Serological response to SARS-CoV-2 vaccination in patients with inflammatory rheumatic disease treated with disease modifying anti-rheumatic drugs: A cohort study and a meta-analysis.

Introduction: Vaccination is considered as a cornerstone of the management of COVID-19 pandemic. However, while vaccines provide a robust protection in immunocompetent individuals, the immunogenicity in patients with inflammatory rheumatic diseases (IRD) is not well established.

Methods: A monocentric observational study evaluated the immunogenicity of a two-dose regimen vaccine in adult patients with IRD (n=123) treated with targeted or biological therapies.

Rapid Turnover of Hepatitis B Virus Covalently Closed Circular DNA Indicated by Monitoring Emergence and Reversion of Signature-Mutation in Treated Chronic Hepatitis B Patients.

Background And Aims: Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) plays a pivotal role in the establishment and persistence of HBV infection. Understanding the turnover time of preexisting cccDNA pools would be helpful in designing strategies to clear HBV by fully blocking the de novo generation of cccDNA.

Approach And Results: In this study, we retrospectively monitored the emergence and reversion of the rtM204I/V mutant, a signature lamivudine resistance (LAM ) mutation serving as a biomarker of cccDNA turnover in liver biopsies and longitudinal serum samples from two clinical trials.

Mapping of histone modifications in episomal HBV cccDNA uncovers an unusual chromatin organization amenable to epigenetic manipulation.

Chronic hepatitis B virus (HBV) infection affects 240 million people worldwide and is a major risk factor for liver failure and hepatocellular carcinoma. Current antiviral therapy inhibits cytoplasmic HBV genomic replication, but is not curative because it does not directly affect nuclear HBV closed circular DNA (cccDNA), the genomic form that templates viral transcription and sustains viral persistence. Novel approaches that directly target cccDNA regulation would therefore be highly desirable.

Compensatory induction of MYC expression by sustained CDK9 inhibition via a BRD4-dependent mechanism.

CDK9 is the kinase subunit of positive transcription elongation factor b (P-TEFb) that enables RNA polymerase (Pol) II's transition from promoter-proximal pausing to productive elongation. Although considerable interest exists in CDK9 as a therapeutic target, little progress has been made due to lack of highly selective inhibitors. Here, we describe the development of i-CDK9 as such an inhibitor that potently suppresses CDK9 phosphorylation of substrates and causes genome-wide Pol II pausing.

Fra2 is a co-regulator of Fep1 inhibition in response to iron starvation.

Iron is required for several metabolic functions involved in cellular growth. Although several players involved in iron transport have been identified, the mechanisms by which iron-responsive transcription factors are controlled are still poorly understood. In Schizosaccharomyces pombe, the Fep1 transcription factor represses genes involved in iron acquisition in response to high levels of iron.

Site-specific association with host and viral chromatin by Kaposi's sarcoma-associated herpesvirus LANA and its reversal during lytic reactivation.

Unlabelled: Latency-associated nuclear antigen (LANA), a multifunctional protein expressed by the Kaposi sarcoma-associated herpesvirus (KSHV) in latently infected cells, is required for stable maintenance of the viral episome. This is mediated by two interactions: LANA binds to specific sequences (LBS1 and LBS2) on viral DNA and also engages host histones, tethering the viral genome to host chromosomes in mitosis. LANA has also been suggested to affect host gene expression, but both the mechanism(s) and role of this dysregulation in KSHV biology remain unclear.

KSHV 2.0: a comprehensive annotation of the Kaposi's sarcoma-associated herpesvirus genome using next-generation sequencing reveals novel genomic and functional features.

Productive herpesvirus infection requires a profound, time-controlled remodeling of the viral transcriptome and proteome. To gain insights into the genomic architecture and gene expression control in Kaposi's sarcoma-associated herpesvirus (KSHV), we performed a systematic genome-wide survey of viral transcriptional and translational activity throughout the lytic cycle. Using mRNA-sequencing and ribosome profiling, we found that transcripts encoding lytic genes are promptly bound by ribosomes upon lytic reactivation, suggesting their regulation is mainly transcriptional.

The monothiol glutaredoxin Grx4 exerts an iron-dependent inhibitory effect on Php4 function.

When iron is scarce, Schizosaccharomyces pombe cells repress transcription of several genes that encode iron-using proteins. Php4 mediates this transcriptional control by specifically interacting with the CCAAT-binding core complex that is composed of Php2, Php3, and Php5. In contrast, when there is sufficient iron, Php4 is inactivated, thus allowing the transcription of many genes that encode iron-requiring proteins.

Grx4 monothiol glutaredoxin is required for iron limitation-dependent inhibition of Fep1.

The expression of iron transport genes in Schizosaccharomyces pombe is controlled by the Fep1 transcription factor. When iron levels exceed those needed by the cells, Fep1 represses iron transport genes. In contrast, Fep1 is unable to bind chromatin under low-iron conditions, and that results in activation of genes involved in iron acquisition.

Copper-dependent trafficking of the Ctr4-Ctr5 copper transporting complex.

