Evidence in disease and non-disease contexts that nonsense mutations cause altered splicing via motif disruption

Transcripts containing premature termination codons (PTCs) can be subject to nonsense-associated alternative splicing (NAS). Two models have been evoked to explain this, scanning and splice motif disruption. The latter postulates that exonic cis motifs, such as exonic splice enhancers (ESEs), are disrupted by nonsense mutations. We employ genome-wide transcriptomic and k-mer enrichment methods to scrutinize this model. First, we show that ESEs are prone to disruptive nonsense mutations owing to their purine richness and paucity of TGA, TAA and TAG. The motif model correctly predicts that NAS rates should be low (we estimate 5–30%) and approximately in line with estimates for the rate at which random point mutations disrupt splicing (8–20%). Further, we find that, as expected, NAS-associated PTCs are predictable from nucleotide-based machine learning approaches to predict splice disruption and, at least for pathogenic variants, are enriched in ESEs. Finally, we find that both in and out of frame mutations to TAA, TGA or TAG are associated with exon skipping. While a higher relative frequency of such skip-inducing mutations in-frame than out of frame lends some credence to the scanning model, these results reinforce the importance of considering splice motif modulation to understand the etiology of PTC-associated disease

Enhanced stability and local structure in biologically relevant amorphous materials containing pyrophosphate

There is increasing evidence that amorphous inorganic materials play a key role in biomineralisation in many organisms, however the inherent instability of synthetic analogues in the absence of the complex in vivo matrix limits their study and clinical exploitation. To address this, we report here an approach that enhances long-term stability to >1 year of biologically relevant amorphous metal phosphates, in the absence of any complex stabilisers, by utilising pyrophosphates (P2O7 4-); species themselves ubiquitous in vivo. Ambient temperature precipitation reactions were employed to synthesise amorphous Ca2P2O7.nH2O and Sr2P2O7.nH2O (3.8 < n < 4.2) and their stability and structure were investigated. Pair distribution functions (PDF) derived from synchrotron X-ray data indicated a lack of structural order beyond ~8 A° in both phases, with this local order found to resemble crystalline analogues. Further studies, including 1H and 31P solid state NMR, suggest the unusually high stability of these purely inorganic amorphous phases is partly due to disorder in the P–O–P bond angles within the P2O7 units, which impede crystallization, and to water molecules, which are involved in H-bonds of various strengths within the structures and hamper the formation of an ordered network. In situ high temperature powder X-ray diffraction data indicated that the amorphous nature of both phases surprisingly persisted to ~450° C. Further NMR and TGA studies found that above ambient temperature some water molecules reacted with P2O7 anions, leading to the hydrolysis of some P–O–P linkages and the formation of HPO4 2- anions within the amorphous matrix. The latter anions then recombined into P2O7 ions at higher temperatures prior to crystallization. Together, these findings provide important new materials with unexplored potential for enzyme-assisted resorption and establish factors crucial to isolate further stable amorphous inorganic materials

EyeG2P: an automated variant filtering approach improves efficiency of diagnostic genomic testing for inherited ophthalmic disorders

BACKGROUND: Genomic variant prioritisation is one of the most significant bottlenecks to mainstream genomic testing in healthcare. Tools to improve precision while ensuring high recall are critical to successful mainstream clinical genomic testing, in particular for whole genome sequencing where millions of variants must be considered for each patient. METHODS: We developed EyeG2P, a publicly available database and web application using the Ensembl Variant Effect Predictor. EyeG2P is tailored for efficient variant prioritisation for individuals with inherited ophthalmic conditions. We assessed the sensitivity of EyeG2P in 1234 individuals with a broad range of eye conditions who had previously received a confirmed molecular diagnosis through routine genomic diagnostic approaches. For a prospective cohort of 83 individuals, we assessed the precision of EyeG2P in comparison with routine diagnostic approaches. For 10 additional individuals, we assessed the utility of EyeG2P for whole genome analysis. RESULTS: EyeG2P had 99.5% sensitivity for genomic variants previously identified as clinically relevant through routine diagnostic analysis (n=1234 individuals). Prospectively, EyeG2P enabled a significant increase in precision (35% on average) in comparison with routine testing strategies (p<0.001). We demonstrate that incorporation of EyeG2P into whole genome sequencing analysis strategies can reduce the number of variants for analysis to six variants, on average, while maintaining high diagnostic yield. CONCLUSION: Automated filtering of genomic variants through EyeG2P can increase the efficiency of diagnostic testing for individuals with a broad range of inherited ophthalmic disorders

