The intestine is a complex organ that promotes digestion, extracts nutrients, participates in immune surveillance, maintains critical symbiotic relationships with microbiota and affects overall ...health
. The intesting has a length of over nine metres, along which there are differences in structure and function
. The localization of individual cell types, cell type development trajectories and detailed cell transcriptional programs probably drive these differences in function. Here, to better understand these differences, we evaluated the organization of single cells using multiplexed imaging and single-nucleus RNA and open chromatin assays across eight different intestinal sites from nine donors. Through systematic analyses, we find cell compositions that differ substantially across regions of the intestine and demonstrate the complexity of epithelial subtypes, and find that the same cell types are organized into distinct neighbourhoods and communities, highlighting distinct immunological niches that are present in the intestine. We also map gene regulatory differences in these cells that are suggestive of a regulatory differentiation cascade, and associate intestinal disease heritability with specific cell types. These results describe the complexity of the cell composition, regulation and organization for this organ, and serve as an important reference map for understanding human biology and disease.
Many forces influence genetic variation across the genome including mutation, recombination, selection, and demography. Increased mutation and recombination both lead to increases in genetic ...diversity in a region-specific manner, while complex demographic patterns shape patterns of diversity on a more global scale. While these processes act across the entire genome, the X chromosome is particularly interesting because it contains several distinct regions that are subject to different combinations and strengths of these forces: the pseudoautosomal regions (PARs) and the X-transposed region (XTR). The X chromosome thus can serve as a unique model for studying how genetic and demographic forces act in different contexts to shape patterns of observed variation. We therefore sought to explore diversity, divergence, and linkage disequilibrium in each region of the X chromosome using genomic data from 26 human populations. Across populations, we find that both diversity and substitution rate are consistently elevated in PAR1 and the XTR compared to the rest of the X chromosome. In contrast, linkage disequilibrium is lowest in PAR1, consistent with the high recombination rate in this region, and highest in the region of the X chromosome that does not recombine in males. However, linkage disequilibrium in the XTR is intermediate between PAR1 and the autosomes, and much lower than the non-recombining X. Finally, in addition to these global patterns, we also observed variation in ratios of X versus autosomal diversity consistent with population-specific evolutionary history as well. While our results were generally consistent with previous work, two unexpected observations emerged. First, our results suggest that the XTR does not behave like the rest of the recombining X and may need to be evaluated separately in future studies. Second, the different regions of the X chromosome appear to exhibit unique patterns of linked selection across different human populations. Together, our results highlight profound regional differences across the X chromosome, simultaneously making it an ideal system for exploring the action of evolutionary forces as well as necessitating its careful consideration and treatment in genomic analyses.
Ancient Rome was the capital of an empire of ~70 million inhabitants, but little is known about the genetics of ancient Romans. Here we present 127 genomes from 29 archaeological sites in and around ...Rome, spanning the past 12,000 years. We observe two major prehistoric ancestry transitions: one with the introduction of farming and another prior to the Iron Age. By the founding of Rome, the genetic composition of the region approximated that of modern Mediterranean populations. During the Imperial period, Rome's population received net immigration from the Near East, followed by an increase in genetic contributions from Europe. These ancestry shifts mirrored the geopolitical affiliations of Rome and were accompanied by marked interindividual diversity, reflecting gene flow from across the Mediterranean, Europe, and North Africa.
Background
Serum creatinine and symmetric dimethylarginine (SDMA) are used as surrogate markers of glomerular filtration rate (GFR) in clinical practice. Data pertaining to the correlations between ...GFR, SDMA, and serum creatinine in client‐owned dogs are limited.
Objectives
To describe the relationship between GFR, SDMA, and serum creatinine in a population of client‐owned dogs, and to compare clinical utility of SDMA to GFR estimation for detecting pre‐azotemic chronic kidney disease.
Animals
Medical records of 119 dogs that had GFR estimation performed via serum iohexol clearance between 2012 and 2017.
Methods
Prospective study using archived samples. GFR, SDMA, and serum creatinine results were reviewed and submitting practices contacted for outcome data. All dogs included in the study population were non‐azotemic. Correlations between GFR, SDMA, and serum creatinine were determined by regression analysis. Sensitivity, specificity, and positive and negative likelihood ratios of different cutoffs for SDMA and serum creatinine for detecting decreased GFR were calculated, using a 95% confidence interval.
Results
Serum creatinine and SDMA were moderately correlated with GFR (R2 = 0.52 and 0.27, respectively, P < .0001) and with each other (R2 = 0.33, P < .0001). SDMA >14 μg/dL was sensitive (90%) but nonspecific (50%) for detecting a ≥40% decrease in GFR. Optimal SDMA concentration cutoff for detecting a ≥40% GFR decrease was >18 μg/dL (sensitivity 90%, specificity 83%).
