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We present avidity sequencing, a sequencing chemistry that separately optimizes the processes of stepping along a DNA template and that of identifying each nucleotide within the template. Nucleotide identification uses multivalent nucleotide ligands on dye-labeled cores to form polymerase–polymer–nucleotide complexes bound to clonal copies of DNA targets. These polymer–nucleotide substrates, termed avidites, decrease the required concentration of reporting nucleotides from micromolar to nanomolar and yield negligible dissociation rates. Avidity sequencing achieves high accuracy, with 96.2% and 85.4% of base calls having an average of one error per 1,000 and 10,000 base pairs, respectively. We show that the average error rate of avidity sequencing remained stable following a long homopolymer. A sequencing chemistry that separates nucleotide identification from nucleotide incorporation achieves high accuracy.

We present avidity sequencing - a novel sequencing chemistry that separately optimizes the process of stepping along a DNA template and the process of identifying each nucleotide within the template. Nucleotide identification uses multivalent nucleotide ligands on dye-labeled cores to form polymerase-polymer nucleotide complexes bound to clonal copies of DNA targets. These polymer-nucleotide substrates, termed avidites, decrease the required concentration of reporting nucleotides from micromolar to nanomolar, and yield negligible dissociation rates. We demonstrate the use of avidites as a key component of a sequencing technology that surpasses Q40 accuracy and enables a diversity of applications that include single cell RNA-seq and whole human genome sequencing. We also show the advantages of this technology in sequencing through long homopolymers.

Although Huntington’s disease (HD) is a well studied Mendelian genetic disorder, less is known about its associated epigenetic changes. Here, we characterize DNA methylation levels in six different tissues from 3 species: a mouse huntingtin (Htt) gene knock-in model, a transgenic HTT sheep model, and humans. Our epigenome-wide association study (EWAS) of human blood reveals that HD mutation status is significantly ( p  < 10 −7 ) associated with 33 CpG sites, including the HTT gene ( p  = 6.5 × 10 −26 ). These Htt/HTT associations were replicated in the Q175 Htt knock-in mouse model ( p  = 6.0 × 10 −8 ) and in the transgenic sheep model ( p  = 2.4 × 10 −88 ). We define a measure of HD motor score progression among manifest HD cases based on multiple clinical assessments. EWAS of motor progression in manifest HD cases exhibits significant ( p  < 10 −7 ) associations with methylation levels at three loci: near PEX14 ( p  = 9.3 × 10 −9 ), GRIK4 ( p  = 3.0 × 10 −8 ), and COX4I2 ( p  = 6.5 × 10 −8 ). We conclude that HD is accompanied by profound changes of DNA methylation levels in three mammalian species. Although Huntington’s disease (HD) is a well-studied genetic disorder, less is known about the epigenetic changes underlying it. Here, the authors characterize DNA methylation levels in tissues from patients, a mouse huntingtin (Htt) gene knock-in model, and a transgenic HTT sheep model, and provide evidence that HD is accompanied by DNA methylation changes in these three species.

Mingsheng Chen, Klaus Mayer, Steve Rounsley, Rod Wing and colleagues report the genome sequence of African rice ( Oryza glaberrima ), a different species than Asian rice. The authors resequenced 20 O. glaberrima accessions and 94 Oryza barthii accessions (the putative progenitor species of O. glaberrima ), and their analyses support the hypothesis that O. glaberrima was domesticated in a single region along the upper Niger river. The cultivation of rice in Africa dates back more than 3,000 years. Interestingly, African rice is not of the same origin as Asian rice ( Oryza sativa L.) but rather is an entirely different species (i.e., Oryza glaberrima Steud.). Here we present a high-quality assembly and annotation of the O. glaberrima genome and detailed analyses of its evolutionary history of domestication and selection. Population genomics analyses of 20 O. glaberrima and 94 Oryza barthii accessions support the hypothesis that O. glaberrima was domesticated in a single region along the Niger river as opposed to noncentric domestication events across Africa. We detected evidence for artificial selection at a genome-wide scale, as well as with a set of O. glaberrima genes orthologous to O. sativa genes that are known to be associated with domestication, thus indicating convergent yet independent selection of a common set of genes during two geographically and culturally distinct domestication processes.

Tin adatoms on a Si(111) substrate with a one-third monolayer coverage form a two-dimensional triangular lattice with one unpaired electron per site. These electrons order into an antiferromagnetic Mott-insulating state, but doping the Sn layer with holes creates a two-dimensional conductor that becomes superconducting at low temperatures. Although the pairing symmetry of the superconducting state is currently unknown, the combination of repulsive interactions and frustration inherent in the triangular adatom lattice opens up the possibility of a chiral order parameter. Here we study the superconducting state of Sn/Si(111) using scanning tunnelling microscopy, scanning tunnelling spectroscopy and quasiparticle interference imaging. We find evidence for a doping-dependent superconducting critical temperature with a fully gapped order parameter, the presence of time-reversal symmetry breaking and a strong enhancement in zero-bias conductance near the edges of the superconducting domains. Although each individual piece of evidence could have a more mundane interpretation, our combined results suggest the possibility that Sn/Si(111) is an unconventional chiral d-wave superconductor.Adatoms on the surface of silicon can create two-dimensional superconductivity, the order parameter symmetry of which is currently not known. Now, evidence suggests it might be a topological chiral d-wave state.

