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Large grazers modify vegetated ecosystems and are increasingly viewed as keystone species in trophic rewilding schemes. Yet, as their ecosystem influences are context‐dependent, a crucial challenge is identifying where grazers sustain, versus undermine, important ecosystem properties and their resilience.Previous work in diverse European saltmarshes found that, despite changing plant and invertebrate community structure, grazers do not suppress below‐ground properties, including soil organic carbon (SOC). We hypothesised that, in contrast, eastern US saltmarshes would be sensitive to large grazers as extensive areas are dominated by a single grass, Spartina alterniflora. We predicted that grazers would reduce above‐ and below‐ground Spartina biomass, suppress invertebrate densities, shift soil texture and ultimately reduce SOC concentration.We tested our hypotheses using a replicated 51‐month large grazer (horse) exclusion experiment in Georgia, coupled with observations of 14 long‐term grazed sites, spanning ~1000 km of the eastern US coast.Grazer exclusion quickly led to increased Spartina height, cover and flowering, and increased snail density. Changes in vegetation structure were reflected in modified soil texture (reduced sand, increased clay) and elevated root biomass, yet we found no response of SOC. Large grazer exclusion also reduced drought‐associated vegetation die‐off.We also observed vegetation shifts in sites along the eastern US seaboard where grazing has occurred for hundreds of years. Unlike in the exclusion experiment, long‐term grazing was associated with reduced SOC. A structural equation model implicated grazing by revealing reduced stem height as a key driver of reduced soil organic carbon.Synthesis: These results illustrate the context dependency of large grazer impacts on ecosystem properties in coastal wetlands. In contrast to well‐studied European marshes, eastern US marshes are dominated and structured by a single foundational grass species resulting in vegetation and soil properties being more sensitive to grazing. Coastal systems characterised by a single foundation species might be inherently vulnerable to large grazers and lack resilience in the face of other disturbances, underlining that frameworks to explain and predict large grazer impacts must account for geographic variation in ecosystem structure. [ABSTRACT FROM AUTHOR]

Background: The majority of cases of Dent's disease are caused by pathogenic variants in the CLCN5 gene, which encodes a voltage-gated chloride ion channel (ClC-5), resulting in proximal tubular dysfunction. We present three members of the same family and one unrelated paediatric patient with the same insertion-deletion CLCN5 variant. The identification of these patients and positive familial segregation led to the re-classification of this variant from one of unknown significance to one of likely pathogenicity. Case presentation: A 41 year old male presented with end stage kidney failure, proteinuria and haematuria. Whole genome sequencing identified an insertion-deletion variant in CLCN5, resulting in a missense change (c.1744_1745delinsAA p.(Ala582Lys)). His brother and nephew, who both exhibited renal impairment, haematuria, proteinuria, glycosuria and nephrocalcinosis, were found to have the same variant. In addition, genetic testing of an unrelated paediatric patient who presented with proteinuria and hypercalciuria, demonstrated the same variant. Conclusions: The identification of this novel variant in four individuals with features of Dent's disease, has led to the re-classification of the variant to one of likely pathogenicity. As a result, our patients and any future patients with the same variant can be offered a likely diagnosis, without the need for kidney biopsy, and their family members can be offered genetic screening. [ABSTRACT FROM AUTHOR]

Background: Cancer genome sequencing enables accurate classification of tumours and tumour subtypes. However, prediction performance is still limited using exome-only sequencing and for tumour types with low somatic mutation burden such as many paediatric tumours. Moreover, the ability to leverage deep representation learning in discovery of tumour entities remains unknown. Methods: We introduce here Mutation-Attention (MuAt), a deep neural network to learn representations of simple and complex somatic alterations for prediction of tumour types and subtypes. In contrast to many previous methods, MuAt utilizes the attention mechanism on individual mutations instead of aggregated mutation counts. Results: We trained MuAt models on 2587 whole cancer genomes (24 tumour types) from the Pan-Cancer Analysis of Whole Genomes (PCAWG) and 7352 cancer exomes (20 types) from the Cancer Genome Atlas (TCGA). MuAt achieved prediction accuracy of 89% for whole genomes and 64% for whole exomes, and a top-5 accuracy of 97% and 90%, respectively. MuAt models were found to be well-calibrated and perform well in three independent whole cancer genome cohorts with 10,361 tumours in total. We show MuAt to be able to learn clinically and biologically relevant tumour entities including acral melanoma, SHH-activated medulloblastoma, SPOP-associated prostate cancer, microsatellite instability, POLE proofreading deficiency, and MUTYH-associated pancreatic endocrine tumours without these tumour subtypes and subgroups being provided as training labels. Finally, scrunity of MuAt attention matrices revealed both ubiquitous and tumour-type specific patterns of simple and complex somatic mutations. Conclusions: Integrated representations of somatic alterations learnt by MuAt were able to accurately identify histological tumour types and identify tumour entities, with potential to impact precision cancer medicine. [ABSTRACT FROM AUTHOR]

Autosomal recessive whole gene deletions of nephrocystin-1 (NPHP1) result in abnormal structure and function of the primary cilia. These deletions can result in a tubulointerstitial kidney disease known as nephronophthisis and retinal (Senior–Løken syndrome) and neurological (Joubert syndrome) diseases. Nephronophthisis is a common cause of end-stage kidney disease (ESKD) in children and up to 1% of adult onset ESKD. Single nucleotide variants (SNVs) and small insertions and deletions (Indels) have been less well characterised. We used a gene pathogenicity scoring system (GenePy) and a genotype-to-phenotype approach on individuals recruited to the UK Genomics England (GEL) 100,000 Genomes Project (100kGP) (n = 78,050). This approach identified all participants with NPHP1-related diseases reported by NHS Genomics Medical Centres and an additional eight participants. Extreme NPHP1 gene scores, often underpinned by clear recessive inheritance, were observed in patients from diverse recruitment categories, including cancer, suggesting the possibility of a more widespread disease than previously appreciated. In total, ten participants had homozygous CNV deletions with eight homozygous or compound heterozygous with SNVs. Our data also reveals strong in-silico evidence that approximately 44% of NPHP1 related disease may be due to SNVs with AlphaFold structural modelling evidence for a significant impact on protein structure. This study suggests historical under-reporting of SNVS in NPHP1 related diseases compared with CNVs. [ABSTRACT FROM AUTHOR]

In passive acoustic ranging, a correlation function is frequently used to measure the signal propagation time difference between two sensors, or between two paths to a single sensor. The same device can be used to measure the Doppler differences when the source is in motion. The joint use of time and Doppler differences can result in more accurate range estimation than is possible from time or Doppler differences alone. Examples are given of the use of the use of time and Doppler correlation in passive ranging on a submarine. [ABSTRACT FROM AUTHOR]