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Background and objectivesThe clinical diagnosis of Huntington disease (HD) is typically made once motor symptoms and chorea are evident. Recent reports highlight the onset of cognitive and psychiatric symptoms before motor manifestations. These findings support further investigations of cognitive function across the lifespan of HD sufferers.MethodsTo assess cognitive symptoms in the developing brain, we administered assessments from the National Institutes of Health Toolbox Cognitive Battery, an age-appropriate cognitive assessment with population norms, to a cohort of children, adolescents and young adults with (gene-expanded; GE) and without (gene-not-expanded; GNE) the trinucleotide cytosine, adenine, guanine (CAG) expansion in the Huntingtin gene. These five assessments that focus on executive function are well validated and form a composite score, with population norms. We modelled these scores across age, and CAP score to estimate the slope of progression, comparing these results to motor symptoms.ResultsWe find significant deficits in the composite measure of executive function in GE compared with GNE participants. GE participant performance on working memory was significantly lower compared with GNE participants. Modelling these results over age suggests that these deficits occur as early as 18 years of age, long before motor manifestations of HD.ConclusionsThis work provides strong evidence that impairments in executive function occur as early as the second decade of life, well before anticipated motor onset. Future investigations should delineate whether these impairments in executive function are due to abnormalities in neurodevelopment or early sequelae of a neurodegenerative process.

Daily biological rhythms, conserved across all kingdoms of life, are governed by internal molecular oscillations of circadian clocks. In Drosophila, the timekeeping function of the biological clock depends on molecular oscillators present in circadian clock neurons located in the brain. PERIOD (PER) protein is an integral component of the oscillator and mutations in per are known to cause shorter and longer circadian rhythms, and even arrhythmia. PER subcellular localization, stability, transcriptional activity, and degradation are regulated by post-translational modifications (PTMs) occurring at many sites on PER. In this thesis, I characterize the effects of phosphorylation at PER(S596), a phosphorylation site which has previously been shown to be important in delaying PER degradation. I show that when this site is unable to be phosphorylated in per(S596A) mutants, both gene and protein expression of core clock components are advanced in whole fly head lysates, corresponding to the short-period behavioral phenotype. In per(S596A) mutants, I show an advance in PER depletion from the nucleus in circadian clock neurons, further explaining the shortened circadian period observed in these flies. I show that phosphorylation of PER(S596) by the nuclear kinase NEMO commences immediately as PER enters the nucleus of circadian clock neurons, suggesting that nuclear PER stability is important in maintaining the pace of the clock. Finally, an examination of PER at cell-type specific resolution shows that nuclear PER abundance oscillates in phase in circadian clock neurons and other non-clock cells in WT flies, evidence that the clock oscillates in phase throughout cells in the fly brain.

Prevention behaviors represent important public health tools to limit spread of SARS-CoV-2. Adherence with recommended public health prevention behaviors among 20000 + members of a COVID-19 syndromic surveillance cohort from the mid-Atlantic and southeastern United States was assessed via electronic survey following the 2020 Thanksgiving and winter holiday (WH) seasons. Respondents were predominantly non-Hispanic Whites (90%), female (60%), and ≥ 50 years old (59%). Non-household members (NHM) were present at 47.1% of Thanksgiving gatherings and 69.3% of WH gatherings. Women were more likely than men to gather with NHM (p < 0.0001). Attending gatherings with NHM decreased with older age (Thanksgiving: 60.0% of participants aged < 30 years to 36.3% aged ≥ 70 years [p-trend < 0.0001]; WH: 81.6% of those < 30 years to 61.0% of those ≥ 70 years [p-trend < 0.0001]). Non-Hispanic Whites were more likely to gather with NHM than were Hispanics or non-Hispanic Blacks (p < 0.0001). Mask wearing, reported by 37.3% at Thanksgiving and 41.9% during the WH, was more common among older participants, non-Hispanic Blacks, and Hispanics when gatherings included NHM. In this survey, most people did not fully adhere to recommended public health safety behaviors when attending holiday gatherings. It remains unknown to what extent failure to observe these recommendations may have contributed to the COVID-19 surges observed following Thanksgiving and the winter holidays in the United States.