Moderate intraoperative hypothermia promotes myocardial injury, surgical site infections, and blood loss. Whether aggressive warming to a truly normothermic temperature near 37°C improves outcomes remains unknown. We aimed to test the hypothesis that aggressive intraoperative warming reduces major perioperative complications. In this multicentre, parallel group, superiority trial, patients at 12 sites in China and at the Cleveland Clinic in the USA were randomly assigned (1:1) to receive either aggressive warming to a target core temperature of 37°C (aggressively warmed group) or routine thermal management to a target of 35·5°C (routine thermal management group) during non-cardiac surgery. Randomisation was stratified by site, with computer-generated, randomly sized blocks. Eligible patients (aged ≥45 years) had at least one cardiovascular risk factor, were scheduled for inpatient non-cardiac surgery expected to last 2–6 h with general anaesthesia, and were expected to have at least half of the anterior skin surface available for warming. Patients requiring dialysis and those with a body-mass index exceeding 30 kg/m2 were excluded. The primary outcome was a composite of myocardial injury (troponin elevation, apparently of ischaemic origin), non-fatal cardiac arrest, and all-cause mortality within 30 days of surgery, as assessed in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03111875. Between March 27, 2017, and March 16, 2021, 5056 participants were enrolled, of whom 5013 were included in the intention-to-treat population (2507 in the aggressively warmed group and 2506 in the routine thermal management group). Patients assigned to aggressive warming had a mean final intraoperative core temperature of 37·1°C (SD 0·3) whereas the routine thermal management group averaged 35·6°C (SD 0·3). At least one of the primary outcome components (myocardial injury after non-cardiac surgery, cardiac arrest, or mortality) occurred in 246 (9·9%) of 2497 patients in the aggressively warmed group and in 239 (9·6%) of 2490 patients in the routine thermal management group. The common effect relative risk of aggressive versus routine thermal management was an estimated 1·04 (95% CI 0·87–1·24, p=0·69). There were 39 adverse events in patients assigned to aggressive warming (17 of which were serious) and 54 in those assigned to routine thermal management (30 of which were serious). One serious adverse event, in an aggressively warmed patient, was deemed to be possibly related to thermal management. The incidence of a 30-day composite of major cardiovascular outcomes did not differ significantly in patients randomised to 35·5°C and to 37°C. At least over a 1·5°C range from very mild hypothermia to full normothermia, there was no evidence that any substantive outcome varied. Keeping core temperature at least 35·5°C in surgical patients appears sufficient. 3M and the Health and Medical Research Fund, Food and Health Bureau, Hong Kong. For the Chinese translation of the abstract see Supplementary Materials section.

Background Successfully restoring facial contours continues to pose a significant challenge for surgeons. This study aims to utilize head-mounted display-based augmented reality (AR) navigation technology for facial soft tissue defect reconstruction and to evaluate its accuracy and effectiveness, exploring its feasibility in craniofacial surgery. Methods Hololens 2 was utilized to construct the AR guidance system for facial fat grafting. Twenty artificial cases with facial soft tissue defects were randomly assigned to Group A and Group B, undergoing filling surgeries with the AR guidance system and conventional methods, respectively. All postoperative three-dimensional models were superimposed onto virtual plans to evaluate the accuracy of the system versus conventional filling methods. Additionally, procedure completion time was recorded to assess system efficiency relative to conventional methods. Results The error in facial soft tissue defect reconstruction assisted by the system in Group A was 2.09 ± 0.56 mm, significantly lower than the 3.23 ± 1.15 mm observed with conventional methods in Group B ( p  < 0.05). Additionally, the time required for facial defect filling reconstruction using the system in Group A was 25.45 ± 2.58 min, markedly shorter than the 37.05 ± 3.34 min needed with conventional methods in Group B ( p  < 0.05). Conclusion The visual navigation offered by the fat grafting AR guidance system presents obvious advantages in facial soft tissue defect reconstruction, facilitating enhanced precision and efficiency in these filling procedures.

