Targeting miR-181a/b in retinitis pigmentosa: implications for disease progression and therapy.

Background: Retinitis pigmentosa (RP) is a genetically heterogeneous group of degenerative disorders causing progressive vision loss due to photoreceptor death. RP affects other retinal cells, including the retinal pigment epithelium (RPE). MicroRNAs (miRs) are implicated in RP pathogenesis, and downregulating miR-181a/b has shown therapeutic benefit in RP mouse models by improving mitochondrial function.

Assembly and function of the amyloid-like translational repressor Rim4 is coupled with nutrient conditions.

Amyloid-like protein assemblies have been associated with toxic phenotypes because of their repetitive and stable structure. However, evidence that cells exploit these structures to control function and activity of some proteins in response to stimuli has questioned this paradigm. How amyloid-like assembly can confer emergent functions and how cells couple assembly with environmental conditions remains unclear.

Rie1 and Sgn1 form an RNA-binding complex that enforces the meiotic entry cell fate decision.

Budding yeast cells have the capacity to adopt few but distinct physiological states depending on environmental conditions. Vegetative cells proliferate rapidly by budding while spores can survive prolonged periods of nutrient deprivation and/or desiccation. Whether or not a yeast cell will enter meiosis and sporulate represents a critical decision that could be lethal if made in error.

Clearance of an amyloid-like translational repressor is governed by 14-3-3 proteins.

Amyloids are fibrous protein aggregates associated with age-related diseases. While these aggregates are typically described as irreversible and pathogenic, some cells use reversible amyloid-like structures that serve important functions. The RNA-binding protein Rim4 forms amyloid-like assemblies that are essential for translational control during Saccharomyces cerevisiae meiosis.

Identification of 14-3-3 proteins, Polo kinase, and RNA-binding protein Pes4 as key regulators of meiotic commitment in budding yeast.

The initiation of the cell division process of meiosis requires exogenous signals that activate internal gene regulatory networks. Meiotic commitment ensures the irreversible continuation of meiosis, even upon withdrawal of the meiosis-inducing signals. A loss of meiotic commitment can cause highly abnormal polyploid cells and can ultimately lead to germ cell tumors.

Aborting meiosis allows recombination in sterile diploid yeast hybrids.

Hybrids between diverged lineages contain novel genetic combinations but an impaired meiosis often makes them evolutionary dead ends. Here, we explore to what extent an aborted meiosis followed by a return-to-growth (RTG) promotes recombination across a panel of 20 Saccharomyces cerevisiae and S. paradoxus diploid hybrids with different genomic structures and levels of sterility.

Corrigendum: Identification of a Two-Gene () Signature With Independent Prognostic Value in Osteosarcoma.

[This corrects the article DOI: 10.3389/fonc.2019.

Acceptability, Appropriateness, and Preliminary Effects of the PrEP Diffusion Training for Lay HIV Workers: Increased PrEP Knowledge, Decreased Stigma, and Diffusion of Innovation.

Training lay health workers is a critical intervention strategy to support HIV pre-exposure prophylaxis (PrEP) implementation. However, few evaluations of such trainings have been published. We conducted multi-time-point surveys to evaluate the effect of a training intervention on knowledge, PrEP stigma, and implementation behavior among lay HIV workers in China.

Meiotic Cells Counteract Programmed Retrotransposon Activation via RNA-Binding Translational Repressor Assemblies.

Retrotransposon proliferation poses a threat to germline integrity. While retrotransposons must be activated in developing germ cells in order to survive and propagate, how they are selectively activated in the context of meiosis is unclear. We demonstrate that the transcriptional activation of Ty3/Gypsy retrotransposons and host defense are controlled by master meiotic regulators.

Identification of a Two-Gene () Signature With Independent Prognostic Value in Osteosarcoma.

Osteosarcoma (OSA) is the most prevalent form of malignant bone cancer and it occurs predominantly in children and adolescents. OSA is associated with a poor prognosis and highest cause of cancer-related death. However, there are a few biomarkers that can serve as reasonable assessments of prognosis.

Translation factor mRNA granules direct protein synthetic capacity to regions of polarized growth.

mRNA localization serves key functions in localized protein production, making it critical that the translation machinery itself is present at these locations. Here we show that translation factor mRNAs are localized to distinct granules within yeast cells. In contrast to many messenger RNP granules, such as processing bodies and stress granules, which contain translationally repressed mRNAs, these granules harbor translated mRNAs under active growth conditions.

Generating Genetic Mosaic Mouse Embryos or Organoids for Studies of Kidney Development.

For studies of gene function during development, it can be very useful to generate mosaic embryos in which a small subset of cells in a given cell lineage lacks a gene of interest and carries a marker that allows the mutant cells to be specifically visualized and compared to wild-type cells. Several methods have been used to generate genetically mosaic mouse kidneys for such studies. These include (1) chimeric embryos generated using embryonic stem cells, (2) chimeric renal organoids generated by dissociation and reaggregation of the fetal kidneys, (3) generation of a knockout allele with a built-in reporter gene, (4) mosaic analysis with double markers (MADM), and (5) mosaic mutant analysis with spatial and temporal control of recombination (MASTR).

Emerging Southeast Asian PfCRT mutations confer Plasmodium falciparum resistance to the first-line antimalarial piperaquine.

The widely used antimalarial combination therapy dihydroartemisinin + piperaquine (DHA + PPQ) has failed in Cambodia. Here, we perform a genomic analysis that reveals a rapid increase in the prevalence of novel mutations in the Plasmodium falciparum chloroquine resistance transporter PfCRT following DHA + PPQ implementation. These mutations occur in parasites harboring the K13 C580Y artemisinin resistance marker.

