicans isolates and mrr1Δ mutants derived from them and of C. albicans strains carrying wild-type and mutated MRR1 alleles, we defined the target genes that are controlled by Mrr1p. Many of the Mrr1p target genes encode oxidoreductases, whose upregulation in fluconazole-resistant isolates may help to prevent cell damage resulting from the generation of toxic molecules in the presence of fluconazole and thereby contribute to drug resistance. The identification of MRR1 as the central regulator of the MDR1 efflux pump and the elucidation of the mutations that have occurred in fluconazole-resistant, clinical C. albicans isolates and result in constitutive activity of this trancription factor provide detailed insights into the molecular basis of multidrug resistance in this important human fungal pathogen

Fungicide-Driven Evolution and Molecular Basis of Multidrug Resistance in Field Populations of the Grey Mould Fungus Botrytis cinerea

The grey mould fungus Botrytis cinerea causes losses of commercially important fruits, vegetables and ornamentals worldwide. Fungicide treatments are effective for disease control, but bear the risk of resistance development. The major resistance mechanism in fungi is target protein modification resulting in reduced drug binding. Multiple drug resistance (MDR) caused by increased efflux activity is common in human pathogenic microbes, but rarely described for plant pathogens. Annual monitoring for fungicide resistance in field isolates from fungicide-treated vineyards in France and Germany revealed a rapidly increasing appearance of B. cinerea field populations with three distinct MDR phenotypes. All MDR strains showed increased fungicide efflux activity and overexpression of efflux transporter genes. Similar to clinical MDR isolates of Candida yeasts that are due to transcription factor mutations, all MDR1 strains were shown to harbor activating mutations in a transcription factor (Mrr1) that controls the gene encoding ABC transporter AtrB. MDR2 strains had undergone a unique rearrangement in the promoter region of the major facilitator superfamily transporter gene mfsM2, induced by insertion of a retrotransposon-derived sequence. MDR2 strains carrying the same rearranged mfsM2 allele have probably migrated from French to German wine-growing regions. The roles of atrB, mrr1 and mfsM2 were proven by the phenotypes of knock-out and overexpression mutants. As confirmed by sexual crosses, combinations of mrr1 and mfsM2 mutations lead to MDR3 strains with higher broad-spectrum resistance. An MDR3 strain was shown in field experiments to be selected against sensitive strains by fungicide treatments. Our data document for the first time the rising prevalence, spread and molecular basis of MDR populations in a major plant pathogen in agricultural environments. These populations will increase the risk of grey mould rot and hamper the effectiveness of current strategies for fungicide resistance management