The Lantern, 2020-2021

One Thousand and One is Never Enough • House on Hazel Ave. • Crooked Men at Crooked Alley • Home • Honeybee • The Witch\u27s Daughter • Traveling to Reyu • December 31st, 2019 • The Dominator Rolls the Dice Again • Red Flowers • Military Ball • Drowning in Color • Early Bird • Introspection • Hot Water • Reaching Into Space • Floating Marigolds Before COVID-19 • Smokestack 4 • Longing • His Fifth Year on Amstel Road • Wonderful Moments • Clean Glass • Betty, the Debutante • Teakettles Have it Easy • Fuimos, Somos y Seramos Parte de la Historia de la Isla • Kitchen Table • She Couldn\u27t • Cooling Down • Not so Precious Stones • Domestic Wild • Violet Eater • I Will be Sweet • Flavor of Life • Clogged Artery • All Twenty-Six • The Greatest • From Ashes of War to Golden Cities • A Good Thing • Introduction • Devotion • Life of the Gambler • Impressions: Or a Dining Table\u27s Soliloquy • Looking Glass • Montgomery Pie • Under the Hill • Paperback Lesbian • Girl With Pearl Earring • Your Mirror • Jacket • Illusions • Strawberry Girl (Raw Sugar, Shattered Glass) • I Don\u27t Jam With Instagram • The Morning After Saturday • A Brisk Monday Morning • Emergence • Politeness and Pattern Recognition • Douglas Adams\u27 Guide to Florida • A Love Story With Femininity • Roots • Dysmorphia IIIhttps://digitalcommons.ursinus.edu/lantern/1189/thumbnail.jp

The Lantern, 2019-2020

Cochlea, Greek for Snail • That Light in the Sky • Overview Effect • The Running Man • Sunset • Rabbits • What Happened While You Were Drunk Last Saturday Night • 21st Century Frankenstein • Passing • I Saw the Veil • Star Crossed • Subtle Hints • Hungry • Basement High • The Night Who Lost Its Stars • Remnants • Nostalgia • I Want to Go to Bed • Wooden Car Blues • Silver Honey • The Breakup • Here\u27s to Losing You • Marfa • Cold Wind Blows • Last Week • 6/12/2019 • These Feather Earrings • Every Piece of White Trash Comes from Somewhere • Color Motion Blur • Song of the Kauai O\u27o • You/Me/Him • Girl in Three Parts • With Anxiety • Foreigner • Eating Your Own Field • Mary Cassatt Sits for a Self Portrait • Thanatourism • Lost in Transportation • Chicken Pot Pie Picture Show • Curses, Foiled Again • From Amelia Goldstein\u27s Movement in Your Words 2019 • At the Altar • More Than Words • Show Me Your Eyes • Ears • The Deflowering • Space • The Tea Bags • Make No Mistake • What Does He Do With the Body?: Four Possibilities • The Story of How I Died, or What the Witches Gave Me • Fortune-Teller • No Thanks • Winter Words • Fluorescent Adolescent • Etiquettical Triptych • Curls and Flower Petals • Being or Falling • Fond Memories • You • All to My City • The Shoreline • Tranquility • Eggs • Burnt • Anthony • Targets • Looking Up • Nebula • Eastern State • Beachhttps://digitalcommons.ursinus.edu/lantern/1188/thumbnail.jp

COL5A1 gene variants previously associated with reduced soft tissue injury risk are associated with elite athlete status in rugby.

