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To eliminate specific or aberrant transcripts, eukaryotes use nuclear RNA-targeting complexes that deliver them to the exosome for degradation. S. pombe MTREC, and its human counterpart PAXT, are key players in this mechanism but inner workings of these complexes are not understood in sufficient detail. Here, we present an NMR structure of an MTREC scaffold protein Red1 helix-turn-helix domain bound to the Iss10 N-terminus and show this interaction is required for proper cellular growth and meiotic mRNA degradation. We also report a crystal structure of a Red1 - Ars2 complex explaining mutually exclusive interactions of hARS2 with various ED/EGEI/L motif-possessing RNA regulators, including hZFC3H1 of PAXT, hFLASH or hNCBP3. Finally, we show that both Red1 and hZFC3H1 homo-dimerize via their coiled-coil regions indicating that MTREC and PAXT likely function as dimers. Our results, combining structures of three Red1 interfaces with in vivo studies, provide mechanistic insights into conserved features of MTREC/PAXT architecture. Unwanted RNA transcripts are targeted for degradation by nuclear complexes such as MTREC/PAXT. Here, the authors structurally and functionally characterized three interfaces of the scaffold protein Red1, providing mechanistic insights into conserved features of MTREC/PAXT architecture.

A key event in the pathogenesis of Alzheimer's disease (AD) is the accumulation of amyloid-β (Aβ) species in the brain, derived from the sequential cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. Based on a systems biology study to repurpose drugs for AD, we explore the effect of lansoprazole, and other proton-pump inhibitors (PPIs), on Aβ production in AD cellular and animal models. We found that lansoprazole enhances Aβ37, Aβ40 and Aβ42 production and lowers Aβ38 levels on amyloid cell models. Interestingly, acute lansoprazole treatment in wild type and AD transgenic mice promoted higher Aβ40 levels in brain, indicating that lansoprazole may also exacerbate Aβ production in vivo. Overall, our data presents for the first time that PPIs can affect amyloid metabolism, both in vitro and in vivo.

Histone modification: tail spin Brdt1 is a bromodomain-containing chromatin protein that can compact hyperacetylated chromatin and has important functions during spermiogenesis. Here, the crystal structure of a bromodomain of Brdt1 bound to an acetylated histone H4 tail reveals a combinatorial mode of binding to post-translational modifications where a single effector module engages two marks on a histone tail. The recognition of histone post-translational modifications by effector modules such as bromodomains is a key step in many chromatin-related processes. Although effector-mediated recognition of single post-translation modifications is well characterized, combinatorial readout of histones bearing multiple modifications is poorly understood. Here, a distinct mechanism of combinatorial readout for the mouse TAF1 homologue Brdt, a testis-specific member of the BET protein family, is reported. A key step in many chromatin-related processes is the recognition of histone post-translational modifications by effector modules such as bromodomains and chromo-like domains of the Royal family 1 , 2 . Whereas effector-mediated recognition of single post-translational modifications is well characterized 3 , how the cell achieves combinatorial readout of histones bearing multiple modifications is poorly understood. One mechanism involves multivalent binding by linked effector modules 4 . For example, the tandem bromodomains of human TATA-binding protein-associated factor-1 (TAF1) bind better to a diacetylated histone H4 tail than to monoacetylated tails, a cooperative effect attributed to each bromodomain engaging one acetyl-lysine mark 5 . Here we report a distinct mechanism of combinatorial readout for the mouse TAF1 homologue Brdt, a testis-specific member of the BET protein family 6 . Brdt associates with hyperacetylated histone H4 (ref. 7 ) and is implicated in the marked chromatin remodelling that follows histone hyperacetylation during spermiogenesis, the stage of spermatogenesis in which post-meiotic germ cells mature into fully differentiated sperm 7 , 8 , 9 , 10 . Notably, we find that a single bromodomain (BD1) of Brdt is responsible for selectively recognizing histone H4 tails bearing two or more acetylation marks. The crystal structure of BD1 bound to a diacetylated H4 tail shows how two acetyl-lysine residues cooperate to interact with one binding pocket. Structure-based mutagenesis that reduces the selectivity of BD1 towards diacetylated tails destabilizes the association of Brdt with acetylated chromatin in vivo . Structural analysis suggests that other chromatin-associated proteins may be capable of a similar mode of ligand recognition, including yeast Bdf1, human TAF1 and human CBP/p300 (also known as CREBBP and EP300, respectively). Our findings describe a new mechanism for the combinatorial readout of histone modifications in which a single effector module engages two marks on a histone tail as a composite binding epitope.

