[SWI+], the Prion Formed by the Chromatin Remodeling Factor Swi1, Is Highly Sensitive to Alterations in Hsp70 Chaperone System Activity

The yeast prion [SWI+], formed of heritable amyloid aggregates of the Swi1 protein, results in a partial loss of function of the SWI/SNF chromatin-remodeling complex, required for the regulation of a diverse set of genes. Our genetic analysis revealed that [SWI+] propagation is highly dependent upon the action of members of the Hsp70 molecular chaperone system, specifically the Hsp70 Ssa, two of its J-protein co-chaperones, Sis1 and Ydj1, and the nucleotide exchange factors of the Hsp110 family (Sse1/2). Notably, while all yeast prions tested thus far require Sis1, [SWI+] is the only one known to require the activity of Ydj1, the most abundant J-protein in yeast. The C-terminal region of Ydj1, which contains the client protein interaction domain, is required for [SWI+] propagation. However, Ydj1 is not unique in this regard, as another, closely related J-protein, Apj1, can substitute for it when expressed at a level approaching that of Ydj1. While dependent upon Ydj1 and Sis1 for propagation, [SWI+] is also highly sensitive to overexpression of both J-proteins. However, this increased prion-loss requires only the highly conserved 70 amino acid J-domain, which serves to stimulate the ATPase activity of Hsp70 and thus to stabilize its interaction with client protein. Overexpression of the J-domain from Sis1, Ydj1, or Apj1 is sufficient to destabilize [SWI+]. In addition, [SWI+] is lost upon overexpression of Sse nucleotide exchange factors, which act to destabilize Hsp70's interaction with client proteins. Given the plethora of genes affected by the activity of the SWI/SNF chromatin-remodeling complex, it is possible that this sensitivity of [SWI+] to the activity of Hsp70 chaperone machinery may serve a regulatory role, keeping this prion in an easily-lost, meta-stable state. Such sensitivity may provide a means to reach an optimal balance of phenotypic diversity within a cell population to better adapt to stressful environments

2021 Taxonomic update of phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales.

Correction to: 2021 Taxonomic update of phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales. Archives of Virology (2021) 166:3567–3579. https://doi.org/10.1007/s00705-021-05266-wIn March 2021, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote on newly proposed taxa, the phylum Negarnaviricota was amended and emended. The phylum was expanded by four families (Aliusviridae, Crepuscuviridae, Myriaviridae, and Natareviridae), three subfamilies (Alpharhabdovirinae, Betarhabdovirinae, and Gammarhabdovirinae), 42 genera, and 200 species. Thirty-nine species were renamed and/or moved and seven species were abolished. This article presents the updated taxonomy of Negarnaviricota as now accepted by the ICTV.This work was supported in part through Laulima Government Solutions, LLC prime contract with the US National Institute of Allergy and Infectious Diseases (NIAID) under Contract No. HHSN272201800013C. J.H.K. performed this work as an employee of Tunnell Government Services (TGS), a subcontractor of Laulima Government Solutions, LLC under Contract No. HHSN272201800013C. This work was also supported in part with federal funds from the National Cancer Institute (NCI), National Institutes of Health (NIH), under Contract No. 75N91019D00024, Task Order No. 75N91019F00130 to I.C., who was supported by the Clinical Monitoring Research Program Directorate, Frederick National Lab for Cancer Research. This work was also funded in part by Contract No. HSHQDC-15-C-00064 awarded by DHS S&T for the management and operation of The National Biodefense Analysis and Countermeasures Center, a federally funded research and development center operated by the Battelle National Biodefense Institute (V.W.); and NIH contract HHSN272201000040I/HHSN27200004/D04 and grant R24AI120942 (N.V., R.B.T.). S.S. acknowledges partial support from the Special Research Initiative of Mississippi Agricultural and Forestry Experiment Station (MAFES), Mississippi State University, and the National Institute of Food and Agriculture, US Department of Agriculture, Hatch Project 1021494. Part of this work was supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC001030), the UK Medical Research Council (FC001030), and the Wellcome Trust (FC001030).S

