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

Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study

Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown

Catalytic mechanism of Phenylacetone monooxygenases for non-native linear substrates: implications on rational engineering of BVMOs to expand the substrate specificity

In this work, we provide, for the first time, the catalytic mechanism of PAMO for the native substrate phenylacetone as well as for a linear non-native substrate 2-octanone.</p

miRNA detection frequency.

<p>Most highly detected miRNAs grouped on mature sequence, normalised to total annotated reads (expressed in reads per million mapped (RPMM) from 3 rat mid-myocardial samples).</p

Epicardial/endocardial differential expression of unique sequences (≥ ±2 fold difference for miRs of ≥100 mean normalised reads detected in either layer). P<0.05 Baggerleys multiple comparison test.

<p>Epicardial/endocardial differential expression of unique sequences (≥ ±2 fold difference for miRs of ≥100 mean normalised reads detected in either layer). P<0.05 Baggerleys multiple comparison test.</p

Epicardial/endocardial differential expression of exact mature (or mature*) miRNAs (≥ ±1.5 fold difference for miRs of ≥10 raw reads detected in either layer).

<p>P<0.001,</p><p>P<0.01, Baggerleys multiple comparison test.</p

Differential suppression of a gelsolin sequence-tagged reporter gene by miR-133a isomiRs.

<p>HEK293 cells were transfected with expression plasmids encoding mCherry with a 3′ partial gelsolin sequence and pSM30 containing inserts for miR-133a, miR-133a(v), a random non-targeting sequence (NTC) or siRNA against mCherry (siR-mCh). Cells were imaged and analysed for both green and red fluorescence intensity. A decrease in red/green ratio <i>vs</i> NTC indicates downregulation of target gene expression. Data were log transformed and compared by one-way ANOVA with Bonferroni's Multiple Comparison Test. All pairwise comparisons were significant (p<.001). Comparison of miR-133a <i>vs</i> miR-133a(v) is indicated (***). Number of cells (n): miR-133a 4640; miR-133a(v) 2843; NTC 4088; siR-mCh 3884. Representative of 3 separate experiments in which miR-133a(v) was significantly more effective than miR-133a.</p

Length distribution analysis of small RNA sequences in 3 mid-myocardial rat samples.

<p>Reads greater than 12 nt are included. Red bars represent reads annotated to known rat miRNAs (miRBase v18), green bars represent reads annotated to miRNAs in other species (novel orthologs) and black bars represent unannotated small RNA sequences.</p

Epicardial/endocardial differential expression of 'grouped on mature' miRNAs (≥ ±1.5 fold difference for miRs of ≥10 raw reads detected in either layer).

<p>P<0.001.</p><p>P<0.01,</p><p>P<0.05 Baggerleys multiple comparison test.</p

Pathway analysis of MAP Kinase signaling (Kegg pathway).

<p>Highlighted genes are targets predicted by 2 or more algorithms of the top 16 highest detected miRNAs (boxed in red; P = 1.86×10⁻⁶; 75 targets) showing overlap with genes expressed in the heart (highlighted; expression data 9 SD rat left ventricular myocardium samples from 2 microarray experiments, (GSE6943; GSM160095–100 & GSE6880; GSM158589–91; <a href="http://www.ncbi.nlm.nih.gov/gds" target="_blank">http://www.ncbi.nlm.nih.gov/gds</a>).</p