Intrinsically disordered RNA-binding motifs cooperate to catalyze RNA folding and drive phase separation.

RNA-binding proteins are essential for gene regulation and the spatial organization of cells. Here, we report that the yeast ribosome biogenesis factor Loc1p is an intrinsically disordered RNA-binding protein with eight repeating positively charged, unstructured nucleic acid binding (PUN) motifs. While a single of these previously undefined motifs stabilizes folded RNAs, multiple copies strongly cooperate to catalyze RNA folding.

Inherited Pathogenic Variant Associated With a Mild Neurodevelopmental Disorder.

Objectives: Purine-rich element-binding protein alpha (PURA) regulates gene expression and is ubiquitously expressed with an enrichment in neural tissues. Pathogenic variants in cause the neurodevelopmental disorder PURA syndrome that has a variable phenotype but typically comprises moderate-to-severe global developmental delay, intellectual disability, early-onset hypotonia and hypothermia, epilepsy, feeding difficulties, movement disorders, and subtle facial dysmorphism. Speech is reportedly absent in most, but the specific linguistic phenotype is not well described.

Parenting for Lifelong Health for Young Children in Montenegro: Preliminary Outcomes, Dissemination, and Broader Embedding of the Program.

The quality of parenting program implementation significantly affects the extent to which a program is delivered effectively as well as the likelihood of it becoming embedded in everyday services. The group based Parenting for Lifelong Health for Young Children (PLH-YC) program for parents of children aged 2-9 years was developed specifically for implementation in low- and middle-income contexts, has been tested in five randomized trials, and incorporates a number of strategies to encourage fidelity of delivery. This paper reports on the introduction of PLH-YC to Montenegro, including initial work to engage government agencies and service providers, adapt the program and, following initial evidence of effectiveness, implement strategies to promote effective delivery and embed the program.

PURA syndrome-causing mutations impair PUR-domain integrity and affect P-body association.

Mutations in the human gene cause the neurodevelopmental PURA syndrome. In contrast to several other monogenetic disorders, almost all reported mutations in this nucleic acid-binding protein result in the full disease penetrance. In this study, we observed that patient mutations across PURA impair its previously reported co-localization with processing bodies.

A hybrid digital parenting programme to prevent abuse of adolescents in Tanzania: study protocol for a pragmatic cluster-randomised controlled trial.

Background: Evidence-based parenting programmes have strong evidence in preventing and mitigating violence, but in-person programmes are challenging to deliver at scale. ParentApp is an open-source, offline-first app-based adaptation of the Parenting for Lifelong Health for Parents and Teens programme to promote playful and positive parenting, reduce risks for sexual violence victimisation, and prevent violence against adolescents. This study aims to evaluate the effectiveness and cost-effectiveness of ParentApp compared to an attention-control group.

Crystal structure of the RNA-recognition motif of Drosophila melanogaster tRNA (uracil-5-)-methyltransferase homolog A.

Human tRNA (uracil-5-)-methyltransferase 2 homolog A (TRMT2A) is the dedicated enzyme for the methylation of uridine 54 in transfer RNA (tRNA). Human TRMT2A has also been described as a modifier of polyglutamine (polyQ)-derived neuronal toxicity. The corresponding human polyQ pathologies include Huntington's disease and constitute a family of devastating neurodegenerative diseases.

Human TRMT2A methylates tRNA and contributes to translation fidelity.

5-Methyluridine (m5U) is one of the most abundant RNA modifications found in cytosolic tRNA. tRNA methyltransferase 2 homolog A (hTRMT2A) is the dedicated mammalian enzyme for m5U formation at tRNA position 54. However, its RNA binding specificity and functional role in the cell are not well understood.

Optimising engagement in a digital parenting intervention to prevent violence against adolescents in Tanzania: protocol for a cluster randomised factorial trial.

Background: Violence against adolescents is a universal reality, with severe individual and societal costs. There is a critical need for scalable and effective violence prevention strategies such as parenting programmes, particularly in low- and middle-income countries where rates of maltreatment are highest. Digital interventions may be a scalable and cost-effective alternative to in-person delivery, yet maximising caregiver engagement is a substantial challenge.