BACKGROUND: Two common single nucleotide polymorphisms within the COL5A1 gene (SNPs; rs12722 C/T and rs3196378 C/A) have previously been associated with tendon and ligament pathologies. Given the high incidence of tendon and ligament injuries in elite rugby athletes, we hypothesised that both SNPs would be associated with career success. RESULTS: In 1105 participants (RugbyGene project), comprising 460 elite rugby union (RU), 88 elite rugby league athletes and 565 non-athlete controls, DNA was collected and genotyped for the COL5A1 rs12722 and rs3196378 variants using real-time PCR. For rs12722, the injury-protective CC genotype and C allele were more common in all athletes (21% and 47%, respectively) and RU athletes (22% and 48%) than in controls (16% and 41%, P ≤ 0.01). For rs3196378, the CC genotype and C allele were overrepresented in all athletes (23% and 48%) and RU athletes (24% and 49%) compared with controls (16% and 41%, P ≤ 0.02). The CC genotype in particular was overrepresented in the back and centres (24%) compared with controls, with more than twice the odds (OR = 2.25, P = 0.006) of possessing the injury-protective CC genotype. Furthermore, when considering both SNPs simultaneously, the CC-CC SNP-SNP combination and C-C inferred allele combination were higher in all the athlete groups (≥18% and ≥43%) compared with controls (13% and 40%; P = 0.01). However, no genotype differences were identified for either SNP when RU playing positions were compared directly with each other. CONCLUSION: It appears that the C alleles, CC genotypes and resulting combinations of both rs12722 and rs3196378 are beneficial for rugby athletes to achieve elite status and carriage of these variants may impart an inherited resistance against soft tissue injury, despite exposure to the high-risk environment of elite rugby. These data have implications for the management of inter-individual differences in injury risk amongst elite athletes

Acquired resistance to oxaliplatin is not directly associated with increased resistance to DNA damage in SK-N-ASrOXALI4000, a newly established oxaliplatin-resistant sub-line of the neuroblastoma cell line SK-N-AS

The formation of acquired drug resistance is a major reason for the failure of anti-cancer therapies after initial response. Here, we introduce a novel model of acquired oxaliplatin resistance, a sub-line of the non-MYCN-amplified neuroblastoma cell line SK-N-AS that was adapted to growth in the presence of 4000 ng/mL oxaliplatin (SK-N-ASrOXALI4000). SK-N-ASrOXALI4000 cells displayed enhanced chromosomal aberrations compared to SK-N-AS, as indicated by 24-chromosome fluorescence in situ hybridisation. Moreover, SK-N-ASrOXALI4000 cells were resistant not only to oxaliplatin but also to the two other commonly used anti-cancer platinum agents cisplatin and carboplatin. SK-N-ASrOXALI4000 cells exhibited a stable resistance phenotype that was not affected by culturing the cells for 10 weeks in the absence of oxaliplatin. Interestingly, SK-N-ASrOXALI4000 cells showed no cross resistance to gemcitabine and increased sensitivity to doxorubicin and UVC radiation, alternative treatments that like platinum drugs target DNA integrity. Notably, UVC-induced DNA damage is thought to be predominantly repaired by nucleotide excision repair and nucleotide excision repair has been described as the main oxaliplatin-induced DNA damage repair system. SK-N-ASrOXALI4000 cells were also more sensitive to lysis by influenza A virus, a candidate for oncolytic therapy, than SK-N-AS cells. In conclusion, we introduce a novel oxaliplatin resistance model. The oxaliplatin resistance mechanisms in SK-N-ASrOXALI4000 cells appear to be complex and not to directly depend on enhanced DNA repair capacity. Models of oxaliplatin resistance are of particular relevance since research on platinum drugs has so far predominantly focused on cisplatin and carboplatin

Overview of The Lost Meteorites of Antarctica Field Campaigns

The Lost Meteorites of Antarctica project was the first UK-led Antarctic meteorite recovery expedition. The project has successfully confirmed two new high-density meteorite stranding zones in the Hutchison Icefield and Outer Recovery Icefields areas and investigated the geology of three previously unvisited Antarctic nunataks (Turner Nunatak, Pillinger Nunatak, Halliday Nunatak). The project undertook meteorite searching on the ice surface via skidoo reconnaissance and systematic searching and developed a novel pulse induction metal detection system to search for englacial iron-rich meteorites trapped within the upper one meter of ice. In total, 121 meteorites have been recovered from the ice surface searching activities, which are now curated in the United Kingdom at the Natural History Museum London and are available for scientific analysis