Identifying candidate drivers of alcohol dependence-induced excessive drinking by assembly and interrogation of brain-specific regulatory networks.

Background: A systems biology approach based on the assembly and interrogation of gene regulatory networks, or interactomes, was used to study neuroadaptation processes associated with the transition to alcohol dependence at the molecular level.

Results: Using a rat model of dependent and non-dependent alcohol self-administration, we reverse engineered a global transcriptional regulatory network during protracted abstinence, a period when relapse rates are highest. We then interrogated the network to identify master regulator genes that mechanistically regulate brain region-specific signatures associated with dependent and non-dependent alcohol self-administration.

Artemisinin-based combination therapies: a vital tool in efforts to eliminate malaria.

Plasmodium falciparum resistance to chloroquine and sulphadoxine-pyrimethamine has led to the recent adoption of artemisinin-based combination therapies (ACTs) as the first line of treatment against malaria. ACTs comprise semisynthetic artemisinin derivatives paired with distinct chemical classes of longer acting drugs. These artemisinins are exceptionally potent against the pathogenic asexual blood stages of Plasmodium parasites and also act on the transmissible sexual stages.

Host proteins interacting with the Moloney murine leukemia virus integrase: multiple transcriptional regulators and chromatin binding factors.

Background: A critical step for retroviral replication is the stable integration of the provirus into the genome of its host. The viral integrase protein is key in this essential step of the retroviral life cycle. Although the basic mechanism of integration by mammalian retroviruses has been well characterized, the factors determining how viral integration events are targeted to particular regions of the genome or to regions of a particular DNA structure remain poorly defined.

How to build a biofilm: a fungal perspective.

Biofilms are differentiated masses of microbes that form on surfaces and are surrounded by an extracellular matrix. Fungal biofilms, especially those of the pathogen Candida albicans, are a cause of infections associated with medical devices. Such infections are particularly serious because biofilm cells are relatively resistant to many common antifungal agents.

The ATPase activity of MCM2-7 is dispensable for pre-RC assembly but is required for DNA unwinding.

Eukaryotes have six minichromosome maintenance (MCM) proteins that are essential for DNA replication. The contribution of ATPase activity of MCM complexes to their function in replication is poorly understood. We have established a cell-free system competent for replication in which all MCM proteins are supplied by purified recombinant Xenopus MCM complexes.

ATM and ATR check in on origins: a dynamic model for origin selection and activation.

Initiation of DNA replication occurs at origins of replication, traditionally defined by specific sequence elements. Sequence-dependent initiation of replication is the rule in prokaryotes and in the yeast Saccharomyces cereviseae. However, sequence-dependent initiation does not appear to be absolutely required in metazoan eukaryotes.

Adenovirus IVa2 protein plays an important role in transcription from the major late promoter in vivo.

Adenovirus IVa2 protein is essential and multifunctional, with roles in encapsidation and transcriptional activation of the Major Late Promoter (MLP), but the importance of the transcriptional function to viability has not been assessed. To address this question, viral genomes with multiple nonbinding mutations in the MLP downstream elements DE1 and DE2, alone or in combination with nonbinding mutations in the UPE (USF0), were constructed. The results show that DE1/2 and the UPE are functionally redundant, suggesting an important role of IVa2 protein in the activation of the MLP in vivo.

Regulation of DNA replication by ATR: signaling in response to DNA intermediates.

The nuclear protein kinase ATR controls S-phase progression in response to DNA damage and replication fork stalling, including damage caused by ultraviolet irradiation, hyperoxia, and replication inhibitors like aphidicolin and hydroxyurea. ATR activation and substrate specificity require the presence of adapter and mediator molecules, ultimately resulting in the downstream inhibition of the S-phase kinases that function to initiate DNA replication at origins of replication. The data reviewed strongly support the hypothesis that ATR is activated in response to persistent RPA-bound single-stranded DNA, a common intermediate of unstressed and damaged DNA replication and metabolism.

ATR and ATM regulate the timing of DNA replication origin firing.

Timing of DNA replication initiation is dependent on S-phase-promoting kinase (SPK) activity at discrete origins and the simultaneous function of many replicons. DNA damage prevents origin firing through the ATM- and ATR-dependent inhibition of Cdk2 and Cdc7 SPKs. Here, we establish that modulation of ATM- and ATR-signalling pathways controls origin firing in the absence of DNA damage.

A map of the binding site for catalytic domain 5 in the core of a group II intron ribozyme.

Group II introns are ribozymes with a complex tertiary architecture that is of great interest as a model for RNA folding. Domain 5 (D5) is a highly conserved region of the intron that is considered one of the most critical structures in the catalytic core. Despite its central importance, the means by which D5 interacts with other core elements is unclear.

Defining functional groups, core structural features and inter-domain tertiary contacts essential for group II intron self-splicing: a NAIM analysis.

Group II introns are self-splicing RNA molecules that are of considerable interest as ribozymes, mobile genetic elements and examples of folded RNA. Although these introns are among the most common ribozymes, little is known about the chemical and structural determinants for their reactivity. By using nucleotide analog interference mapping (NAIM), it has been possible to identify the nucleotide functional groups (Rp phosphoryls, 2'-hydroxyls, guanosine exocyclic amines, adenosine N7 and N6) that are most important for composing the catalytic core of the intron.

Human somatic cell gene therapy.

The prelude to successful human somatic gene therapy, i.e. the efficient transfer and expression of a variety of human genes into target cells, has already been accomplished in several systems.