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1. Efficient and effective control of confounding in eQTL mapping studies through joint differential expression and Mendelian randomization analyses

   https://doi.org/10.1093/bioinformatics/btaa715  

   Fan, Yue ; Zhu, Huanhuan ; Song, Yanyi ; Peng, Qinke ; Zhou, Xiang ( February 2021 , Bioinformatics)

   Robinson, Peter (Ed.)

   Identifying cis-acting genetic variants associated with gene expression levels—an analysis commonly referred to as expression quantitative trait loci (eQTLs) mapping—is an important first step toward understanding the genetic determinant of gene expression variation. Successful eQTL mapping requires effective control of confounding factors. A common method for confounding effects control in eQTL mapping studies is the probabilistic estimation of expression residual (PEER) analysis. PEER analysis extracts PEER factors to serve as surrogates for confounding factors, which is further included in the subsequent eQTL mapping analysis. However, it is computationally challenging to determine the optimal number of PEER factors used for eQTL mapping. In particular, the standard approach to determine the optimal number of PEER factors examines one number at a time and chooses a number that optimizes eQTLs discovery. Unfortunately, this standard approach involves multiple repetitive eQTL mapping procedures that are computationally expensive, restricting its use in large-scale eQTL mapping studies that being collected today.

   Here, we present a simple and computationally scalable alternative, Effect size Correlation for COnfounding determination (ECCO), to determine the optimal number of PEER factors used for eQTL mapping studies. Instead of performing repetitive eQTL mapping, ECCO jointly applies differential expression analysis and Mendelian randomization analysis, leading to substantial computational savings. In simulations and real data applications, we show that ECCO identifies a similar number of PEER factors required for eQTL mapping analysis as the standard approach but is two orders of magnitude faster. The computational scalability of ECCO allows for optimized eQTL discovery across 48 GTEx tissues for the first time, yielding an overall 5.89% power gain on the number of eQTL harboring genes (eGenes) discovered as compared to the previous GTEx recommendation that does not attempt to determine tissue-specific optimal number of PEER factors.

   Our method is implemented in the ECCO software, which, along with its GTEx mapping results, is freely available at www.xzlab.org/software.html. All R scripts used in this study are also available at this site.

   Supplementary data are available at Bioinformatics online.

    

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2. Structure and role for active site lid of lactate monooxygenase from Mycobacterium smegmatis

   https://doi.org/10.1002/pro.3506  

   Kean, Kelsey M. ; Karplus, P. Andrew ( October 2018 , Protein Science)

   Lactate monooxygenase (LMO) catalyzes the FMN‐dependent “coupled” oxidation of lactate and O₂to acetate, carbon dioxide, and water, involving pyruvate and hydrogen peroxide as enzyme‐bound intermediates. Other α‐hydroxy acid oxidase family members follow an “uncoupled pathway,” wherein the α‐keto acid product quickly dissociates before the reduced flavin reacts with oxygen. Here, we report the structures ofMycobacterium smegmatiswild‐type LMO and a wild‐type‐like C203A variant at 2.1 Å and 1.7 Å resolution, respectively. The overall LMO fold and active site organization, including a bound sulfate mimicking substrate, resemble those of other α‐hydroxy acid oxidases. Based on structural similarity, LMO is similarly distant from lactate oxidase, glycolate oxidase, mandelate dehydrogenase, and flavocytochrome b₂and is the first representative enzyme of its type. Comparisons with other α‐hydroxy acid oxidases reveal that LMO has a longer and more compact folded active site loop (Loop 4), which is known in related flavoenzymes to undergo order/disorder transitions to allow substrate/product binding and release. We propose that LMO's Loop 4 has an enhanced stability that is responsible for the slow product release requisite for the coupled pathway. We also note electrostatic features of the LMO active site that promote substrate binding. Whereas the physiological role of LMO remains unknown, we document what can currently be assessed of LMO's distribution in nature, including its unexpected occurrence, presumably through horizontal gene transfer, in halophilic archaea and in a limited group of fungi of the genusBeauveria.

   This first crystal structure of the FMN‐dependent α‐hydroxy acid oxidase family member lactate monooxygenase (LMO) reveals it has a uniquely large active site lid that we hypothesize is stable enough to explain the slow dissociation of pyruvate that leads to its “coupled” oxidation of lactate and O₂to produce acetate, carbon dioxide, and water. Also, the relatively widespread distribution of putative LMOs supports their importance and provides new motivation for their further study.