Recent meta-analyses confirm that the strength of trophic cascades (indirect positive effects of predators on plant biomass through control of herbivores) varies among ecosystem types. In particular, most terrestrial systems show smaller cascades than most aquatic ones. Ecologists still remain challenged to explain this variation. Here, we examine a food quality hypothesis which states that higher quality plants should promote stronger trophic cascades. Food quality involves two components: digestion resistance of plants and magnitude of stoichiometric imbalance between plants and herbivores (where stoichiometry involves ratios of nutrient:carbon ratio of tissues). Both factors vary among ecosystems and could mediate conversion efficiency of plants into new herbivores (and hence control of plants by herbivores). We explored the food quality hypothesis using two models, one assuming that plant stoichiometry is a fixed trait, the other one allowing this trait to vary dynamically (but with a minimal nutrient:carbon ratio of structural mass). Both models produce the same suite of results. First, as expected, systems with more easily digested plants promote stronger cascades. Second, contrary to expectations, higher (fixed or minimal) nutrient:carbon ratio of plants do not promote stronger cascades, largely because of the net result of ecosystem feedbacks. Still, the model with dynamic stoichiometry permits positive correlations of realized plant nutrient:carbon ratio and cascade strength (as predicted), mediated through digestion resistance. Third, lower nutrient:carbon ratio of herbivores promotes stronger cascades. However, this result likely cannot explain variation in cascade strength because nutrient:carbon stoichiometry of herbivores does not vary greatly between terrestrial and aquatic ecosystems. Finally, we found that predation promotes nutrient limitation of herbivores. This finding highlights that food web processes, such as predation, can influence stoichiometry-mediated interactions of plants and herbivores.

Recent meta-analyses confirm that the strength of trophic cascades (indirect positive effects of predators on plant biomass through control of herbivores) varies among ecosystem types. In particular, most terrestrial systems show smaller cascades than most aquatic ones. Ecologists still remain challenged to explain this variation. Here, we examine a food quality hypothesis which states that higher quality plants should promote stronger trophic cascades. Food quality involves two components: digestion resistance of plants and magnitude of stoichiometric imbalance between plants and herbivores (where stoichiometry involves ratios of nutrient: carbon ratio of tissues). Both factors vary among ecosystems and could mediate conversion efficiency of plants into new herbivores (and hence control of plants by herbivores). We explored the food quality hypothesis using two models, one assuming that plant stoichiometry is a fixed trait, the other one allowing this trait to vary dynamically (but with a minimal nutrient: carbon ratio of structural mass). Both models produce the same suite of results. First, as expected, systems with more easily digested plants promote stronger cascades. Second, contrary to expectations, higher (fixed or minimal) nutrientxarbon ratio of plants do not promote stronger cascades, largely because of the net result of ecosystem feedbacks. Still, the model with dynamic stoichiometry permits positive correlations of realized plant nutrient: carbon ratio and cascade strength (as predicted), mediated through digestion resistance. Third, lower nutrientxarbon ratio of herbivores promotes stronger cascades. However, this result likely cannot explain variation in cascade strength because nutrient: carbon stoichiometry of herbivores does not vary greatly between terrestrial and aquatic ecosystems. Finally, we found that predation promotes nutrient limitation of herbivores. This finding highlights that food web processes, such as predation, can influence stoichiometry-mediated interactions of plants and herbivores.

Eight of the 175 patients (4.6%) were IgG seropositive and 6 (3.4%) had borderline reactivity by EIA. [...]14 of 175 patients (8%) were seroreactive (defined as positive or borderline by EIA). According to our laboratory criteria, Western blot results were only positive in 4 (including 2 with borderline enzyme-linked immunosorbent assay results) (Table II). Only 6 of 77 patients (7.8%) with severe heart failure that had been considered idiopathic had serologic evidence of exposure to B. burgdorferi and, of these, only 1 met our criteria for a confirmatory Western blot. [...]B. burgdorferi infection appears to be infrequently associated with idiopathic cardiomyopathy in our geographic area. [...]the B. burgdorferi seroreactivity reported in the European patients may have been due to either unrelated past infection or to false-positive serologic assay results which, as we have demonstrated, can be quite common using EIA methodologies.

