Holding On: Older Californians With Disabilities Rely on Public Services to Remain Independent

Presents findings from a study of low-income older Californians with disabilities receiving Medicare, Medi-Cal, and In-Home Supportive Services; their unmet physical, mental health, and social needs; and limited care options. Outlines policy implications

Memory Acquisition and Retrieval Impact Different Epigenetic Processes that Regulate Gene Expression

Background: A fundamental question in neuroscience is how memories are stored and retrieved in the brain. Long-term memory formation requires transcription, translation and epigenetic processes that control gene expression. Thus, characterizing genome-wide the transcriptional changes that occur after memory acquisition and retrieval is of broad interest and importance. Genome-wide technologies are commonly used to interrogate transcriptional changes in discovery-based approaches. Their ability to increase scientific insight beyond traditional candidate gene approaches, however, is usually hindered by batch effects and other sources of unwanted variation, which are particularly hard to control in the study of brain and behavior. Results: We examined genome-wide gene expression after contextual conditioning in the mouse hippocampus, a brain region essential for learning and memory, at all the time-points in which inhibiting transcription has been shown to impair memory formation. We show that most of the variance in gene expression is not due to conditioning and that by removing unwanted variance through additional normalization we are able provide novel biological insights. In particular, we show that genes downregulated by memory acquisition and retrieval impact different functions: chromatin assembly and RNA processing, respectively. Levels of histone 2A variant H2AB are reduced only following acquisition, a finding we confirmed using quantitative proteomics. On the other hand, splicing factor Rbfox1 and NMDA receptor-dependent microRNA miR-219 are only downregulated after retrieval, accompanied by an increase in protein levels of miR-219 target CAMKIIγ. Conclusions: We provide a thorough characterization of coding and non-coding gene expression during long-term memory formation. We demonstrate that unwanted variance dominates the signal in transcriptional studies of learning and memory and introduce the removal of unwanted variance through normalization as a necessary step for the analysis of genome-wide transcriptional studies in the context of brain and behavior. We show for the first time that histone variants are downregulated after memory acquisition, and splicing factors and microRNAs after memory retrieval. Our results provide mechanistic insights into the molecular basis of cognition by highlighting the differential involvement of epigenetic mechanisms, such as histone variants and post-transcriptional RNA regulation, after acquisition and retrieval of memory

A model of the dynamics of boundary film formation

The dynamics of formation and loss of the boundary films formed during sliding on steel surfaces were investigated over a range of temperature. Tests are performed on a cylinder-on-disk machine using mineral oil with various concentrations of zinc dialkyldithiophosphate (ZDP). The thickness and refractive index of the boundary films during step load test were monitored in situ with an ellipsometer, and the composition of the films was analyzed by X-ray photoelectron spectroscopy (XPS). As temperature increases, chemical reactivity increases the film formation rate, while the film removal rate increases owing to (a) the decrease of durability of the boundary film material and (b) the reduction of hydrodynamic fluid film thickness due to decreasing viscosity of the lubricant. There is a balance between these two competing mechanisms, and this balance is reflected in the boundary film thickness. The boundary films consist of a film of oxide and metallic compound (OMM) covered by an organo-iron compound (OIC). Their relative effectiveness in preventing scuffing depends on temperature and composition. In particular, the OIC is effective in reducing wear of the opposing surfaces by covering the OMM.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31341/1/0000251.pd

Optimized polyepitope neoantigen DNA vaccines elicit neoantigen-specific immune responses in preclinical models and in clinical translation

BACKGROUND: Preclinical studies and early clinical trials have shown that targeting cancer neoantigens is a promising approach towards the development of personalized cancer immunotherapies. DNA vaccines can be rapidly and efficiently manufactured and can integrate multiple neoantigens simultaneously. We therefore sought to optimize the design of polyepitope DNA vaccines and test optimized polyepitope neoantigen DNA vaccines in preclinical models and in clinical translation. METHODS: We developed and optimized a DNA vaccine platform to target multiple neoantigens. The polyepitope DNA vaccine platform was first optimized using model antigens in vitro and in vivo. We then identified neoantigens in preclinical breast cancer models through genome sequencing and in silico neoantigen prediction pipelines. Optimized polyepitope neoantigen DNA vaccines specific for the murine breast tumor E0771 and 4T1 were designed and their immunogenicity was tested in vivo. We also tested an optimized polyepitope neoantigen DNA vaccine in a patient with metastatic pancreatic neuroendocrine tumor. RESULTS: Our data support an optimized polyepitope neoantigen DNA vaccine design encoding long (≥20-mer) epitopes with a mutant form of ubiquitin (Ub CONCLUSIONS: We have developed and optimized a novel polyepitope neoantigen DNA vaccine platform that can target multiple neoantigens and induce antitumor immune responses in preclinical models and neoantigen-specific responses in clinical translation

