No abstract

Post-transcriptional regulation of mRNA by the RNA binding protein HuR (Elavl1) is required in B cells for the germinal centre reaction and for the production of class-switched antibodies in response to T-independent antigens. Transcriptome-wide examination of RNA isoforms, abundance and translation in HuR-deficient B cells, together with direct measurements of HuR-RNA interaction, revealed that HuR-dependent mRNA splicing affects hundreds of transcripts including the dihydrolipoamide S-succinyltransferase (Dlst), a subunit of the 2-oxoglutarate dehydrogenase complex (αKGDH). In the absence of HuR, defective mitochondrial metabolism results in high amounts of reactive oxygen species and B cell death. Our study shows how post-transcriptional processes control the balance of energy metabolism required for B cell proliferation and differentiation.

TBZE-029 {1-(2,6-difluorophenyl)-6-trifluoromethyl-1H,3H-thiazolo[3,4-a]benzimidazole} is a novel selec-Entero-and rhinoviruses are involved in a wide range of infections in humans and animals. Among the species in the enterovirus genus are the coxsackieviruses, which have been reported to be associated with various clinical manifestations, including myocarditis, pancreatitis, meningitis, and encephalitis. Other clinically relevant enteroviruses are poliovirus, which can cause paralytic poliomyelitis, and echovirus, causing aseptic meningitis or encephalomyelitis (33,36,43). Rhinoviruses are the main pathogens associated with the common cold, and, although usually mild and self-limiting, rhinovirus infections have an enormous socioeconomical impact (47,59).Enteroviruses belong to the family Picornaviridae, which consists of small, nonenveloped viruses containing a singlestranded positive-strand RNA [(ϩ)RNA] genome of 7.5 kb, which is covalently linked to a small viral protein (VPg) at its 5Ј end and polyadenylated at its 3Ј end (49). The genomic RNA has a long, highly structured 5Ј noncoding region, which contains the internal ribosome entry site, necessary for translation initiation, and a shorter 3Ј noncoding region preceding the poly(A) tract, which are both thought to be involved in RNA replication and translation (9). The coding region encodes a single polyprotein that will eventually be cleaved to generate 4 structural and 10 nonstructural proteins (either mature or in their precursor form). The icosahedral capsid of the virus is formed by 60 protomers, each one assembled by the four structural proteins, designated VP1 to -4. The nonstructural region comprises two proteases, the viral RNA-dependent RNA polymerase and seven other proteins that are involved in viral replication (8).One of the most conserved nonstructural viral proteins among picornaviruses is 2C. Although this protein is an indispensable component of the replication complex, its exact role in viral replication has remained elusive. Protein 2C appears to be multifunctional, and this entails multiple interactions (23). The amino acid sequence of 2C contains three conserved motifs which are typically found in NTP-binding proteins (motifs A and B) or in members of helicase superfamily III (motif C) (28)(29)(30)(31)69). In fact, ATPase activity has been demonstrated for several picornavirus 2C proteins (37, 57, 60) whereas so far, every attempt to demonstrate in vitro RNA helicase activity has failed. Protein 2C contains two regions involved in RNA binding (58). It has been suggested that, in poliovirus, this binding occurs at the 3Ј cloverleaf of (Ϫ)RNA (3-5); for echovirus, RNA binding was reported to occur in a nonspecific way