Conclusions and Clinical Importance
In non‐azotemic dogs being screened for decreased renal function, using a cutoff of >18 μg/dL rather than >14 μg/dL increases the specificity of SDMA, without compromising sensitivity.
Abstract
In studying allele-frequency variation across populations, it is often convenient to classify an allelic type as “rare,” with nonzero frequency less than or equal to a specified threshold, ...“common,” with a frequency above the threshold, or entirely unobserved in a population. When sample sizes differ across populations, however, especially if the threshold separating “rare” and “common” corresponds to a small number of observed copies of an allelic type, discreteness effects can lead a sample from one population to possess substantially more rare allelic types than a sample from another population, even if the two populations have extremely similar underlying allele-frequency distributions across loci. We introduce a rarefaction-based sample-size correction for use in comparing rare and common variation across multiple populations whose sample sizes potentially differ. We use our approach to examine rare and common variation in worldwide human populations, finding that the sample-size correction introduces subtle differences relative to analyses that use the full available sample sizes. We introduce several ways in which the rarefaction approach can be applied: we explore the dependence of allele classifications on subsample sizes, we permit more than two classes of allelic types of nonzero frequency, and we analyze rare and common variation in sliding windows along the genome. The results can assist in clarifying similarities and differences in allele-frequency patterns across populations.
By providing additional opportunities for coalescence within families, the presence of consanguineous unions in a population reduces coalescence times relative to non-consanguineous populations. ...First-cousin consanguinity can take one of six forms differing in the configuration of sexes in the pedigree of the male and female cousins who join in a consanguineous union: patrilateral parallel, patrilateral cross, matrilateral parallel, matrilateral cross, bilateral parallel, and bilateral cross. Considering populations with each of the six types of first-cousin consanguinity individually and a population with a mixture of the four unilateral types, we examine coalescent models of consanguinity. We previously computed, for first-cousin consanguinity models, the mean coalescence time for X-chromosomal loci and the limiting distribution of coalescence times for autosomal loci. Here, we use the separation-of-time-scales approach to obtain the limiting distribution of coalescence times for X-chromosomal loci. This limiting distribution has an instantaneous coalescence probability that depends on the probability that a union is consanguineous; lineages that do not coalesce instantaneously coalesce according to an exponential distribution. We study the effects on the coalescence time distribution of the type of first-cousin consanguinity, showing that patrilateral-parallel and patrilateral-cross consanguinity have no effect on X-chromosomal coalescence time distributions and that matrilateral-parallel consanguinity decreases coalescence times to a greater extent than does matrilateral-cross consanguinity.
Consanguineous unions increase the frequency at which identical genomic segments are inherited along separate paths of descent, decreasing coalescence times for pairs of alleles drawn from an ...individual who is the offspring of a consanguineous pair. For an autosomal locus, it has recently been shown that the mean time to the most recent common ancestor (TMRCA) for two alleles in the same individual and the mean TMRCA for two alleles in two separate individuals both decrease with increasing consanguinity in a population. Here, we extend this analysis to the X chromosome, considering X-chromosomal coalescence times under a coalescent model with diploid, male–female mating pairs. We examine four possible first-cousin mating schemes that are equivalent in their effects on autosomes, but that have differing effects on the X chromosome: patrilateral-parallel, patrilateral-cross, matrilateral-parallel, and matrilateral-cross. In each mating model, we calculate mean TMRCA for X-chromosomal alleles sampled either within or between individuals. We describe a consanguinity effect on X-chromosomal TMRCA that differs from the autosomal pattern under matrilateral but not under patrilateral first-cousin mating. For matrilateral first cousins, the effect of consanguinity in reducing TMRCA is stronger on the X chromosome than on the autosomes, with an increased effect of parallel-cousin mating compared to cross-cousin mating. The theoretical computations support the utility of the model in understanding patterns of genomic sharing on the X chromosome.