Virgo's Intracluster Globular Clusters as Seen by the Advanced Camera for Surveys

We report the discovery of 4 candidate intracluster globular clusters (IGCs) in a single deep HST ACS field of the Virgo Cluster. We show that each cluster is roughly spherical, has a magnitude near the peak of the Virgo globular cluster luminosity function, has a radial profile that is best-fit by a King model, and is surrounded by an excess of point sources which have the colors and magnitudes of cluster red giant stars. Despite the fact that two of our IGC candidates have integrated colors redder than the mean of the M87 globular cluster system, we propose that all of the objects are metal-poor with [M/H] < -1. We show that the tidal radii of our intracluster globulars are all larger than the mean for Milky Way clusters, and suggest that the clusters have undergone less tidal stress than their Galactic counterparts. Finally, we normalize our globular cluster observations to the luminosity of intracluster stars, and derive a value of S_N ~ 6 for the specific frequency of Virgo intracluster globular clusters. We use these data to constrain the origins of Virgo's intracluster population, and suggest that globular clusters in our intracluster field have a different origin than globular clusters in the vicinity of M87. In particular, we argue that dwarf elliptical galaxies may be an important source of intracluster stars.Comment: 24 pages, 1 table, 5 figures, accepted for publication in Ap

It Takes Two

Theories of conflict emphasize dyadic interaction, yet existing empirical studies of civil war focus largely on state attributes and pay little attention to nonstate antagonists. We recast civil war in a dyadic perspective, and consider how nonstate actor attributes and their relationship to the state influence conflict dynamics. We argue that strong rebels, who pose a military challenge to the government, are likely to lead to short wars and concessions. Conflicts where rebels seem weak can become prolonged if rebels can operate in the periphery so as to defy a government victory yet are not strong enough to extract concessions. Conflicts should be shorter when potential insurgents can rely on alternative political means to violence. We examine these hypotheses in a dyadic analysis of civil war duration and outcomes, using new data on nonstate actors and conflict attributes, finding support for many of our conjectures. </jats:p

Unique V3 Loop Sequence Derived from the R2 Strain of HIV-Type 1 Elicits Broad Neutralizing Antibodies

DNA vaccines expressing the envelope (Env) of the human immunodeficiency virus type 1 (HIV-1) have been relatively ineffective at generating high-titer, long-lasting, neutralizing antibodies. In this study, DNA vaccines were constructed to express the gp120 subunit of Env from the isolate HIV-1R2 using both wild-type and codon- ptimized gene sequences. Three copies of the murine C3d were added to the carboxyl terminus to enhance the immunogenicity of the expressed fusion protein. Mice (BALB/c) vaccinated with DNA plasmid expressing the gp120R2 using codon-optimized Env sequences elicited high-titer anti-Env antibodies regardless of conjugation to C3d. In contrast, only mice vaccinated with DNA using wild-type gp120R2 sequences fused to mC3d3, had detectable anti- Env antibodies. Interestingly, mice vaccinated with DNA expressing gp120R2 from codon-optimized sequences elicited antibodies that neutralized both homologous and heterologous HIV-1 isolates. To determine if the unique sequence found in the crown of the V3 loop of the EnvR2 was responsible for the elicitation of the cross-clade neutralizing antibodies, the codons encoding for the Pro-Met (amino acids 313–314) were introduced into the sequences encoding the gp120ADA (R5) or gp12089.6 (R5X4). Mice vaccinated with gp120ADA–mC3d3–DNA with the Pro–Met mutation had antibodies that neutralized HIV-1 infection, but not the gp12089.6–mC3d3–DNA. Therefore, the use of the unique sequences in the EnvR2 introduced into an R5 tropic envelope, in conjunction with C3d fusion, was effective at broadening the number of viruses that could be neutralized. However, the introduction of this same sequence into an R5X4-tropic envelope was ineffective in eliciting improved cross-clade neutralizing antibodies. Originally published AIDS Research and Human Retroviruses, Vol. 20, No. 11, Nov 200

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes