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Understanding how breaks form and are repaired in the genome depends on the accurate measurement of the frequency and position of DNA double strand breaks (DSBs). This is crucial for identification of a chemical’s DNA damage potential and for safe development of therapies, including genome editing technologies. Current DSB sequencing methods suffer from high background levels, the inability to accurately measure low frequency endogenous breaks and high sequencing costs. Here we describe INDUCE-seq, which overcomes these problems, detecting simultaneously the presence of low-level endogenous DSBs caused by physiological processes, and higher-level recurrent breaks induced by restriction enzymes or CRISPR-Cas nucleases. INDUCE-seq exploits an innovative NGS flow cell enrichment method, permitting the digital detection of breaks. It can therefore be used to determine the mechanism of DSB repair and to facilitate safe development of therapeutic genome editing. We further discuss how the method can be adapted to detect other genomic features. Understanding how DNA double strand breaks (DSBs) form and are repaired in the genome depends on their accurate measurement. Here the authors describe INDUCE-seq; a DSB-detection method that simultaneously measures physiological and induced breaks throughout the genome.

The South Pole Telescope (SPT) is a 10 m diameter, wide-field, offset Gregorian telescope with a 966 pixel, multicolor, millimeter-wave, bolometer camera. It is located at the Amundsen-Scott South Pole station in Antarctica. The design of the SPT emphasizes careful control of spillover and scattering, to minimize noise and false signals due to ground pickup. The key initial project is a large-area survey at wavelengths of 3, 2, and 1.3 mm, to detect clusters of galaxies via the Sunyaev-Zel’dovich effect and to measure the small-scale angular power spectrum of the cosmic microwave background (CMB). The data will be used to characterize the primordial matter power spectrum and to place constraints on the equation of state of dark energy. A second-generation camera will measure the polarization of the CMB, potentially leading to constraints on the neutrino mass and the energy scale of inflation.

The South Pole Telescope Summertime Line Intensity Mapper (SPT-SLIM) is a pathfinder experiment that will demonstrate the use of on-chip filter-bank spectrometers for mm-wave line intensity mapping. The SPT-SLIM focal plane consists of 18 dual-polarization filter-bank spectrometers covering 120–180 GHz with resolving power of 300, coupled to aluminum kinetic inductance detectors. A compact cryostat holds the detectors at 100 mK. SPT-SLIM will be deployed to the 10-m South Pole Telescope for observations during the 2023–2024 austral summer without removing the primary receiver. We discuss the overall instrument design, expected detector performance, and sensitivity to the carbon monoxide line signal at 0.5 < z < 2 . The technology and observational techniques demonstrated by SPT-SLIM will enable next-generation line intensity mapping experiments that constrain cosmology beyond the redshift reach of galaxy surveys.

Background miR-346 was identified as an activator of Androgen Receptor (AR) signalling that associates with DNA damage response (DDR)-linked transcripts in prostate cancer (PC). We sought to delineate the impact of miR-346 on DNA damage, and its potential as a therapeutic agent. Methods RNA-IP, RNA-seq, RNA-ISH, DNA fibre assays, in vivo xenograft studies and bioinformatics approaches were used alongside a novel method for amplification-free, single nucleotide-resolution genome-wide mapping of DNA breaks (INDUCE-seq). Results miR-346 induces rapid and extensive DNA damage in PC cells - the first report of microRNA-induced DNA damage. Mechanistically, this is achieved through transcriptional hyperactivation, R-loop formation and replication stress, leading to checkpoint activation and cell cycle arrest. miR-346 also interacts with genome-protective lncRNA NORAD to disrupt its interaction with PUM2, leading to PUM2 stabilisation and its increased turnover of DNA damage response (DDR) transcripts. Confirming clinical relevance, NORAD expression and activity strongly correlate with poor PC clinical outcomes and increased DDR in biopsy RNA-seq studies. In contrast, miR-346 is associated with improved PC survival. INDUCE-seq reveals that miR-346-induced DSBs occur preferentially at binding sites of the most highly-transcriptionally active transcription factors in PC cells, including c-Myc, FOXA1, HOXB13, NKX3.1, and importantly, AR, resulting in target transcript downregulation. Further, RNA-seq reveals widespread miR-346 and shNORAD dysregulation of DNA damage, replication and cell cycle processes. NORAD drives target-directed miR decay (TDMD) of miR-346 as a novel genome protection mechanism: NORAD silencing increases mature miR-346 levels by several thousand-fold, and WT but not TDMD-mutant NORAD rescues miR-346-induced DNA damage. Importantly, miR-346 sensitises PC cells to DNA-damaging drugs including PARP inhibitor and chemotherapy, and induces tumour regression as a monotherapy in vivo, indicating that targeting miR-346:NORAD balance is a valid therapeutic strategy. Conclusions A balancing act between miR-346 and NORAD regulates DNA damage and repair in PC. miR-346 may be particularly effective as a therapeutic in the context of decreased NORAD observed in advanced PC, and in transcriptionally-hyperactive cancer cells.

