Amplification Dynamics of Platy-1 Retrotransposons in the Cebidae Platyrrhine Lineage

Platy-1 elements are Platyrrhine-specific, short interspersed elements originally discovered in the Callithrix jacchus (common marmoset) genome. To date, only the marmoset genome has been analyzed for Platy-1 repeat content. Here, we report full-length Platy-1 insertions in other New World monkey (NWM) genomes (Saimiri boliviensis, squirrel monkey; Cebus imitator, capuchin monkey; and Aotus nancymaae, owl monkey) and analyze the amplification dynamics of lineage-specific Platy-1 insertions. A relatively small number of full-length and lineage-specific Platy-1 elements were found in the squirrel, capuchin, and owl monkey genomes compared with the marmoset genome. In addition, only a few older Platy-1 subfamilies were recovered in this study, with no Platy-1 subfamilies younger than Platy-1-6. By contrast, 62 Platy-1 subfamilies were discovered in the marmoset genome. All of the lineage-specific insertions found in the squirrel and capuchin monkeys were fixed present. However, similar to 15% of the lineage-specific Platy-1 loci in Aotus were polymorphic for insertion presence/absence. In addition, two new Platy-1 subfamilies were identified in the owl monkey genome with low nucleotide divergences compared with their respective consensus sequences, suggesting minimal ongoing retrotransposition in the Aotus genus and no current activity in the Saimiri, Cebus, and Sapajus genera. These comparative analyses highlight the finding that the high number of Platy-1 elements discovered in the marmoset genome is an exception among NWM analyzed thus far, rather than the rule. Future studies are needed to expand upon our knowledge of Platy-1 amplification in other NWM genomes

Discovery of a new repeat family in the Callithrix jacchus genome

We identified a novel repeat family, termed Platy-1, in the Callithrix jacchus (common marmoset) genome that arose around the time of the divergence of platyrrhines and catarrhines and established itself as a repeat family in New World monkeys (NWMs). A full-length Platy-1 element is ∼100 bp in length, making it the shortest known short interspersed element (SINE) in primates, and harbors features characteristic of non-LTR retrotransposons. We identified 2268 full-length Platy-1 elements across 62 subfamilies in the common marmoset genome. Our subfamily reconstruction and phylogenetic analyses support Platy-1 propagation throughout the evolution of NWMs in the lineage leading to C. jacchus. Platy-1 appears to have reached its amplification peak in the common ancestor of current day marmosets and has since moderately declined. However, identification of more than 200 Platy-1 elements identical to their respective consensus sequence, and the presence of polymorphic elements within common marmoset populations, suggests ongoing retrotransposition activity. Platy-1, a SINE, appears to have originated from an Alu element, and hence is likely derived from 7SL RNA. Our analyses illustrate the birth of a new repeat family and its propagation dynamics in the lineage leading to the common marmoset over the last 40 million years

Excitatory and inhibitory D-serine binding to the NMDA receptor

N-methyl-D-aspartate receptors (NMDARs) uniquely require binding of two different neurotransmitter agonists for synaptic transmission. D-serine and glycine bind to one subunit, GluN1, while glutamate binds to the other, GluN2. These agonists bind to the receptor's bi-lobed ligand-binding domains (LBDs), which close around the agonist during receptor activation. To better understand the unexplored mechanisms by which D-serine contributes to receptor activation, we performed multi-microsecond molecular dynamics simulations of the GluN1/GluN2A LBD dimer with free D-serine and glutamate agonists. Surprisingly, we observed D-serine binding to both GluN1 and GluN2A LBDs, suggesting that D-serine competes with glutamate for binding to GluN2A. This mechanism is confirmed by our electrophysiology experiments, which show that D-serine is indeed inhibitory at high concentrations. Although free energy calculations indicate that D-serine stabilizes the closed GluN2A LBD, its inhibitory behavior suggests that it either does not remain bound long enough or does not generate sufficient force for ion channel gating. We developed a workflow using pathway similarity analysis to identify groups of residues working together to promote binding. These conformation-dependent pathways were not significantly impacted by the presence of N-linked glycans, which act primarily by interacting with the LBD bottom lobe to stabilize the closed LBD

Amplification dynamics of platy-1 retrotransposons in the cebidae platyrrhine lineage

© 2019 The Author(s). Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. Platy-1 elements are Platyrrhine-specific, short interspersed elements originally discovered in the Callithrix jacchus (common marmoset) genome. To date,only themarmoset genomehas been analyzed for Platy-1 repeat content.Here,we report full-length Platy-1 insertions in other NewWorld monkey (NWM) genomes (Saimiri boliviensis, squirrel monkey; Cebus imitator, capuchin monkey; and Aotus nancymaae, owl monkey) and analyze the amplification dynamics of lineage-specific Platy-1 insertions. A relatively small number of full-length and lineage-specific Platy-1 elements were found in the squirrel, capuchin, and owl monkey genomes compared with the marmoset genome. In addition, only a few older Platy-1 subfamilies were recovered in this study, with no Platy-1 subfamilies younger than Platy-1-6. By contrast, 62 Platy-1 subfamilieswere discovered in themarmoset genome.All of the lineagespecific insertions found in the squirrel and capuchin monkeys were fixed present. However, 15%of the lineage-specific Platy-1 loci in Aotus were polymorphic for insertion presence/absence. In addition, two new Platy-1 subfamilies were identified in the owl monkey genome with low nucleotide divergences compared with their respective consensus sequences, suggesting minimal ongoing retrotransposition in the Aotus genus and no current activity in the Saimiri, Cebus, and Sapajus genera. These comparative analyses highlight the finding that the high number of Platy-1 elements discovered in themarmoset genome is an exception among NWManalyzed thus far, rather than the rule. Future studies are needed to expand upon our knowledge of Platy-1 amplification in other NWM genomes

