Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

COVID‐19 Affects Short‐Term, But Not 90‐Day, Outcome in Patients With Stroke Treated With Mechanical Thrombectomy

Background COVID‐19 is associated with an increased stroke risk. Moreover, outcome at discharge was worse in patients with large‐vessel occlusion stroke with concomitant COVID‐19 receiving endovascular treatment (ET). We aimed to investigate the impact of concomitant COVID‐19 on later functional outcome in patients with large‐vessel occlusion stroke treated with ET. Methods We analyzed patients from the GSR‐ET (German Stroke Registry–Endovascular Treatment), an observational multicenter registry of patients with large‐vessel occlusion stroke receiving ET. Baseline characteristics, procedural parameters, discharge parameters, and functional outcome at 90 days were compared between patients with concomitant COVID‐19 and propensity score–matched controls (ratio, 1:4; matched for age, sex, prestroke modified Rankin Scale score, and stroke severity), and multivariable ordinal regression analysis was performed. Results Among 4010 patients receiving ET between February 2020 and December 2021, 72 (1.8%) had concomitant COVID‐19. Compared with 224 matched patients without COVID‐19, they (n=56) were more severely affected, with a higher median National Institutes of Health Stroke Scale (NIHSS) score after 24 hours (NIHSS score, 14.5 [interquartile range {IQR}, 9–22] versus 12 [IQR, 6–18.75]; P=0.015), and NIHSS score and modified Rankin Scale score at discharge (NIHSS score, 12 [IQR, 6.75‐16.75] versus 6 [IQR, 2–13]; P=0.001; and modified Rankin Scale score, 5 [IQR, 4–5] versus 4 [IQR, 2–5]; P=0.023), but functional outcome at 90‐day follow‐up was similar (modified Rankin Scale score, 4 [IQR, 4–6] versus 4 [IQR, 2–6]; P=0.34). After adjustment for prespecified confounders, COVID‐19 was associated with worse functional outcome at discharge (common odds ratio [OR], 0.40 [95% CI, 0.19–0.80]; P=0.011), but not at 90‐day follow‐up (common OR, 0.72 [95% CI, 0.32–1.60]; P=0.43). Conclusions COVID‐19 affected short‐term, but not 90‐day, functional outcome in patients with large‐vessel occlusion stroke treated with ET. Hence, ET should not be withheld in patients with concomitant COVID‐19

Graded murine wire-induced aortic valve stenosis model mimics human functional and morphological disease phenotype

Aortic valve stenosis (AS) is the most common valve disease requiring therapeutic intervention. Even though the incidence of AS has been continuously rising and AS is associated with significant morbidity and mortality, to date, no medical treatments have been identified that can modify disease progression. This unmet medical need is likely attributed to an incomplete understanding of the molecular mechanism driving disease development. To investigate the pathophysiology leading to AS, reliable and reproducible animal models that mimic human pathophysiology are needed. We have tested and expanded the protocols of a wire-injury induced AS mouse model. For this model, coronary wires were used to apply shear stress to the aortic valve cusps with increasing intensity. These protocols allowed distinction of mild, moderate and severe wire-injury. Upon moderate or severe injury, AS developed with a significant increase in aortic valve peak blood flow velocity. While moderate injury promoted solitary AS, severe-injury induced mixed aortic valve disease with concomitant mild to moderate aortic regurgitation. The changes in aortic valve function were reflected by dilation and hypertrophy of the left ventricle, as well as a decreased left ventricular ejection fraction. Histological analysis revealed the classic hallmarks of human disease with aortic valve thickening, increased macrophage infiltration, fibrosis and calcification. This new mouse model of AS promotes functional and morphological changes similar to moderate and severe human AS. It can be used to investigate the pathomechanisms contributing to AS development and to test novel therapeutic strategies

The DNA sequence of the human X chromosome

The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence