scholarly journals Functional characterization of 3D protein structures informed by human genetic diversity

2019 ◽  
Vol 116 (18) ◽  
pp. 8960-8965 ◽  
Author(s):  
Michael Hicks ◽  
Istvan Bartha ◽  
Julia di Iulio ◽  
J. Craig Venter ◽  
Amalio Telenti

Sequence variation data of the human proteome can be used to analyze 3D protein structures to derive functional insights. We used genetic variant data from nearly 140,000 individuals to analyze 3D positional conservation in 4,715 proteins and 3,951 homology models using 860,292 missense and 465,886 synonymous variants. Sixty percent of protein structures harbor at least one intolerant 3D site as defined by significant depletion of observed over expected missense variation. Structural intolerance data correlated with deep mutational scanning functional readouts for PPARG, MAPK1/ERK2, UBE2I, SUMO1, PTEN, CALM1, CALM2, and TPK1 and with shallow mutagenesis data for 1,026 proteins. The 3D structural intolerance analysis revealed different features for ligand binding pockets and orthosteric and allosteric sites. Large-scale data on human genetic variation support a definition of functional 3D sites proteome-wide.

2017 ◽  
Author(s):  
Michael Hicks ◽  
Istvan Bartha ◽  
Julia di Iulio ◽  
Ruben Abagyan ◽  
J. Craig Venter ◽  
...  

Sequence variation data of the human proteome can be used to analyze 3-dimensional (3D) protein structures to derive functional insights. We used genetic variant data from nearly 150,000 individuals to analyze 3D positional conservation in 4,390 protein structures using 481,708 missense and 264,257 synonymous variants. Sixty percent of protein structures harbor at least one intolerant 3D site as defined by significant depletion of observed over expected missense variation. We established an Angstrom-scale distribution of annotated pathogenic missense variants and showed that they accumulate in proximity to the most intolerant 3D sites. Structural intolerance data correlated with experimental functional read-outsin vitro. The 3D structural intolerance analysis revealed characteristic features of ligand binding pockets, orthosteric and allosteric sites. The identification of novel functional 3D sites based on human genetic data helps to validate, rank or predict drug target binding sitesin vivo.


2018 ◽  
Vol 33 (2) ◽  
pp. 1-25
Author(s):  
Yael Halevi-Wise ◽  
Madeleine Gottesman

This article charts the international reception of modern Hebrew literature over the last hundred years. It brings large-scale data on the translation of Hebrew literature into conversation with current studies on the dissemination of ‘small’ languages around the world. We pay special attention to publishing trends, genres, literary awards, and other indicators of international recognition. More broadly, we question the scope and definition of a body of literature whose ancient traces have become invisible through translation and whose international readership includes, to some extent, members of its ‘own’ nation who do not share, however, the same language, territory, or cultural experiences. Our goal is to provide a more nuanced understanding of the presence of Hebrew literature beyond its national borders.


Author(s):  
Benito van der Zander

Pattern matching in a broad sense is a common feature of modern functional programming languages, answering the question, if one complex structured object has a form that is the same as another complex structured object, for some definition of “the same”. In XQuery path expressions, switch, and typeswitch statements are often described as performing pattern matching, but these are merely impoverished flavors of matching when compared to the real thing. We describe a syntax for general pattern matching based on regular expressions for XML/HTML/JSONiq trees, how these patterns are matched against input data, and how this pattern matching can be integrated into the syntax and semantics of the XQuery language. At the end we summarize real-world experience using it for large-scale data mining of library webcatalogs.


Lingua Sinica ◽  
2020 ◽  
Vol 6 (1) ◽  
pp. 1-24
Author(s):  
Yipu Wei ◽  
Dirk Speelman ◽  
Jacqueline Evers-Vermeul

Abstract Collocation analysis can be used to extract meaningful linguistic information from large-scale corpus data. This paper reviews the methodological issues one may encounter when performing collocation analysis for discourse studies on Chinese. We propose four crucial aspects to consider in such analyses: (i) the definition of collocates according to various parameters; (ii) the choice of analysis and association measures; (iii) the definition of the search span; and (iv) the selection of corpora for analysis. To illustrate how these aspects can be addressed when applying a Chinese collocation analysis, we conducted a case study of two Chinese causal connectives: yushi ‘that is why’ and yin’er ‘as a result’. The distinctive collocation analysis shows how these two connectives differ in volitionality, an important dimension of discourse relations. The study also demonstrates that collocation analysis, as an explorative approach based on large-scale data, can provide valuable converging evidence for corpus-based studies that have been conducted with laborious manual analysis on limited datasets.


PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0251513
Author(s):  
Barry Smyth

Introduction In the marathon, how runners pace and fuel their race can have a major impact on race outcome. The phenomenon known as hitting the wall (HTW) refers to the iconic hazard of the marathon distance, in which runners experience a significant slowing of pace late in the race, typically after the 20-mile mark, and usually because of a depletion of the body’s energy stores. Aim This work investigates the occurrence of significant late-race slowing among recreational marathoners, as a proxy for runners hitting the wall, to better understand the likelihood and nature of such slowdowns, and their effect on race performance. Methods Using pacing data from more than 4 million race records, we develop a pacing-based definition of hitting the wall, by identifying runners who experience a sustained period of slowing during the latter stages of the marathon. We calculate the cost of these slowdowns relative to estimates of the recent personal-best times of runners and compare slowdowns according to runner sex, age, and ability. Results We find male runners more likely to slow significantly (hit the wall) than female runners; 28% of male runners hit the wall compared with 17% of female runners, χ2(1, N = 1, 928, 813) = 27, 693.35, p < 0.01, OR = 1.43. Such slowdowns are more frequent in the 3 years immediately before and after a recent personal-best (PB) time; for example, 36% of all runners hit the wall in the 3 years before a recent PB compared with just 23% in earlier years, χ2(1, N = 509, 444) = 8, 120.74, p < 0.01, OR = 1.31. When runners hit the wall, males slow more than females: a relative slowdown of 0.40 vs. 0.37 is noted, for male and female runners, when comparing their pace when they hit the wall to their earlier race (5km-20km) pace, with t(475, 199) = 60.19, p < 0.01, d = 0.15. And male runners slow over longer distances than female runners: 10.7km vs. 9.6km, respectively, t(475, 199) = 68.44, p < 0.01, d = 0.17. Although, notably the effect size of these differences is small. We also find the finish-time costs of hitting the wall (lost minutes) to increase with ability; r2(7) = 0.91, p < 0.01 r2(7) = 0.81, p < 0.01 for male and female runners, respectively. Conclusions While the findings from this study are consistent with qualitative results from earlier single-race or smaller-scale studies, the new insights into the risk and nature of slowdowns, based on the runner sex, age, and ability, have the potential to help runners and coaches to better understand and calibrate the risk/reward trade-offs that exist as they plan for future races.


2020 ◽  
Vol 6 (3) ◽  
pp. 173-186
Author(s):  
Jakim Berndsen ◽  
Aonghus Lawlor ◽  
Barry Smyth

The wall is an iconic feature of the marathon. If runners hit the wall, usually around the 30km (20mi) mark, their pace slows dramatically, leaving them to struggle to the finish-line. While the physiology of the wall is reasonably well understood – a critical combination of fatigue and a lack of available fuel as the body’s glycogen stores become depleted – its actual impact is less well studied. In this paper we present a large-scale data-driven study of how and when recreational marathon runners hit the wall. We do this by analysing the pacing patterns of almost 60,000 runners across more than 250 races. The main contributions are: (1) an operational definition of the wall by identifying its key pacing features; and (2) and analysis of hitting the wall for runners, based on their age, gender and ability, using this definition.


2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Si Wu ◽  
Roslyn N. Brown ◽  
Samuel H. Payne ◽  
Da Meng ◽  
Rui Zhao ◽  
...  

The periplasm of Gram-negative bacteria is a dynamic and physiologically important subcellular compartment where the constant exposure to potential environmental insults amplifies the need for proper protein folding and modifications. Top-down proteomics analysis of the periplasmic fraction at the intact protein level provides unrestricted characterization and annotation of the periplasmic proteome, including the post-translational modifications (PTMs) on these proteins. Here, we used single-dimension ultra-high pressure liquid chromatography coupled with the Fourier transform mass spectrometry (FTMS) to investigate the intact periplasmic proteome of Novosphingobium aromaticivorans. Our top-down analysis provided the confident identification of 55 proteins in the periplasm and characterized their PTMs including signal peptide removal, N-terminal methionine excision, acetylation, glutathionylation, pyroglutamate, and disulfide bond formation. This study provides the first experimental evidence for the expression and periplasmic localization of many hypothetical and uncharacterized proteins and the first unrestrictive, large-scale data on PTMs in the bacterial periplasm.


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