Laughter is a nonverbal vocal expression that often communicates positive affect and cooperative intent in humans. Temporally coincident laughter occurring within groups is a potentially rich cue of affiliation to overhearers. We examined listeners’ judgments of affiliation based on brief, decontextualized instances of colaughter between either established friends or recently acquainted strangers. In a sample of 966 participants from 24 societies, people reliably distinguished friends from strangers with an accuracy of 53–67%. Acoustic analyses of the individual laughter segments revealed that, across cultures, listeners’ judgments were consistently predicted by voicing dynamics, suggesting perceptual sensitivity to emotionally triggered spontaneous production. Colaughter affords rapid and accurate appraisals of affiliation that transcend cultural and linguistic boundaries, and may constitute a universal means of signaling cooperative relationships.

Nucleosomes provide additional regulatory mechanisms to transcription and DNA replication by mediating the access of proteins to DNA. During the cell cycle chromatin undergoes several conformational changes, however the functional significance of these changes to cellular processes are largely unexplored. Here, we present the first comprehensive genome-wide study of nucleosome plasticity at single base-pair resolution along the cell cycle in Saccharomyces cerevisiae . We determined nucleosome organization with a specific focus on two regulatory regions: transcription start sites (TSSs) and replication origins (ORIs). During the cell cycle, nucleosomes around TSSs display rearrangements in a cyclic manner. In contrast to gap (G1 and G2) phases, nucleosomes have a fuzzier organization during S and M phases, Moreover, the choreography of nucleosome rearrangements correlate with changes in gene expression during the cell cycle, indicating a strong association between nucleosomes and cell cycle-dependent gene functionality. On the other hand, nucleosomes are more dynamic around ORIs along the cell cycle, albeit with tighter regulation in early firing origins, implying the functional role of nucleosomes on replication origins. Our study provides a dynamic picture of nucleosome organization throughout the cell cycle and highlights the subsequent impact on transcription and replication activity.

IntroductionFrom 2012 to 2017, the Cervical Cancer Prevention in El Salvador (CAPE) piloted and scaled up a human papillomavirus (HPV) screen-and-treat intervention. Findings resulted in El Salvador’s adoption of the strategy as part of the national programme, but long-term clinical outcomes are unknown. Here, we compare the detection of high-grade cervical intraepithelial neoplasia grade 2 or higher (CIN2+) and HPV infection after recommended screening intervals between two groups: women who participated in CAPE and a comparable group screened via cytology.MethodsCAPE participants who had undergone screening at least 5 years previously (screen-and-treat group) and women in the same age range with conventional cytology screening 2 to 3 years previously (cytology group) were recruited for repeat screening with primary HPV testing. Women with positive HPV results were referred for colposcopy and cervical biopsy to determine further management. Women with negative HPV results received recommendations for routine future screening according to national guidelines.ResultsA total of 6631 women were enrolled (screen-and-treat = 4087; cytology=2544). Significantly less CIN2+ was detected in the screen-and-treat group at 0.7% (29/4087) than in the cytology group at 2.1% (54/2544) (p<0.001) with a risk ratio of 0.41 (95% CI 0.26 to 0.61). HPV positivity was also lower in the screen-and-treat group at 9.5% (388/4077) compared with the cytology group at 11.5% (293/2445) (p=0.008).ConclusionAt the first round of repeat screening after the implementation of CAPE, women who underwent HPV testing in a screen-and-treat strategy had significantly less CIN2+ and HPV positivity compared with those who underwent cytology. These outcomes occurred despite a longer screening interval for HPV testing than cytology. Findings provide reassurance for women and health systems that primary HPV screen-and-treat programmes with extended screening intervals, like the one in El Salvador, are achievable and effective in low- and middle-income settings.

A key element to delineate the biology of individual tumors is the regulation of apoptosis. In this work, we functionally characterize two breast cancer associated genes, the proteasome 26S subunit ATPase 3 interacting protein (PSMC3IP) and the epithelial-stromal interaction 1 (EPSTI1), to explore their potential apoptotic role in breast cancer. We first explore the existence of direct physical interactions with annotated BC-apoptotic genes. Based on the generated interaction network, we examine several apoptotic markers to determine the effect of PSMC3IP and EPSTI1 gene expression modulation in two different human breast cancer cell lines to suggest potential molecular mechanisms to unveil their role in the disease. Our results show that PSMC3IP and EPSTI1 are able to modulate the extrinsic apoptotic pathway in estrogen receptor positive and triple negative breast cancer cell lines, highlighting them as potential therapeutic targets.