A novel compound, TTP-8307, was identified as a potent inhibitor of the replication of several rhino-and enteroviruses. TTP-8307 inhibits viral RNA synthesis in a dose-dependent manner, without affecting polyprotein synthesis and/or processing. Drug-resistant variants of coxsackievirus B3 were all shown to carry at least one amino acid mutation in the nonstructural protein 3A. In particular, three mutations located in a nonstructured region preceding the hydrophobic domain (V45A, I54F, and H57Y) appeared to contribute to the drug-resistant phenotype. This region has previously been identified as a hot sport for mutations that resulted in resistance to enviroxime, the sole 3A-targeting enterovirus inhibitor reported thus far. This was corroborated by the fact that TTP-8307 and enviroxime proved cross-resistant. It is hypothesized that TTP-8307 and enviroxime disrupt proper interactions of 3A(B) with other viral or cellular proteins that are required for efficient replication.Enteroviruses comprise several pathogens that are implicated in an large variety of clinical manifestations that range from mild illnesses to more serious or even life-threatening diseases, such as meningitis, encephalitis, myocarditis, pancreatitis, acute paralysis, or neonatal sepsis (30,40). Enteroviruses are small, nonenveloped, and spherical in shape, with a diameter of about 30 nm. The icosahedrally shaped capsids are assembled from 60 protomers, each composed of four structural proteins, designated VP1 (for viral protein 1), VP2, VP3, and VP4 (38, 39). The enteroviral genome consists of a singlestranded, positive-sense RNA of approximately 7,500 bases in length. The coding region of the viral genome is divided into three primary precursor molecules which contain the four structural (derived from P1) and 10 nonstructural viral proteins (derived from P2 and P3).The nonstructural protein 3A and its precursor 3AB are derived from P3 and are indispensable for viral replication. A feature of 3A that has been the subject of many studies is its ability to serve as a membrane anchor through the presence of a 22-residue hydrophobic domain that forms an amphipathic helix near its C terminus (25). In infected cells, both 3A and 3AB are found in association with membranes (17). In the context of the viral replication complex, 3AB serves to deliver the basic protein VPg (3B) at the 5Ј ends of plus-and minusstrand RNA during replication (18, 41) and, hence, to recruit the other proteins of the replication complex to the cellular membranes, the site of viral replication. The 3B protein then serves as a primer for the initiation of RNA synthesis, probably only after it has been cleaved from the 3A portion and not when it is still in the 3AB membrane-bound state (17). Cleavage of 3AB is mediated by 3C pro /3CD pro and can only occur when the protein is membrane bound (26). Moreover, this proteolysis was shown to be enhanced in the presence of purified 3AB but not 3A (26,31,49). Stimulation of catalytic activity by 3AB has also been observed for the 3D p...

The failing heart has an increased metabolic demand and at the same time suffers from impaired energy efficiency, which is a detrimental combination. Therefore, therapies targeting the energy-deprived failing heart and rewiring cardiac metabolism are of great potential, but are lacking in daily clinical practice. Metabolic impairment in heart failure patients has been well characterized for patients with reduced ejection fraction, and is coming of age in patients with 'preserved' ejection fraction. Targeting cardiomyocyte metabolism in heart failure could complement current heart failure treatments that do improve cardiovascular haemodynamics, but not the energetic status of the heart. In this review, we discuss the hallmarks of normal cardiac metabolism, typical metabolic disturbances in heart failure, and past and present therapeutic targets that impact on cardiac metabolism.

The miR-221/-222 cluster orchestrates the antiviral and inflammatory immune response to viral infection of the heart. Its inhibition increases viral load, inflammation, and overall cardiac injury upon VM.

Despite an enormous improvement in heart failure management during the last decades, the hospitalization and mortality rate of heart failure patients still remain very high. Clinical inertia, defined as the lack of treatment intensification in a patient not at evidence-based goals for care, is an important underlying cause. Clinical inertia is extensively described in hypertension and type 2 diabetes mellitus, but increasingly recognized in heart failure as well. Given the well-established guidelines for the management of heart failure, these are still not being reflected in clinical practice. While the absolute majority of patients were treated by guideline-directed heart failure drugs, only a small percentage of these patients reached the correct guideline-recommended target dose of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers, mineralocorticoid receptor antagonists, and angiotensin receptor-neprilysin inhibitors. This considerable under-treatment leads to a large number of avoidable hospitalizations and deaths. This review discusses clinical inertia in heart failure and explains its major contributing factors (i.e., physician, patient, and system) and touches upon some recommendations to prevent clinical inertia and ameliorate heart failure treatment.

Altogether we show that the microRNA-146a and its target DLST are important metabolic players in left ventricular dysfunction.