Factors influencing terrestriality in primates of the Americas and Madagascar

Among mammals, the order Primates is exceptional in having a high taxonomic richness in which the taxa are arboreal, semiterrestrial, or terrestrial. Although habitual terrestriality is pervasive among the apes and African and Asian monkeys (catarrhines), it is largely absent among monkeys of the Americas (platyrrhines), as well as galagos, lemurs, and lorises (strepsirrhines), which are mostly arboreal. Numerous ecological drivers and species-specific factors are suggested to set the conditions for an evolutionary shift from arboreality to terrestriality, and current environmental conditions may provide analogous scenarios to those transitional periods. Therefore, we investigated predominantly arboreal, diurnal primate genera from the Americas and Madagascar that lack fully terrestrial taxa, to determine whether ecological drivers (habitat canopy cover, predation risk, maximum temperature, precipitation, primate species richness, human population density, and distance to roads) or species-specific traits (body mass, group size, and degree of frugivory) associate with increased terrestriality. We collated 150,961 observation hours across 2,227 months from 47 species at 20 sites in Madagascar and 48 sites in the Americas. Multiple factors were associated with ground use in these otherwise arboreal species, including increased temperature, a decrease in canopy cover, a dietary shift away from frugivory, and larger group size. These factors mostly explain intraspecific differences in terrestriality. As humanity modifies habitats and causes climate change, our results suggest that species already inhabiting hot, sparsely canopied sites, and exhibiting more generalized diets, are more likely to shift toward greater ground use

2020 taxonomic update for phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales.

In March 2020, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote on newly proposed taxa, the phylum Negarnaviricota was amended and emended. At the genus rank, 20 new genera were added, two were deleted, one was moved, and three were renamed. At the species rank, 160 species were added, four were deleted, ten were moved and renamed, and 30 species were renamed. This article presents the updated taxonomy of Negarnaviricota as now accepted by the ICTV

2021 Taxonomic update of phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales.

In March 2021, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote on newly proposed taxa, the phylum Negarnaviricota was amended and emended. The phylum was expanded by four families (Aliusviridae, Crepuscuviridae, Myriaviridae, and Natareviridae), three subfamilies (Alpharhabdovirinae, Betarhabdovirinae, and Gammarhabdovirinae), 42 genera, and 200 species. Thirty-nine species were renamed and/or moved and seven species were abolished. This article presents the updated taxonomy of Negarnaviricota as now accepted by the ICTV

The Polymerase Associated Factor Complex-Protein Arginine Methyltransferase Axis: A Mechanism of Acute Leukemia

Transcriptional and epigenetic mechanisms are pivotal to the maintenance of gene programs responsible for cellular homeostasis. Like many cancers, acute myeloid leukemia (AML) is a disease associated with transcriptional and epigenetic dysregulation. Chromosomal translocations involving the 11q23 locus harboring the H3K4 methyltransferase Mixed Lineage Leukemia 1 (MLL1), are found in AML and generate oncogenic fusion proteins with deregulated transcriptional potential. The Polymerase Associated Factor complex (PAFc) is an epigenetic co-activator complex that makes direct contact with MLL fusion proteins and wild type MLL. Disruption of this interaction impedes leukemic progression and diminishes MLL-fusion driven target gene expression. However, the role of the PAFc in AML remains incompletely understood. Conditional excision of the PAFc subunit Cdc73, relieved the differentiation block of AML cells, induced global epigenetic changes, and halted leukemic growth and cell cycling. To mechanistically assess these phenotypes, we explored the transcriptional targets regulated by the PAFc that facilitate leukemia by performing RNA-sequencing after conditional loss of Cdc73. We found Cdc73 promotes expression of an early hematopoietic progenitor gene program that prevents differentiation. Among the target genes, we confirmed the protein arginine methyltransferase (Prmt) family is broadly downregulated upon excision of Cdc73. Phenotypic analysis revealed that Prmt1, Prmt4, and Prmt5 knockdown could hinder leukemic progression in vitro. We determined that Prmt5 is a direct target that is positively regulated by a transcriptional unit that includes the PAFc, MLL1, Hoxa9, and Stat5 in leukemic cells. We observed reduced Prmt5-mediated H4R3me2s following excision of Cdc73 placing this histone modification downstream of the PAFc and revealing an epigenetic axis between the PAFc and Prmt5. Knockdown or pharmacologic inhibition of Prmt5 causes a G1 arrest and reduced proliferation resulting in extended leukemic disease latency in vivo. Notably, we observed a strong selective pressure to maintain Prmt5 in vitro and in vivo supporting its role in leukemic progression. Additionally, chemical inhibition of PRMT5 disrupted the proliferation of a range of human derived leukemic cell lines suggesting a broader relevance for a PAFc-Prmt5 axis beyond MLL-fusion AML. Overall, we demonstrate the PAFc-Prmt5 axis facilitates leukemic development and is a potential therapeutic target for AMLs.PHDMolecular & Cellular PathologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/140915/1/jserio_1.pd