A spectroscopic redshift survey of extraordinarily bright millimetre-wave-selected sources of carbon monoxide line emission — originating from star-forming molecular gas — shows that at least ten of these sources lie at redshifts greater than four, indicating that the fraction of dusty starburst galaxies at high redshifts is greater than previously thought. ALMA focused on star-forming galaxies Luminous, dusty, starburst galaxies were abundant in the early Universe, but it has been difficult to measure the complete redshift distribution of these objects, especially at the highest redshifts. The ALMA interferometer in Chile, now coming on-stream, provides high-resolution imaging at the millimetre/submillimetre wavelengths at which star-forming gases are best observed. Using ALMA, Joaquin Vieira and co-workers targeted carbon monoxide line emissions from gravitationally lensed galaxies discovered in a wide-field survey using the South Pole Telescope. The ten z > 4 objects revealed in this work more than double the number of spectroscopically confirmed, ultra-luminous galaxies discovered at extreme redshifts. Two sources at z = 5.7 are among the most distant ultra-luminous starburst galaxies known, seen as they were about a billion years after the Big Bang. In the past decade, our understanding of galaxy evolution has been revolutionized by the discovery that luminous, dusty starburst galaxies were 1,000 times more abundant in the early Universe than at present 1 , 2 . It has, however, been difficult to measure the complete redshift distribution of these objects, especially at the highest redshifts ( z  > 4). Here we report a redshift survey at a wavelength of three millimetres, targeting carbon monoxide line emission from the star-forming molecular gas in the direction of extraordinarily bright millimetre-wave-selected sources. High-resolution imaging demonstrates that these sources are strongly gravitationally lensed by foreground galaxies. We detect spectral lines in 23 out of 26 sources and multiple lines in 12 of those 23 sources, from which we obtain robust, unambiguous redshifts. At least 10 of the sources are found to lie at z  > 4, indicating that the fraction of dusty starburst galaxies at high redshifts is greater than previously thought. Models of lens geometries in the sample indicate that the background objects are ultra-luminous infrared galaxies, powered by extreme bursts of star formation.

Abstract Purpose Congenital clubfoot is a serious birth defect that affects nearly 0.1% of all births. Though there is strong evidence for a genetic basis of isolated clubfoot, aside from a handful of associations, much of the heritability remains unexplained. Methods By systematically examining the genes involved in syndromic clubfoot, we may find new candidate genes and pathways to investigate in isolated clubfoot. Results In addition to the expected enrichment of extracellular matrix and transforming growth factor beta (TGF-β) signalling genes, we find many genes involved in syndromic clubfoot encode peroxisomal matrix proteins, as well as enzymes necessary for sulfation of proteoglycans, an important part of connective tissue. Further, the association of Filamin B with isolated clubfoot as well as syndromic clubfoot is an encouraging finding. Conclusion We should examine these categories for enrichment in isolated clubfoot patients to increase our understanding of the underlying biology and pathophysiology of this deformity. Understanding the spectrum of syndromes that have clubfoot as a feature enables a better understanding of the underlying pathophysiology of the disorder and directs future genetic screening efforts toward certain genes and genetic pathways. Level of evidence V

The micro-mechanisms of brittle failure affect the bulk mechanical behaviour and permeability of crustal rocks. In low-porosity crystalline rocks, these mechanisms are related to mineralogy and fabric anisotropy, while confining pressure, temperature and strain rates regulate the transition from brittle to ductile behaviour. However, the effects of folded anisotropic fabrics, widespread in orogenic settings, on the mechanical behaviour of crustal rocks are largely unknown. Here we explore the deformation and failure behaviour of a representative folded gneiss, by combining the results of triaxial deformation experiments carried out while monitoring microseismicity with microstructural and damage proxies analyses. We show that folded crystalline rocks in upper crustal conditions exhibit dramatic strength heterogeneity and contrasting failure modes at identical confining pressure and room temperature, depending on the geometrical relationships between stress and two different anisotropies associated to the folded rock fabric. These anisotropies modulate the competition among quartz- and mica-dominated microscopic damage processes, resulting in transitional brittle to semi-brittle modes under P and T much lower than expected. This has significant implications on scales relevant to seismicity, energy resources, engineering applications and geohazards.