Unlike the autosomes, recombination between the X chromosome and the Y chromosome is often thought to be constrained to two small pseudoautosomal regions (PARs) at the tips of each sex chromosome. ...PAR1 spans the first 2.7 Mb of the proximal arm of the human sex chromosomes, whereas the much smaller PAR2 encompasses the distal 320 kb of the long arm of each sex chromosome. In addition to PAR1 and PAR2, there is a human-specific X-transposed region that was duplicated from the X to the Y chromosome. The X-transposed region is often not excluded from X-specific analyses, unlike the PARs, because it is not thought to routinely recombine. Genetic diversity is expected to be higher in recombining regions than in nonrecombining regions because recombination reduces the effect of linked selection. In this study, we investigated patterns of genetic diversity in noncoding regions across the entire X chromosome of a global sample of 26 unrelated genetic females. We found that genetic diversity in PAR1 is significantly greater than in the nonrecombining regions (nonPARs). However, rather than an abrupt drop in diversity at the pseudoautosomal boundary, there is a gradual reduction in diversity from the recombining through the nonrecombining regions, suggesting that recombination between the human sex chromosomes spans across the currently defined pseudoautosomal boundary. A consequence of recombination spanning this boundary potentially includes increasing the rate of sex-linked disorders (e.g., de la Chapelle) and sex chromosome aneuploidies. In contrast, diversity in PAR2 is not significantly elevated compared to the nonPARs, suggesting that recombination is not obligatory in PAR2. Finally, diversity in the X-transposed region is higher than in the surrounding nonPARs, providing evidence that recombination may occur with some frequency between the X and Y chromosomes in the X-transposed region.
Patients undergoing a total shoulder arthroplasty (TSA) through a deltopectoral approach will require repair of the subscapularis tendon. There are no universal postoperative guidelines for ...rehabilitation of the subscapularis specifically. We hypothesize that the addition of a subscapularis-specific regimen will result in improved subscapularis strength and function.
Adult patients undergoing anatomic TSA for the treatment of primary glenohumeral osteoarthritis were included. Patients were randomized into either the traditional rehabilitation (TR) control group or the subscapularis rehabilitation (SR) group, which consisted of the traditional therapy along with early and additional subscapularis exercises. Baseline demographics, patient reported outcome measures(PROMs), range of motion (ROM), provocative tests, and subscapularis strength using a handheld dynamometer were measured preoperatively at the initial clinic visit (ICV) as well as 3-months, 6-months, and one-year postoperatively. The primary outcome of interest was a comparison of subscapularis strength between cohorts relative to preoperative baseline, while secondary outcomes were functional, ROM and PROMs.
Sixty-six patients were included in final analysis (32 TR vs 34 SR). There were no statistically significant differences between cohorts at the ICV with regards to demographics, baseline subscapularis strength, functional testing, or PROMs. All postoperative time points demonstrated similar subscapularis strength testing between TR and SR groups (p>0.05). Additionally, peak and average subscapularis strength testing at 3, 6, and 12 months postoperatively were similar to baseline ICV testing in both groups. Both groups demonstrated improvements across several provocative tests, ROM and PROM outcome metrics at every postoperative timepoint as compared to baseline ICV values (p<0.05).
Patients undergoing anatomic total shoulder arthroplasty return to baseline internal rotation strength by 3-months postoperatively and demonstrate significant improvements in function, range of motion, and several patient reported outcome measures. The addition of early and focused subscapularis strengthening exercises does not appear to significantly impact any outcomes when compared to traditional rehabilitation programs.
Abstract
Runs of homozygosity (ROH) and identity-by-descent (IBD) sharing can be studied in diploid coalescent models by noting that ROH and IBD-sharing at a genomic site are predicted to be ...inversely related to coalescence times—which in turn can be mathematically obtained in terms of parameters describing consanguinity rates. Comparing autosomal and X-chromosomal coalescent models, we consider ROH and IBD-sharing in relation to consanguinity that proceeds via multiple forms of first-cousin mating. We predict that across populations with different levels of consanguinity, (1) in a manner that is qualitatively parallel to the increase of autosomal IBD-sharing with autosomal ROH, X-chromosomal IBD-sharing increases with X-chromosomal ROH, owing to the dependence of both quantities on consanguinity levels; (2) even in the absence of consanguinity, X-chromosomal ROH and IBD-sharing levels exceed corresponding values for the autosomes, owing to the smaller population size and lower coalescence time for the X chromosome than for autosomes; (3) with matrilateral consanguinity, the relative increase in ROH and IBD-sharing on the X chromosome compared to the autosomes is greater than in the absence of consanguinity. Examining genome-wide SNPs in human populations for which consanguinity levels have been estimated, we find that autosomal and X-chromosomal ROH and IBD-sharing levels generally accord with the predictions. We find that each 1% increase in autosomal ROH is associated with an increase of 2.1% in X-chromosomal ROH, and each 1% increase in autosomal IBD-sharing is associated with an increase of 1.6% in X-chromosomal IBD-sharing. For each calculation, particularly for ROH, the estimate is reasonably close to the increase of 2% predicted by the population-size difference between autosomes and X chromosomes. The results support the utility of coalescent models for understanding patterns of genomic sharing and their dependence on sex-biased processes.
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