'It provides practical tips, practical solutions!': acceptability, usability, and satisfaction of a digital parenting intervention across African countries.

The parenting evidence base is well established, and the question is how best to transfer the evidence to an app. App-based interventions could expand access to evidence-based parenting support; however, current provision lacks rigorous evidence, shows low user engagement, and is primarily for commercial gain. This study aimed at testing the feasibility and acceptability of ParentApp for Teens, an open-source, mobile parenting intervention application based on the Parenting for Lifelong Health Teens programme targeting parents of teens.

Presence and function of Hbl B', the fourth protein component encoded by the operon in .

The genes , and encode the components Hbl L2, L1 and B of the pore forming enterotoxin haemolysin BL of . Two variants of the operon existand the more common one additionally contains downstream of . Up to now, it was completely unclear whether the corresponding protein, Hbl B', is widely expressed among strains and if it has a distinct function.

Small-molecule modulators of TRMT2A decrease PolyQ aggregation and PolyQ-induced cell death.

Polyglutamine (polyQ) diseases are characterized by an expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats encoding for an uninterrupted prolonged polyQ tract. We previously identified TRMT2A as a strong modifier of polyQ-induced toxicity in an unbiased large-scale screen in . This work aimed at identifying and validating pharmacological TRMT2A inhibitors as treatment opportunities for polyQ diseases in humans.

Genetically encoded photo-switchable molecular sensors for optoacoustic and super-resolution imaging.

Reversibly photo-switchable proteins are essential for many super-resolution fluorescence microscopic and optoacoustic imaging methods. However, they have yet to be used as sensors that measure the distribution of specific analytes at the nanoscale or in the tissues of live animals. Here we constructed the prototype of a photo-switchable Ca sensor based on GCaMP5G that can be switched with 405/488-nm light and describe its molecular mechanisms at the structural level, including the importance of the interaction of the core barrel structure of the fluorescent protein with the Ca receptor moiety.

UGT76B1, a promiscuous hub of small molecule-based immune signaling, glucosylates N-hydroxypipecolic acid, and balances plant immunity.

Glucosylation modulates the biological activity of small molecules and frequently leads to their inactivation. The Arabidopsis thaliana glucosyltransferase UGT76B1 is involved in conjugating the stress hormone salicylic acid (SA) as well as isoleucic acid (ILA). Here, we show that UGT76B1 also glucosylates N-hydroxypipecolic acid (NHP), which is synthesized by FLAVIN-DEPENDENT MONOOXYGENASE 1 (FMO1) and activates systemic acquired resistance (SAR).

The Science of Scale for Violence Prevention: A New Agenda for Family Strengthening in Low- and Middle-Income Countries.

Ending all violence against children by 2030 is a core part of Sustainable Development Goals 5 and 16. A number of promising violence reduction strategies have been identified in research studies. However, we lack an understanding of the implementation and impact of these programs in respect to their delivery at a large scale or within existing service systems, particularly in low- and middle-income countries (LMICs).

Evaluating the dissemination and scale-up of two evidence-based parenting interventions to reduce violence against children: study protocol.

Background: Eliminating violence against children is a prominent policy goal, codified in the Sustainable Development Goals, and parenting programs are one approach to preventing and reducing violence. However, we know relatively little about dissemination and scale-up of parenting programs, particularly in low- and middle-income countries (LMICs). The scale-up of two parenting programs, Parenting for Lifelong Health (PLH) for Young Children and PLH for Parents and Teens, developed under Creative Commons licensing and tested in randomized trials, provides a unique opportunity to study their dissemination in 25 LMICs.

Challenging a Preconception: Optoacoustic Spectrum Differs from the Optical Absorption Spectrum of Proteins and Dyes for Molecular Imaging.

Optoacoustic (photoacoustic) imaging has seen marked advances in detection and data analysis, but there is less progress in understanding the photophysics of common optoacoustic contrast agents. This gap blocks the development of novel agents and the accurate analysis and interpretation of multispectral optoacoustic images. To close it, we developed a multimodal laser spectrometer (MLS) to enable the simultaneous measurement of optoacoustic, absorbance, and fluorescence spectra.