DNA (class 2) transposons are mobile genetic elements which move within their ‘host’ genome through excising and re-inserting elsewhere. Although the rice genome contains tens of thousands of such elements, their actual role in evolution is still unclear. Analysing over 650 transposon polymorphisms in the rice species Oryza sativa and Oryza glaberrima , we find that DNA repair following transposon excisions is associated with an increased number of mutations in the sequences neighbouring the transposon. Indeed, the 3,000 bp flanking the excised transposons can contain over 10 times more mutations than the genome-wide average. Since DNA transposons preferably insert near genes, this is correlated with increases in mutation rates in coding sequences and regulatory regions. Most importantly, we find this phenomenon also in maize, wheat and barley. Thus, these findings suggest that DNA transposon activity is a major evolutionary force in grasses which provide the basis of most food consumed by humankind. DNA transposons are numerous in plant genomes. Here, Wicker et al . analyse transposon polymorphisms in rice and other grasses and show that sequences flanking excision sites contain up to 10 times more mutations than average, suggesting transposons are a major factor shaping the evolution of grass genomes.

Recently it has been observed that cancer tissue is characterised by an increased variability in DNA methylation patterns. However, how the correlative patterns in genome-wide DNA methylation change during the carcinogenic progress has not yet been explored. Here we study genome-wide inter-CpG correlations in DNA methylation, in addition to single site variability, during cervical carcinogenesis. We demonstrate how the study of changes in DNA methylation covariation patterns across normal, intra-epithelial neoplasia and invasive cancer allows the identification of CpG sites that indicate the risk of neoplastic transformation in stages prior to neoplasia. Importantly, we show that the covariation in DNA methylation at these risk CpG loci is maximal immediately prior to the onset of cancer, supporting the view that high epigenetic diversity in normal cells increases the risk of cancer. Consistent with this, we observe that invasive cancers exhibit increased covariation in DNA methylation at the risk CpG sites relative to normal tissue, but lower levels relative to pre-cancerous lesions. We further show that the identified risk CpG sites undergo preferential DNA methylation changes in relation to human papilloma virus infection and age. Results are validated in independent data including prospectively collected samples prior to neoplastic transformation. Our data are consistent with a phase transition model of carcinogenesis, in which epigenetic diversity is maximal prior to the onset of cancer. The model and algorithm proposed here may allow, in future, network biomarkers predicting the risk of neoplastic transformation to be identified.

Background While the effects of sleep deprivation on cognitive function are well-documented, its impact on high-intensity endurance performance and underlying neural mechanisms remains underexplored, especially in the context of search and rescue operations where both physical and mental performance are essential. This study examines the neurophysiological basis of sleep deprivation on high-intensity endurance using electroencephalography (EEG). In this crossover study, twenty firefighters were subjected to both sleep deprivation (SD) and normal sleep conditions, with each participant performing endurance treadmill exercise the following morning after each condition. EEG signals were recorded before and after high-intensity endurance exercise, and power spectrum analysis and functional connectivity analysis were performed on sleep related frequency bands rhythm: δ (0.5–4 Hz) and θ (4–8 Hz). The EEG power spectral and functional connectivity were measured by repeated measure analysis of variance. Results The SD condition had an average sleep duration of 3.78 ± 0.69 h, while the duration for normal sleep was 7.63 ± 0.52 h. After high-intensity endurance exercise, the SD condition had a higher maximum heart rate ( p  < 0.05) and shorter exercise time ( p  < 0.05) than normal sleep. Compared with before exercise, the δ band in the left parietal lobe P7 channel increased significantly ( p  < 0.01), and the θ band in the central Cz channel and the left and right parietal lobe P7 and P8 channel increased significantly ( p  < 0.01 & p  < 0 0.05) in SD and normal sleep conditions after exercise. After exercise, compared with normal sleep, the δ band power in occipital O1 and Oz channels and parietal P7 and TP7 channels in SD significantly decreased ( p  < 0.05 & p  < 0.01); the power of the θ band decreased significantly in the occipital O1 channel, central CZ channel and the left and right parietal P7 and P8 channel ( p  < 0.05 & p  < 0.01). Whole connectivity showed a significant increase ( p  = 0.001) in the δ band for the SD condition at post-exhaustion. Local connectivity analysis identified a localized network in the δ band with reduced ( p  < 0.001) post-exhaustion in the SD condition displaying inter-hemispheric differences in certain connections (FP1-CP4, T7-C4, T7-TP8, and O1-FT8) and intra-hemispheric (C3-CPz and Pz-P4) variations. Conclusions Sleep deprivation significantly reduced maximum endurance performance, indicating decreased neural activity in the central and parietal brain regions. Alterations in δ and θ frequency band power, along with disrupted connectivity, may highlight the neurophysiological basis underlying this decline. Key Points • Sleep deprivation significantly impairs high-intensity endurance performance, demonstrated by reduced time to exhaustion and increased maximum heart rate compared to normal sleep conditions. • Sleep-deprived states result in a marked decrease in δ and θ band activity within the central and parietal brain regions, which are essential for motor control and endurance capacity. • Sleep deprivation diminishes the efficiency of information transmission within the δ band network, suggesting disrupted connectivity that may hinder cognitive and motor processes critical to sustaining performance.