Ideas and perspectives: strengthening the biogeosciences in environmental research networks

Many scientific approaches are improving our understanding and management of the rapidly changing environment. Long-term environmental research networks are one approach to advancing local, regional, and global environmental science and education. A remarkable number and wide variety of environmental research networks operate around the world today. These are diverse in funding, infrastructure, motivating questions, scientific strengths, and the sciences that birthed and maintained the networks. Some networks have individual sites that were selected because they had produced invaluable long-term data, while other networks have new sites selected to span ecological gradients. However, all long-term environmental networks share two challenges. Networks must keep pace with scientific advances and interact with both the scientific community and society at large. If networks fall short of successfully addressing these challenges, they risk becoming irrelevant. The objective of this paper is to assert that the biogeosciences offer environmental research networks a number of opportunities to expand scientific impact and public engagement. We explore some of these opportunities with four networks: the International Long Term Ecological Research programs (ILTERs), the Critical Zone Observatories (CZOs), the Earth and Ecological Observatory networks (EONs), and the FLUXNET program of eddy flux sites. While these networks were founded and grown by interdisciplinary scientists, the preponderance of expertise and funding have gravitated activities of ILTERs and EONs toward ecology and biology, CZOs toward the Earth sciences and geology, and FLUXNET toward ecophysiology and micrometeorology. Our point is not to homogenize networks, nor to diminish disciplinary science. Rather, we argue that by more fully incorporating the integration of biology and geology in long-term environmental research networks, scientists can better leverage network assets, keep pace with the ever-changing science of the environment, and engage with larger scientific and public audiences

The Effects of Tootling Combined with Public Posting in High School Classrooms

A traditional tootling procedure was implemented along with a public posting component to determine the effects on academically engaged, disruptive, and passive off-task behaviors in four general education high school classrooms. Students in the traditional tootling phase were instructed to report on their peers’ positive, prosocial behaviors. At the end of the class period, the teacher read through the tootles and added the total toward the group goal. When the class achieved their goal, they were rewarded, and the goal was reset. During the tooting with public posting phase, the teacher or primary researcher posted the tootles on a designated bulletin board. The results indicated that increases in academically engaged behaviors were maintained in both phases, whereas disruptive and passive off-task behaviors decreased. The differences between phases were minimal, suggesting little additive effect. Social validity measures indicated that intervention was acceptable in terms of effectiveness and utility. This study suggests the benefits of implementing tootling in a high school setting, demonstrating increases in classwide academically engaged behaviors

Comprehensive Process Mapping and Qualitative Interviews to Inform Implementation of Rapid Linkage to HIV Care Programs in a Mid-Sized Urban Setting in the Southern United States

Background:Rapid antiretroviral therapy (ART) initiation, in which people living with HIV start ART within days of diagnosis, is a key component of the US Ending the HIV Epidemic initiative.Setting:The Memphis Metropolitan Statistical Area ranked fourth in the United States for the highest HIV incidence per 100,000 population in 2018. Rapid ART programs are limited in the Memphis Metropolitan Statistical Area, and our objective was to identify local implementation barriers.Methods:We conducted participatory process mapping and in-depth interviews to detail steps between HIV testing at the municipal health department\u27s Sexually Transmitted Infections Clinic and ART prescription from a nearby high-volume Ryan White-funded HIV Clinic.Results:Process mapping identified 4 modifiable, rate-limiting rapid ART barriers: (1) requiring laboratory-based confirmatory HIV results, (2) eligibility documentation requirements for Ryan White-funded services, (3) insufficient HIV Clinic medical provider availability, and (4) variability in ART initiation timing among HIV Clinic providers. Staff at both sites highlighted suboptimal communication and sense of shared management between facilities, limited resources to address important social determinants of health, and lack of Medicaid expansion in Tennessee as key barriers. In-depth interview themes negatively affecting rapid ART initiation included clinic burden; provider knowledge, attitudes, and beliefs; and client psychosocial needs.Conclusions:Our preimplementation work identified modifiable and systemic barriers to systems flow and patient-level outcomes. This work will inform the design and implementation of a locally relevant rapid ART program in Memphis, a community disproportionately affected by the HIV epidemic

Blockade of TGF-β inhibits mammary tumor cell viability, migration, and metastases

TGF-βs are potent inhibitors of epithelial cell proliferation. However, in established carcinomas, autocrine/paracrine TGF-β interactions can enhance tumor cell viability and progression. Thus, we studied the effect of a soluble Fc:TGF-β type II receptor fusion protein (Fc:TβRII) on transgenic and transplantable models of breast cancer metastases. Systemic administration of Fc:TβRII did not alter primary mammary tumor latency in MMTV-Polyomavirus middle T antigen transgenic mice. However, Fc:TβRII increased apoptosis in primary tumors, while reducing tumor cell motility, intravasation, and lung metastases. These effects correlated with inhibition of Akt activity and FKHRL1 phosphorylation. Fc:TβRII also inhibited metastases from transplanted 4T1 and EMT-6 mammary tumors in syngeneic BALB/c mice. Tumor microvessel density in a mouse dorsal skin window chamber was unaffected by Fc:TβRII. Therefore, blockade of TGF-β signaling may reduce tumor cell viability and migratory potential and represents a testable therapeutic approach against metastatic carcinomas