    

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3. Catching a nova X-ray/UV flash in the visible? Early spectroscopy of the very slow Nova Velorum 2022 (Gaia22alz)

   https://doi.org/10.1093/mnras/stad1914  

   Aydi, E. ; Chomiuk, L. ; Mikołajewska, J. ; Brink, J. ; Metzger, B. D. ; Strader, J. ; Buckley, D. A. H. ; Harvey, E. J. ; Holoien, T. W. -S ; Izzo, L. ; et al ( June 2023 , Monthly Notices of the Royal Astronomical Society)

   We present early spectral observations of the very slow Galactic nova Gaia22alz, over its gradual rise to peak brightness that lasted 180 d. During the first 50 d, when the nova was only 3–4 mag above its normal brightness, the spectra showed narrow (FWHM ≈ 400 km s−1) emission lines of H Balmer, He i, He ii, and C iv but no P Cygni absorption. A few weeks later, the high-excitation He ii and C iv lines disappeared, and P Cygni profiles of Balmer, He i, and eventually Fe ii lines emerged, yielding a spectrum typical of classical novae before peak. We propose that the early (first 50 d) spectra of Gaia22alz, particularly the emission lines with no P Cygni profiles, are produced in the white dwarf’s optically thin envelope or accretion disc, reprocessing ultraviolet and potentially X-ray emission from the white dwarf after a dramatic increase in the rate of thermonuclear reactions, during a phase known as the ‘early X-ray/UV flash’. If true, this would be one of the rare times that the optical signature of the early X-ray/UV flash has been detected. While this phase might last only a few hours in other novae and thus be easily missed, it was possible to detect in Gaia22alz due to its very slow and gradual rise and thanks to the efficiency of new all-sky surveys in detecting transients on their rise. We also consider alternative scenarios that could explain the early spectral features of Gaia22alz and its gradual rise.

    

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4. Bluehead chub Nocomis leptocephalus hosts exploit selfish‐herd benefits from their heterospecific nest associates

   https://doi.org/10.1111/fwb.14224  

   Betts, Madison M. ; Abaid, Nicole ; Maurakis, Eugene G. ; Frimpong, Emmanuel A. ( January 2024 , Freshwater Biology)

   Prey species often congregate in groups to detect and evade predators, yet not all group members benefit equally. We observed the nesting aggregations of bluehead chub (Nocomis leptocephalus), where one nest “hosts” as many as several hundred “nest associates.” We predicted that the male chub exploits the aggregation in a manner consistent with selfish‐herd theory – specifically, by locating itself in the safest location within the aggregation (the centre) and using the aggregation to reduce its own vigilance requirements.

   Vigilance was measured as the time it took the host (male) chub, first chub female and first individual of each associate species to return to the nest under differing associate abundances (hypothesised to be inversely related to risk) following a simulated predator scare. Spatial position was investigated by digitising host movement and overlaying it with the aggregation and nest's spawning pit area.

   We used information theoretic statistics to analyse the effect of aggregation characteristics on the return time of chub and their nest associates. The best‐supported model included both species composition and abundance (inverse of risk) as predictors of return time. Hosts returned last under nearly all scenarios and the aggregation as a whole took longest to return in high‐risk environments. The 95% and 99% confidence ellipses of host spatial position contained the centroids of the aggregation and spawning pits, respectively, for all nests analysed (n = 11).

   We conclude that the host locates itself at the centre of both the aggregation and the spawning pit area of the nest, and that the host uses the aggregation to reduce its own vigilance requirements. These results support our hypothesis that hosts use their nest associates to disproportionately decrease their risk of predation during spawning.

   This is the first study to show any mixed‐species fish spawning aggregation as a selfish shoal, and to identify bluehead chub as a selfish participant in the mutualistic reproductive interactions that they host.

    

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5. Radial growth response to climate change along the latitudinal range of the world's southernmost conifer in southern South America

   https://doi.org/10.1111/jbi.13199  

   Holz, Andrés ; Hart, Sarah J. ; Williamson, Grant J. ; Veblen, Thomas T. ; Aravena, Juan C. ( March 2018 , Journal of Biogeography)

   We examined whether and how tree radial‐growth responses to climate have changed for the world's southernmost conifer species throughout its latitudinal distribution following rapid climate change in the second half of the 20th century.

   Temperate forests in southern South America.

   New and existing tree‐ring radial growth chronologies representing the entire latitudinal range ofPilgerodendron uviferumwere grouped according to latitude and then examined for differences in growth trends and non‐stationarity in growth responses to a drought severity index (scPDSI) over the 1900–1993ADperiod and also before and after significant shifts in climate in the 1950s and 1970s.

   The radial‐growth response ofP. uviferumclimate was highly variable across its full latitudinal distribution. There was a long‐term and positive association between radial growth and higher moisture at the northern and southern edges of the distribution of this species and the opposite relationship for the core of its distribution, especially following the climatic shifts of the 1950s and 1970s. In addition, non‐stationarity in moisture‐radial growth relationships was observed in all three latitudinal groups (southern and northern edges and core) for all seasons during the 20th century.

   Climate shifts in southern South America in the 1950s and 1970s resulted in different responses in the mean radial growth ofP. uviferumat the southern and northern edges and at the core of its range. Dendroclimatic analyses document that during the first half of the 20th century climate‐growth relationships were relatively similar between the southern and northern range edges but diverged after the 1950s. Our findings imply that simulated projections of climate impacts on tree growth, and by implication on forest ecosystem productivity, derived from models of past climate‐growth relationships need to carefully consider different and non‐stationarity responses along the wide latitudinal distribution of this species.

    

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