Structural basis for the recognition of transiently structured AU-rich elements by Roquin.

Adenylate/uridylate-rich elements (AREs) are the most common cis-regulatory elements in the 3'-untranslated region (UTR) of mRNAs, where they fine-tune turnover by mediating mRNA decay. They increase plasticity and efficacy of mRNA regulation and are recognized by several ARE-specific RNA-binding proteins (RBPs). Typically, AREs are short linear motifs with a high content of complementary A and U nucleotides and often occur in multiple copies.

The large family of PC4-like domains - similar folds and functions throughout all kingdoms of life.

RNA- and DNA-binding domains are essential building blocks for specific regulation of gene expression. While a number of canonical nucleic acid binding domains share sequence and structural conservation, others are less obviously linked by evolutionary traits. In this review, we describe a protein fold of about 150 aa in length, bearing a conserved β-β-β-β-α-linker-β-β-β-β-α topology and similar nucleic acid binding properties but no apparent sequence conservation.

Crystal Contact Engineering Enables Efficient Capture and Purification of an Oxidoreductase by Technical Crystallization.

Technical crystallization is an attractive method to purify recombinant proteins. However, it is rarely applied due to the limited crystallizability of many proteins. To overcome this limitation, single amino acid exchanges are rationally introduced to enhance intermolecular interactions at the crystal contacts of the industrially relevant biocatalyst Lactobacillus brevis alcohol dehydrogenase (LbADH).

Ferritin-Displayed GLP-1 with Improved Pharmacological Activities and Pharmacokinetics.

Glucagon-like peptide-1 (GLP-1) is an incretin (a type of metabolic hormone that stimulates a decrease in blood glucose levels), holding great potential for the treatment of type 2 diabetes mellitus (T2DM). However, its extremely short half-life of 1-2 min hampers any direct clinical application. Here, we describe the application of the heavy chain of human ferritin (HFt) nanocage as a carrier to improve the pharmacological properties of GLP-1.

Defining and expanding the phenotype of -associated developmental epileptic encephalopathy.

Objective: The study is aimed at widening the clinical and genetic spectrum and at assessing genotype-phenotype associations in encephalopathy.

Methods: Through diagnostic gene panel screening in an epilepsy cohort, and recruiting through GeneMatcher and our international network, we collected 10 patients with biallelic variants. In addition, we collected data on 12 patients described in the literature to further delineate the associated phenotype in a total cohort of 22 patients.

Combinatorial recognition of clustered RNA elements by the multidomain RNA-binding protein IMP3.

How multidomain RNA-binding proteins recognize their specific target sequences, based on a combinatorial code, represents a fundamental unsolved question and has not been studied systematically so far. Here we focus on a prototypical multidomain RNA-binding protein, IMP3 (also called IGF2BP3), which contains six RNA-binding domains (RBDs): four KH and two RRM domains. We establish an integrative systematic strategy, combining single-domain-resolved SELEX-seq, motif-spacing analyses, in vivo iCLIP, functional validation assays, and structural biology.

Esophageal adenocarcinoma in a first-degree relative increases risk for esophageal adenocarcinoma in patients with Barrett's esophagus.

Background: The significance of a family history of esophageal adenocarcinoma in the progression to esophageal adenocarcinoma in patients with Barrett's esophagus has not been thoroughly evaluated. The purpose of this study is to evaluate the presence of esophageal adenocarcinoma in a first-degree relative in patients with Barrett's esophagus.

Methods: A retrospective cohort study was conducted of patients with Barrett's esophagus at a tertiary care center undergoing radiofrequency ablation.

Staufen2-mediated RNA recognition and localization requires combinatorial action of multiple domains.

Throughout metazoans, Staufen (Stau) proteins are core factors of mRNA localization particles. They consist of three to four double-stranded RNA binding domains (dsRBDs) and a C-terminal dsRBD-like domain. Mouse Staufen2 (mStau2)-like Drosophila Stau (dmStau) contains four dsRBDs.