Background Gut‐brain axis is widely implicated in the pathophysiology of Parkinson's disease (PD). We take an integrated approach to considering the gut as a target for disease‐modifying intervention, using continuous measurements of disease facets irrespective of diagnostic divide. Methods We characterised 77 participants with diagnosed‐PD, 113 without, by dietary/exogenous substance intake, faecal metabolome, intestinal inflammation, serum cytokines/chemokines, clinical phenotype including colonic transit time. Complete‐linkage hierarchical cluster analysis of metabolites discriminant for PD‐status was performed. Results Longer colonic transit was linked to deficits in faecal short‐chain‐fatty acids outside PD, to a ‘tryptophan‐containing metabolite cluster’ overall. Phenotypic cluster analysis aggregated colonic transit with brady/hypokinesia, tremor, sleep disorder and dysosmia, each individually associated with tryptophan‐cluster deficit. Overall, a faster pulse was associated with deficits in a metabolite cluster including benzoic acid and an imidazole‐ring compound (anti‐fungals) and vitamin B3 (anti‐inflammatory) and with higher serum CCL20 (chemotactic for lymphocytes/dendritic cells towards mucosal epithelium). The faster pulse in PD was irrespective of postural hypotension. The benzoic acid‐cluster deficit was linked to (well‐recognised) lower caffeine and alcohol intakes, tryptophan‐cluster deficit to higher maltose intake. Free‐sugar intake was increased in PD, maltose intake being 63% higher (p = .001). Faecal calprotectin was 44% (95% CI 5%, 98%) greater in PD [p = .001, adjusted for proton‐pump inhibitors (p = .001)], with 16% of PD‐probands exceeding a cut‐point for clinically significant inflammation compatible with inflammatory bowel disease. Higher maltose intake was associated with exceeding this calprotectin cut‐point. Conclusions Emerging picture is of (i) clinical phenotype being described by deficits in microbial metabolites essential to gut health; (ii) intestinal inflammation; (iii) a systemic inflammatory response syndrome. A marker of intestinal inflammation was 44% greater in Parkinson's disease, exceeding a cut‐point for inflammatory bowel disease in 16%. It was associated with a higher maltose and sucrose intake. The emerging picture is of systemic inflammatory response consequent on intestinal inflammation, clinical phenotype being described by deficits in faecal metabolites essential to gut health.

Cosmic microwave background (CMB) measurements are fundamentally limited by photon statistics. Therefore, ground-based CMB observatories have been increasing the number of detectors that are simultaneously observing the sky. Thanks to the advent of monolithically fabricated transition edge sensor arrays, the number of on-sky detectors has been increasing exponentially for over a decade. The next-generation experiment CMB-S4 will increase this detector count by more than an order of magnitude from the current state of the art to 500,000. The readout of such a huge number of exquisitely precise sub-Kelvin sensors is feasible using an existing technology: frequency-domain multiplexing. To further optimize this system and reduce complexity and cost, we have recently made significant advances including the elimination of 4 K electronics, a massive decrease in parasitic in-series impedances, and a significant increase in multiplexing factor.

Frequency-domain multiplexing (fMux) is an established technique for the readout of large arrays of transition-edge sensor (TES) bolometers. Each TES in a multiplexing module has a unique AC voltage bias that is selected by a resonant filter. This scheme enables the operation and readout of multiple bolometers on a single pair of wires, reducing thermal loading onto sub-Kelvin stages. The current receiver on the South Pole Telescope, SPT-3G, uses a 68x fMux system to operate its large-format camera of ∼ 16,000 TES bolometers. We present here the successful implementation and performance of the SPT-3G readout as measured on-sky. Characterization of the noise reveals a median pair-differenced 1/f knee frequency of 33 mHz, indicating that low-frequency noise in the readout will not limit SPT-3G’s measurements of sky power on large angular scales. Measurements also show that the median readout white noise level in each of the SPT-3G observing bands is below the expectation for photon noise, demonstrating that SPT-3G is operating in the photon-noise-dominated regime.