Symfind: Addressing the Fragility of Subhalo Finders and Revealing the Durability of Subhalos

A major question in $\Lambda$CDM is what this theory actually predicts for the properties of subhalo populations. Subhalos are difficult to simulate and to find within simulations, and this propagates into uncertainty in theoretical predictions for satellite galaxies. We present Symfind, a new particle-tracking-based subhalo finder, and demonstrate that it can track subhalos to orders-of-magnitude lower masses than commonly used halo-finding tools, with a focus on Rockstar and consistent-trees. These longer survival mean that at a fixed peak subhalo mass, we find $\approx 15\%{-}40\%$ more subhalos within the virial radius, $R_\textrm{vir}$, and $\approx 35\%-120\%$ more subhalos within $R_\textrm{vir}/4$ in the Symphony dark-matter-only simulation suite. More subhalos are found as resolution is increased. We perform extensive numerical testing. In agreement with idealized simulations, we show that the $v_{\rm max}$ of subhalos is only resolved at high resolutions ($n_\textrm{peak}\gtrsim3\times 10^4$), but that mass loss itself can be resolved at much more modest particle counts ($n_\textrm{peak}\gtrsim4\times 10^3$). We show that Rockstar converges to false solutions for the mass function, radial distribution, and disruption masses of subhalos. We argue that our new method can trace resolved subhalos until the point of typical galaxy disruption without invoking ``orphan'' modeling. We outline a concrete set of steps for determining whether other subhalo finders meet the same criteria. We publicly release Symfind catalogs and particle data for the Symphony simulation suite at \url{http://web.stanford.edu/group/gfc/symphony}.Comment: 45 pages, 19 figure

Analysis of an artificial zinc finger epigenetic modulator: widespread binding but limited regulation

Artificial transcription factors (ATFs) and genomic nucleases based on a DNA binding platform consisting of multiple zinc finger domains are currently being developed for clinical applications. However, no genome-wide investigations into their binding specificity have been performed. We have created six-finger ATFs to target two different 18 nt regions of the human SOX2 promoter; each ATF is constructed such that it contains or lacks a super KRAB domain (SKD) that interacts with a complex containing repressive histone methyltransferases. ChIP-seq analysis of the effector-free ATFs in MCF7 breast cancer cells identified thousands of binding sites, mostly in promoter regions; the addition of an SKD domain increased the number of binding sites ∼5-fold, with a majority of the new sites located outside of promoters. De novo motif analyses suggest that the lack of binding specificity is due to subsets of the finger domains being used for genomic interactions. Although the ATFs display widespread binding, few genes showed expression differences; genes repressed by the ATF-SKD have stronger binding sites and are more enriched for a 12 nt motif. Interestingly, epigenetic analyses indicate that the transcriptional repression caused by the ATF-SKD is not due to changes in active histone modifications

Programmatic use of molecular xenomonitoring at the level of evaluation units to assess persistence of lymphatic filariasis in Sri Lanka

BACKGROUND:Sri Lanka's Anti Filariasis Campaign distributed 5 rounds of mass drug administration (MDA with DEC plus albendazole) to all endemic regions in the country from 2002-2006. Post-MDA surveillance results have generally been encouraging. However, recent studies have documented low level persistence of Wuchereria bancrofti in Galle district based on comprehensive surveys that include molecular xenomonitoring (MX, detection of filarial DNA in mosquitoes) results. The purposes of this study were to demonstrate the use of MX in large evaluation units (EUs) and to field test different mosquito sampling schemes. METHODOLOGY/PRINCIPAL FINDINGS:Galle district (population 1.1 million) was divided into two EUs. These included a coastal EU with known persistent LF and an inland EU with little persistent LF. Mosquitoes were systematically sampled from ~300 trap locations in 30 randomly selected clusters (health administrative units) per EU. Approximately 28,000 Culex quinquefasciatus were collected with gravid traps and tested for filarial DNA by qPCR. 92/625 pools (14.7%) from the coastal EU and 8/583 pools (1.4%) from the inland EU were positive for filarial DNA. Maximum likelihood estimates (MLE) for filarial DNA rates were essentially the same when the same number of mosquito pools were collected and tested from 75, 150, or 300 trap sites (range 0.61-0.78% for the coastal EU and 0.04-0.07% for the inland EU). The ability to use a smaller number of trap sites reduces the cost and time required for mosquito sampling. CONCLUSIONS/SIGNIFICANCE:These results suggest there is widespread persistence of W. bancrofti infection in the coastal Galle EU 8 years after the last round of MDA in 2006, and this is consistent with other data from the district. This study has shown that MX can be used by national programs to assess and map the persistence of W. bancrofti at the level of large EUs in areas with Culex transmission

Healthy lifestyle and life expectancy with and without Alzheimer's dementia: population based cohort study.