CRISPR-based epi-editors can robustly modulate cellular transcription and chromatin structure, but off-target activity and cytotoxicity limit their utility. Here, we engineer the acyl-CoA binding pocket of the human p300 histone acyltransferase to reduce its cytotoxicity and tune its acylation profile when fused to dCas9. We discover a single amino acid substitution (I1417N) that decreases cytotoxicity related to exogenous p300 overexpression yet preserves dCas9-p300 mediated histone acetylation and gene activation. We find that dCas9-p300 I1417N is less perturbative to the transcriptome and proteome of human cells, and that this behavior is driven by favorable stability kinetics. We also develop a crotonylation-biased dCas-p300 variant (I1395G) that selectively deposits histone crotonylation and activates transcription from endogenous promoters at levels comparable to wild-type p300. The p300 variants generated here enhance epi-editing capabilities and demonstrate that engineering of catalytic domains can be a powerful strategy for tailoring enzymatic activities and mitigating effector-driven toxicity in epi-editing.Competing Interest StatementJ.G., J.L., B.M., M.E., and I.B.H. are inventors on patents related to genome and epigenome editing. K.E.M is an employee of EpiCypher Inc. The remaining authors declare no competing interests.Footnotes* Updated to include new experimental data and clarifications to text.Funder Information DeclaredVarious, The authors thank all members of the Hilton and Diehl labs for helpful discussions and insights. The authors also thank Drs. Martis Cowles and Andrea Johnstone (EpiCypher) for generously providing reagents and scientific input on the project. This work was supported by a Cancer Prevention & Research Institute of Texas (CPRIT) award (RR170030) and NIH awards (R35GM143532 and R56HG012206) to I.B.H and a Welch Foundation award (C-2240-20250403) to I.B.H. and M.R.D. J.G. was supported by NSF NRT Program 1828869. M.E. was supported by the American Heart Association awards (917025 and https://doi.org/10.58275/AHA.25TPA1463933.pc.gr.233910) and a ZOLL foundation award. This project was supported in part by the Baylor College of Medicine (BCM) Genomic and RNA Profiling Core with funding from NIH NCI (P30CA125123), NIH S10 grant (1S10OD023469), and CPRIT (RP200504). This project was also supported by the BCM Single Cell Genomics Core with funding from the NIH (S10OD018033, S10OD023469, S10OD025240) and P30EY002520. The project also received support from the BCM Mass Spectrometry Proteomics Core. The BCM Mass Spectrometry Proteomics Core is supported by the Dan L. Duncan Comprehensive Cancer Center NIH award (P30 CA125123) and a CPRIT Core Facility Award (RP210227).

Measurements of large-scale structure are interpreted using theoretical predictions for the matter distribution, including potential impacts of baryonic physics. We constrain the feedback strength of baryons jointly with cosmology using weak lensing and galaxy clustering observables (3\\(\\times\\)2pt) of Dark Energy Survey (DES) Year 1 data in combination with external information from baryon acoustic oscillations (BAO) and Planck cosmic microwave background polarization. Our baryon modeling is informed by a set of hydrodynamical simulations that span a variety of baryon scenarios; we span this space via a Principal Component (PC) analysis of the summary statistics extracted from these simulations. We show that at the level of DES Y1 constraining power, one PC is sufficient to describe the variation of baryonic effects in the observables, and the first PC amplitude (\\(Q_1\\)) generally reflects the strength of baryon feedback. With the upper limit of \\(Q_1\\) prior being bound by the Illustris feedback scenarios, we reach \\(\\sim 20\\%\\) improvement in the constraint of \\(S_8=\\sigma_8(\\Omega_{\\rm m}/0.3)^{0.5}=0.788^{+0.018}_{-0.021}\\) compared to the original DES 3\\(\\times\\)2pt analysis. This gain is driven by the inclusion of small-scale cosmic shear information down to 2.5 arcmin, which was excluded in previous DES analyses that did not model baryonic physics. We obtain \\(S_8=0.781^{+0.014}_{-0.015}\\) for the combined DES Y1+Planck EE+BAO analysis with a non-informative \\(Q_1\\) prior. In terms of the baryon constraints, we measure \\(Q_1=1.14^{+2.20}_{-2.80}\\) for DES Y1 only and \\(Q_1=1.42^{+1.63}_{-1.48}\\) for DESY1+Planck EE+BAO, allowing us to exclude one of the most extreme AGN feedback hydrodynamical scenario at more than \\(2 \\sigma\\).

We perform a joint analysis of the counts and weak lensing signal of redMaPPer clusters selected from the Dark Energy Survey (DES) Year 1 dataset. Our analysis uses the same shear and source photometric redshifts estimates as were used in the DES combined probes analysis. Our analysis results in surprisingly low values for \\(S_8 =\\sigma_8(\\Omega_{\\rm m}/0.3)^{0.5}= 0.65\\pm 0.04\\), driven by a low matter density parameter, \\(\\Omega_{\\rm m}=0.179^{+0.031}_{-0.038}\\), with \\(\\sigma_8-\\Omega_{\\rm m}\\) posteriors in \\(2.4\\sigma\\) tension with the DES Y1 3x2pt results, and in \\(5.6\\sigma\\) with the Planck CMB analysis. These results include the impact of post-unblinding changes to the analysis, which did not improve the level of consistency with other data sets compared to the results obtained at the unblinding. The fact that multiple cosmological probes (supernovae, baryon acoustic oscillations, cosmic shear, galaxy clustering and CMB anisotropies), and other galaxy cluster analyses all favor significantly higher matter densities suggests the presence of systematic errors in the data or an incomplete modeling of the relevant physics. Cross checks with X-ray and microwave data, as well as independent constraints on the observable--mass relation from SZ selected clusters, suggest that the discrepancy resides in our modeling of the weak lensing signal rather than the cluster abundance. Repeating our analysis using a higher richness threshold (\\(\\lambda \\ge 30\\)) significantly reduces the tension with other probes, and points to one or more richness-dependent effects not captured by our model.