The Mitochondrial Complex I Assembly (MCIA) complex is essential for the biogenesis of respiratory Complex I (CI), the first enzyme in the respiratory chain, which has been linked to Alzheimer’s disease (AD) pathogenesis. However, how MCIA facilitates CI assembly, and how it is linked with AD pathogenesis, is poorly understood. Here we report the structural basis of the complex formation between the MCIA subunits ECSIT and ACAD9. ECSIT binding induces a major conformational change in the FAD-binding loop of ACAD9, releasing the FAD cofactor and converting ACAD9 from a fatty acid β-oxidation (FAO) enzyme to a CI assembly factor. We provide evidence that ECSIT phosphorylation downregulates its association with ACAD9 and is reduced in neuronal cells upon exposure to amyloid-β (Aβ) oligomers. These findings advance our understanding of the MCIA complex assembly and suggest a possible role for ECSIT in the reprogramming of bioenergetic pathways linked to Aβ toxicity, a hallmark of AD. The role that cellular bioenergetics plays in the early stages of Alzheimer’s disease is poorly understood. Here the authors describe structures of key OXPHOS assembly proteins, providing insights into how these pathways are interlinked and regulated.

Background The past decade of research has seen theoretical and methodological advances in both implementation science and health equity research, opening a window of opportunity for facilitating and accelerating cross-disciplinary exchanges across these fields that have largely operated in siloes. In 2019 and 2020, the National Cancer Institute’s Consortium for Cancer Implementation Science convened an action group focused on ‘health equity and context’ to identify opportunities to advance implementation science. In this paper, we present a narrative review and synthesis of the relevant literature at the intersection of health equity and implementation science, highlight identified opportunities (i.e., public goods) by the action group for advancing implementation science in cancer prevention and control, and integrate the two by providing key recommendations for future directions. Discussion In the review and synthesis of the literature, we highlight recent advances in implementation science, relevant to promoting health equity (e.g., theories/models/frameworks, adaptations, implementation strategies, study designs, implementation determinants, and outcomes). We acknowledge the contributions from the broader field of health equity research and discuss opportunities for integration and synergy with implementation science, which include (1) articulating an explicit focus on health equity for conducting and reviewing implementation science; (2) promoting an explicit focus on health equity in the theories, models, and frameworks guiding implementation science; and (3) identifying methods for understanding and documenting influences on the context of implementation that incorporate a focus on equity. Summary To advance the science of implementation with a focus on health equity, we reflect on the essential groundwork needed to promote bi-directional learning between the fields of implementation science and health equity research and recommend (1) building capacity among researchers and research institutions for health equity-focused and community-engaged implementation science; (2) incorporating health equity considerations across all key implementation focus areas (e.g., adaptations, implementation strategies, study design, determinants, and outcomes); and (3) continuing a focus on transdisciplinary opportunities in health equity research and implementation science. We believe that these recommendations can help advance implementation science by incorporating an explicit focus on health equity in the context of cancer prevention and control and beyond.

Background Cervical cancer remains a leading cause of cancer death for women worldwide. Screen-and-treat programs are a key strategy to reduce disease burden in low and middle-income countries (LMICs). Thermal ablation (TA) has emerged as a portable alternative to cryotherapy, the treatment typically used in screen-and-treat initiatives. Interest in TA is growing, but there is limited research on its implementation in public health settings. Here we present results from a preliminary evaluation of the barriers and facilitators of TA in El Salvador, one of the first countries to adopt a national HPV screen-and-treat program. Methods This mixed-methods study took place between August 2022 to February 2023 across five clinics. The Practical, Robust Implementation and Sustainability Model (PRISM) was utilized to map findings to contextual factors that impact implementation and sustainability. Participants were frontline providers and women who presented for treatment after a positive HPV test. Providers took part in semi-structured interviews while women completed questionnaires. Additional data were collected from clinic records. Quantitative data were analyzed using inferential statistics and a rapid qualitative analysis approach was used for interviews. Results Providers perceived TA as easier to use and more comfortable for patients, but cryotherapy was utilized 20% more frequently during the study period (cryotherapy treatments = 133 vs. TA treatments = 100). Although the two treatments have the same contraindications, a greater proportion of women were deemed eligible for treatment with TA vs. cryotherapy (95% vs. 79%, p  < .001). There were discrepancies in provider and women’s perceptions of pain and side-effects. While > 80% of women received counseling during the screen-and-treat process, misconceptions regarding screenings results and treatment remained. Conclusions The new treatment (TA) was highly acceptable to participants. However, there may be a need for additional provider training to support TA adoption and fidelity to program guidelines, while patients would benefit from more effective counseling. As LMICs strive to meet cervical cancer elimination targets set by the World Health Organization, it is expected that innovations will be quickly introduced to clinical practice. Thus, it is critical to understand the factors that impact their implementation and sustainability in these settings.