Background: In Schizosaccharomyces pombe, copper uptake is carried out by a heteromeric complex formed by the Ctr4 and Ctr5 proteins. Copper-induced differential subcellular localization may play a critical role with respect to fine tuning the number of Ctr4 and Ctr5 molecules at the cell surface.

Methodology/principal Findings: We have developed a bimolecular fluorescence complementation (BiFC) assay to analyze protein-protein interactions in vivo in S.

Iron-dependent remodeling of fungal metabolic pathways associated with ferrichrome biosynthesis.

The fission yeast Schizosaccharomyces pombe excretes and accumulates the hydroxamate-type siderophore ferrichrome. The sib1(+) and sib2(+) genes encode, respectively, a siderophore synthetase and an l-ornithine N(5)-oxygenase that participate in ferrichrome biosynthesis. In the present report, we demonstrate that sib1(+) and sib2(+) are repressed by the GATA-type transcriptional repressor Fep1 in response to high levels of iron.

abc3+ encodes an iron-regulated vacuolar ABC-type transporter in Schizosaccharomyces pombe.

Studies have shown the fundamental contribution of the yeast vacuole as a site for storage and detoxification of metals. Whereas the transmembrane proteins responsible for iron transport into and out of the vacuole have been identified in Saccharomyces cerevisiae, less information is available concerning the mobilization of vacuolar iron stores in Schizosaccharomyces pombe. In this study, we report the identification of a gene designated abc3(+) that encodes a protein which exhibits sequence homology with the ABCC subfamily of ATP-binding cassette transporters.

Both Php4 function and subcellular localization are regulated by iron via a multistep mechanism involving the glutaredoxin Grx4 and the exportin Crm1.

In Schizosaccharomyces pombe, the CCAAT-binding factor is a multisubunit complex that contains the proteins Php2, Php3, Php4, and Php5. Under low iron conditions, Php4 acts as a negative regulatory subunit of the CCAAT-binding factor and fosters repression of genes encoding iron-using proteins. Under conditions of iron excess, Php4 expression is turned off by the iron-dependent transcriptional repressor Fep1.

Iron activates in vivo DNA binding of Schizosaccharomyces pombe transcription factor Fep1 through its amino-terminal region.

In Schizosaccharomyces pombe, the iron sensor Fep1 mediates the transcriptional repression of iron transport genes in response to high concentrations of iron. On the other hand, fep1(+) expression is downregulated under conditions of iron starvation by the CCAAT-binding factor Php4. In this study, we created a fep1Delta php4Delta double mutant strain where expression of fep1(+) was disengaged from its iron limitation-dependent repression by Php4 to examine the effects of iron on constitutively expressed functional fep1(+)-GFP and TAP-fep1(+) alleles and their gene products.

Key function for the CCAAT-binding factor Php4 to regulate gene expression in response to iron deficiency in fission yeast.

The fission yeast Schizosaccharomyces pombe responds to the deprivation of iron by inducing the expression of the php4+ gene, which encodes a negative regulatory subunit of the heteromeric CCAAT-binding factor. Once formed, the Php2/3/4/5 transcription complex is required to inactivate a subset of genes encoding iron-using proteins. Here, we used a pan-S.

Expression of Candida albicans Sfu1 in fission yeast complements the loss of the iron-regulatory transcription factor Fep1 and requires Tup co-repressors.

The opportunistic pathogenic yeast Candida albicans contains a gene which encodes a putative member of the iron-regulatory GATA factor protein family. This protein, referred to as suppressor of ferric uptake (Sfu1), has two Cys(2)/Cys(2)-type zinc finger domains separated by a conserved Cys-rich region. In Schizosaccharomyces pombe, the GATA-type transcription factor Fe protein 1 (Fep1) represses target gene expression when iron levels exceed those needed by the cell.

Iron homeostasis in the fission yeast Schizosaccharomyces pombe.

Schizosaccharomyces pombe has acquisition processes for iron, an essential nutrient. One pathway consists to produce, excrete, and capture siderophore-iron complexes. A second pathway requires enzymatic reduction of ferric iron at the cell surface prior to uptake by a permease-oxidase complex.

A transcription factor cascade involving Fep1 and the CCAAT-binding factor Php4 regulates gene expression in response to iron deficiency in the fission yeast Schizosaccharomyces pombe.

We have identified genes encoding candidate proteins involved in iron storage (pcl1+), the tricarboxylic acid cycle (sdh4+), and iron-sulfur cluster assembly (isa1+) that are negatively regulated in response to iron deprivation. Promoter deletion and site-directed mutagenesis permitted identification of a new cis-regulatory element in the promoter region of the pcl1+ gene. This cis-acting regulatory sequence containing the pentanucleotide sequence CCAAT is responsible for transcriptional repression of pcl1+ under low iron supply conditions.

The Schizosaccharomyces pombe Cuf1 is composed of functional modules from two distinct classes of copper metalloregulatory transcription factors.

In fission yeast, the genes encoding proteins that are components of the copper transporter family are controlled at the transcriptional level by the Cuf1 transcription factor. Under low copper availability, Cuf1 induces expression of the copper transporter genes. In contrast, sufficient levels of copper inactivate Cuf1 and expression of its target genes.