Strengthening the Impact of Digital Cognitive Behavioral Interventions Through a Dual Intervention: Proficient Motivational Interviewing–Based Health Coaching Plus In-Application Techniques

BackgroundThe COVID-19 pandemic has accelerated the adoption of digital tools to support individuals struggling with their mental health. The use of a digital intervention plus human coaching (“dual” intervention) is gaining momentum in increasing overall engagement in digital cognitive behavioral interventions (dCBIs). However, there is limited insight into the methodologies and coaching models used by those deploying dual interventions. To achieve a deeper understanding, we need to identify and promote effective engagement that leads to clinical outcomes versus simply monitoring engagement metrics. Motivational interviewing (MI) is a collaborative, goal-oriented communication approach that pays particular attention to the language of change and is an effective engagement approach to help people manage mental health issues. However, this approach has been traditionally used for in-person or telephonic interventions, and less is known about the application of MI to digital interventions. ObjectiveWe sought to provide a dual intervention approach and address multiple factors across two levels of engagement to operationalize a dCBI that combined cognitive behavioral therapy–based techniques and MI-based interactions between the digital health coach (DHC) and user. MethodsWe reviewed hundreds of digital exchanges between DHCs and users to identify and improve training and quality assurance activities for digital interventions. ResultsWe tested five hypotheses and found that: (1) users of a dual digital behavioral health intervention had greater engagement levels than users of a noncoached intervention (P<.001); (2) DHCs with a demonstrated competency in applying MI to digital messages had more engaged users, as measured by the DHC-to-user message exchange ratio (P<.001); (3) the DHC-to-user message exchange ratio was correlated with more engagement in app activities (r=0.28, 95% CI 0.23-0.33); (4) DHCs with demonstrated MI proficiency elicited a greater amount of “change talk” from users than did DHCs without MI proficiency (H=25.12, P<.001); and (5) users who were engaged by DHCs with MI proficiency had better clinical outcomes compared to users engaged by DHCs without MI proficiency (P=.02). ConclusionsTo our knowledge, this pilot was the first of its kind to test the application of MI to digital coaching protocols, and it demonstrated the value of MI proficiency in digital health coaching for enhanced engagement and health improvement. Further research is needed to establish coaching models in dCBIs that incorporate MI to promote effective engagement and optimize positive behavioral outcomes

Homo sapiens and Neanderthals share high cerebral cortex integration into adulthood

There is controversy around the mechanisms that guided the change in brain shape during the evolution of modern humans. It has long been held that different cortical areas evolved independently from each other to develop their unique functional specializations. However, some recent studies suggest that high integration between different cortical areas could facilitate the emergence of equally extreme, highly specialized brain functions. Here, we analyse the evolution of brain shape in primates using three-dimensional geometric morphometrics of endocasts. We aim to determine, firstly, whether modern humans present unique developmental patterns of covariation between brain cortical areas; and secondly, whether hominins experienced unusually high rates of evolution in brain covariation as compared to other primates. On the basis of analyses including modern humans and other extant great apes at different developmental stages, we first demonstrate that, unlike our closest living relatives, Homo sapiens retain high levels of covariation between cortical areas into adulthood. Among the other great apes, high levels of covariation are only found in immature individuals. Secondly, at the macro-evolutionary level, our analysis of 400 endocasts, representing 148 extant primate species and 6 fossil hominins, shows that strong covariation between different areas of the brain in H. sapiens and Homo neanderthalensis evolved under distinctly higher evolutionary rates than in any other primate, suggesting that natural selection favoured a greatly integrated brain in both species. These results hold when extinct species are excluded and allometric effects are accounted for. Our findings demonstrate that high covariation in the brain may have played a critical role in the evolution of unique cognitive capacities and complex behaviours in both modern humans and Neanderthals