OBJECTIVE To determine the impact of lifestyle factors on life expectancy lived with and without Alzheimer's dementia. DESIGN Prospective cohort study. SETTING The Chicago Health and Aging Project, a population based cohort study in the United States. PARTICIPANTS 2449 men and women aged 65 years and older. MAIN EXPOSURE A healthy lifestyle score was developed based on five modifiable lifestyle factors: a diet for brain health (Mediterranean-DASH Diet Intervention for Neurodegenerative Delay-MIND diet score in upper 40% of cohort distribution), late life cognitive activities (composite score in upper 40%), moderate or vigorous physical activity (≥150 min/week), no smoking, and light to moderate alcohol consumption (women 1-15 g/day; men 1-30 g/day). MAIN OUTCOME Life expectancy with and without Alzheimer's dementia in women and men. RESULTS Women aged 65 with four or five healthy factors had a life expectancy of 24.2 years (95% confidence interval 22.8 to 25.5) and lived 3.1 years longer than women aged 65 with zero or one healthy factor (life expectancy 21.1 years, 19.5 to 22.4). Of the total life expectancy at age 65, women with four or five healthy factors spent 10.8% (2.6 years, 2.0 to 3.3) of their remaining years with Alzheimer's dementia, whereas women with zero or one healthy factor spent 19.3% (4.1 years, 3.2 to 5.1) with the disease. Life expectancy for women aged 65 without Alzheimer's dementia and four or five healthy factors was 21.5 years (20.0 to 22.7), and for those with zero or one healthy factor it was 17.0 years (15.5 to 18.3). Men aged 65 with four or five healthy factors had a total life expectancy of 23.1 years (21.4 to 25.6), which is 5.7 years longer than men aged 65 with zero or one healthy factor (life expectancy 17.4 years, 15.8 to 20.1). Of the total life expectancy at age 65, men with four or five healthy factors spent 6.1% (1.4 years, 0.3 to 2.0) of their remaining years with Alzheimer's dementia, and those with zero or one healthy factor spent 12.0% (2.1 years, 0.2 to 3.0) with the disease. Life expectancy for men aged 65 without Alzheimer's dementia and four or five healthy factors was 21.7 years (19.7 to 24.9), and for those with zero or one healthy factor life expectancy was 15.3 years (13.4 to 19.1). CONCLUSION A healthy lifestyle was associated with a longer life expectancy among men and women, and they lived a larger proportion of their remaining years without Alzheimer's dementia. The life expectancy estimates might help health professionals, policy makers, and stakeholders to plan future healthcare services, costs, and needs

The PhanSST global database of Phanerozoic sea surface temperature proxy data

Paleotemperature proxy data form the cornerstone of paleoclimate research and are integral to understanding the evolution of the Earth system across the Phanerozoic Eon. Here, we present PhanSST, a database containing over 150,000 data points from five proxy systems that can be used to estimate past sea surface temperature. The geochemical data have a near-global spatial distribution and temporally span most of the Phanerozoic. Each proxy value is associated with consistent and queryable metadata fields, including information about the location, age, and taxonomy of the organism from which the data derive. To promote transparency and reproducibility, we include all available published data, regardless of interpreted preservation state or vital effects. However, we also provide expert-assigned diagenetic assessments, ecological and environmental flags, and other proxy-specific fields, which facilitate informed and responsible reuse of the database. The data are quality control checked and the foraminiferal taxonomy has been updated. PhanSST will serve as a valuable resource to the paleoclimate community and has myriad applications, including evolutionary, geochemical, diagenetic, and proxy calibration studies

The PhanSST global database of Phanerozoic sea surface temperature proxy data

Paleotemperature proxy data form the cornerstone of paleoclimate research and are integral to understanding the evolution of the Earth system across the Phanerozoic Eon. Here, we present PhanSST, a database containing over 150,000 data points from five proxy systems that can be used to estimate past sea surface temperature. The geochemical data have a near-global spatial distribution and temporally span most of the Phanerozoic. Each proxy value is associated with consistent and queryable metadata fields, including information about the location, age, and taxonomy of the organism from which the data derive. To promote transparency and reproducibility, we include all available published data, regardless of interpreted preservation state or vital effects. However, we also provide expert-assigned diagenetic assessments, ecological and environmental flags, and other proxy-specific fields, which facilitate informed and responsible reuse of the database. The data are quality control checked and the foraminiferal taxonomy has been updated. PhanSST will serve as a valuable resource to the paleoclimate community and has myriad applications, including evolutionary, geochemical, diagenetic, and proxy calibration studies

Rare and low-frequency coding variants alter human adult height

Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome - wide association studies . Here , we report 83 height - associated coding variants with lower minor allele frequenc ies ( range of 0.1 - 4.8% ) and effects of up to 2 16 cm /allele ( e.g. in IHH , STC2 , AR and CRISPLD2 ) , >10 times the average effect of common variants . In functional follow - up studies, rare height - increasing alleles of STC2 (+1 - 2 cm/allele) compromise d proteolytic inhibition of PAPP - A and increased cleavage of IGFBP - 4 in vitro , resulting in higher bioavailability of insulin - like growth factors . The se 83 height - associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates ( e.g. ADAMTS3, IL11RA, NOX4 ) and pathways ( e.g . proteoglycan/ glycosaminoglycan synthesis ) involved in growth . Our results demonstrate that sufficiently large sample sizes can uncover rare and low - frequency variants of moderate to large effect associated with polygenic human phenotypes , and that these variants implicate relevant genes and pathways

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery