bluuebunny/crossref_metadata_2025_split huggingface dataset:
APF2: an improved ensemble method for pharmacogenomic variant effect prediction
Authors: Zhou Yitian , Pirmann Sebastian , Lauschke Volker M. 
Published: May 2024

AbstractLack of efficacy or adverse drug response are common phenomena in pharmacological therapy causing considerable morbidity and mortality. It is estimated that 20–30% of this variability in drug response stems from variations in genes encoding drug targets or factors involved in drug disposition. Leveraging such pharmacogenomic information for the preemptive identification of patients who would benefit from dose adjustments or alternative medications thus constitutes an important frontier of precision medicine. Computational methods can be used to predict the functional effects of variant of unknown significance. However, their performance on pharmacogenomic variant data has been lackluster. To overcome this limitation, we previously developed an ensemble classifier, termed APF, specifically designed for pharmacogenomic variant prediction. Here, we aimed to further improve predictions by leveraging recent key advances in the prediction of protein folding based on deep neural networks. Benchmarking of 28 variant effect predictors on 530 pharmacogenetic missense variants revealed that structural predictions using AlphaMissense were most specific, whereas APF exhibited the most balanced performance. We then developed a new tool, APF2, by optimizing algorithm parametrization of the top performing algorithms for pharmacogenomic variations and aggregating their predictions into a unified ensemble score. Importantly, APF2 provides quantitative variant effect estimates that correlate well with experimental results (R2 = 0.91, p = 0.003) and predicts the functional impact of pharmacogenomic variants with higher accuracy than previous methods, particularly for clinically relevant variations with actionable pharmacogenomic guidelines. We furthermore demonstrate better performance (92% accuracy) on an independent test set of 146 variants across 61 pharmacogenes not used for model training or validation. Application of APF2 to population-scale sequencing data from over 800,000 individuals revealed drastic ethnogeographic differences with important implications for pharmacotherapy. We thus think that APF2 holds the potential to improve the translation of genetic information into pharmacogenetic recommendations, thereby facilitating the use of Next-Generation Sequencing data for stratified medicine.
Outdoor air pollution and risk of incident adult haematologic cancer subtypes in a large US prospective cohort
Authors: Diver W. Ryan , Teras Lauren R. , Deubler Emily L. , Turner Michelle C. 
Published: May 2024

Abstract
Background
Outdoor air pollution and particulate matter (PM) are classified as Group 1 human carcinogens for lung cancer. Pollutant associations with haematologic cancers are suggestive, but these cancers are aetiologically heterogeneous and sub-type examinations are lacking.

Methods
The American Cancer Society Cancer Prevention Study-II Nutrition Cohort was used to examine associations of outdoor air pollutants with adult haematologic cancers. Census block group level annual predictions of particulate matter (PM2.5, PM10, PM10-2.5), nitrogen dioxide (NO2), ozone (O3), sulfur dioxide (SO2), and carbon monoxide (CO) were assigned with residential addresses. Hazard ratios (HR) and 95% confidence intervals (CI) between time-varying pollutants and haematologic subtypes were estimated.

Results
Among 108,002 participants, 2659 incident haematologic cancers were identified from 1992–2017. Higher PM10-2.5 concentrations were associated with mantle cell lymphoma (HR per 4.1 μg/m3 = 1.43, 95% CI 1.08–1.90). NO2 was associated with Hodgkin lymphoma (HR per 7.2 ppb = 1.39; 95% CI 1.01–1.92) and marginal zone lymphoma (HR per 7.2 ppb = 1.30; 95% CI 1.01–1.67). CO was associated with marginal zone (HR per 0.21 ppm = 1.30; 95% CI 1.04–1.62) and T-cell (HR per 0.21 ppm = 1.27; 95% CI 1.00–1.61) lymphomas.

Conclusions
The role of air pollutants on haematologic cancers may have been underestimated previously because of sub-type heterogeneity.
PKA inhibition kills l-asparaginase-resistant leukemic cells from relapsed acute lymphoblastic leukemia patients
Authors: Lee Jung Kwon , Wang Xidi , Wang Jinghua , Rosales Jesusa L. , Lee Ki-Young 
Published: May 2024

AbstractDespite the success in treating newly diagnosed pediatric acute lymphoblastic leukemia (aLL), the long-term cure rate for the 20% of children who relapse is poor, making relapsed aLL the primary cause of cancer death in children. By unbiased genome-wide retroviral RNAi screening and knockdown studies, we previously discovered opioid receptor mu 1 (OPRM1) as a new aLL cell resistance biomarker for the aLL chemotherapeutic drug, l-asparaginase, i.e., OPRM1 loss triggers l-asparaginase resistance. Indeed, aLL cell OPRM1 level is inversely proportional to l-asparaginase IC50: the lower the OPRM1 level, the higher the l-asparaginase IC50, indicating that aLL cells expressing reduced OPRM1 levels show resistance to l-asparaginase. In the current study, we utilized OPRM1-expressing and -knockdown aLL cells as well as relapsed patient aLL cells to identify candidate targeted therapy for l-asparaginase-resistant aLL. In OPRM1-expressing cells, l-asparaginase induces apoptosis via a cascade of events that include OPRM1-mediated decline in [cAMP]i, downregulation of PKA-mediated BAD S118 phosphorylation that can be reversed by 8-CPT-cAMP, cyt C release from the mitochondria, and subsequent caspase activation and PARP1 cleavage. The critical role of PKA inhibition due to a decrease in [cAMP]i in this apoptotic process is evident in the killing of OPRM1-knockdown and low OPRM1-expressing relapsed patient aLL cells by the PKA inhibitors, H89 and 14–22 amide. These findings demonstrate for the first time that PKA can be targeted to kill aLL cells resistant to l-asparaginase due to OPRM1 loss, and that H89 and 14–22 amide may be utilized to destroy l-asparaginase-resistant patient aLL cells.
Characteristics, aetiology and implications for management of multiple primary renal tumours: a systematic review
Authors: Zhang Huairen , Andreou Avgi , Bhatt Rupesh , Whitworth James , Yngvadottir Bryndis , Maher Eamonn R. 
Published: May 2024

AbstractIn a subset of patients with renal tumours, multiple primary lesions may occur. Predisposition to multiple primary renal tumours (MPRT) is a well-recognised feature of some inherited renal cancer syndromes. The diagnosis of MPRT should therefore provoke a thorough assessment for clinical and genetic evidence of disorders associated with predisposition to renal tumourigenesis. To better define the clinical and genetic characteristics of MPRT, a systematic literature review was performed for publications up to 3 April 2024. A total of 7689 patients from 467 articles were identified with MPRT. Compared to all patients with renal cell carcinoma (RCC), patients with MPRT were more likely to be male (71.8% versus 63%) and have an earlier age at diagnosis (<46 years, 32.4% versus 19%). In 61.1% of cases MPRT were synchronous. The proportion of cases with similar histology and the proportion of cases with multiple papillary renal cell carcinoma (RCC) (16.1%) were higher than expected. In total, 14.9% of patients with MPRT had a family history of cancer or were diagnosed with a hereditary RCC associated syndrome with von Hippel-Lindau (VHL) disease being the most common one (69.7%), followed by Birt-Hogg-Dubé (BHD) syndrome (14.2%). Individuals with a known or likely genetic cause were, on average, younger (43.9 years versus 57.1 years). In rare cases intrarenal metastatic RCC can phenocopy MPRT. We review potential genetic causes of MPRT and their implications for management, suggest an approach to genetic testing for individuals presenting with MPRT and considerations in cases in which routine germline genetic testing does not provide a diagnosis.
Refining clinically relevant parameters for mis-splicing risk in shortened introns with donor-to-branchpoint space constraint
Authors: Zhang Katharine Y. , Joshi Himanshu , Marchant Rhett G. , Bryen Samantha J. , Dawes Ruebena , Yuen Michaela , Cooper Sandra T. , Evesson Frances J. 
Published: May 2024

AbstractIntronic deletions that critically shorten donor-to-branchpoint (D-BP) distance of a precursor mRNA impose biophysical space constraint on assembly of the U1/U2 spliceosomal complex, leading to canonical splicing failure. Here we use a series of β-globin (HBB) gene constructs with intron 1 deletions to define D-BP lengths that present low/no risk of mis-splicing and lengths which are critically short and likely elicit clinically relevant mis-splicing. We extend our previous observation in EMD intron 5 of 46 nt as the minimal productive D-BP length, demonstrating spliceosome assembly constraint persists at D-BP lengths of 47-56 nt. We exploit the common HBB exon 1 β-thalassemia variant that strengthens a cryptic donor (NM_000518.5(HBB):c.79G > A) to provide a simple barometer for the earliest signs of space constraint, via cryptic donor activation. For clinical evaluation of intronic deletions, we assert D-BP lengths > 60 nt present low mis-splicing risk while space constraint increases exponentially with D-BP lengths < 55 nt, with critical risk and profound splicing abnormalities with D-BP lengths < 50 nt.
Pushing the envelope: the feasibility of using a mailed contrast sensitivity test to prioritise cataract waiting lists
Authors: Bianchi Eleonora , Reddingius Peter F. , Rathore Mehal , Lindfield Dan , Crabb David P. , Jones Pete R. 
Published: May 2024

Abstract
Background
Cataract waiting lists are growing globally. Pragmatic, cost-effective methods are required to prioritise the most urgent cases. Here we investigate the feasibility of using a third-party pen-and-paper contrast sensitivity, CS, test (SpotChecksTM), delivered by mail, and performed by patients at home unsupervised, to flag eyes requiring surgery.

Methods
Pen-and-paper CS tests were mailed to 233 people waiting for a cataract assessment, along with a prepaid return envelope (cross-sectional study). Response rates were tabulated (stratified by age, sex and socioeconomic status), and test scores analysed to see how well the home tests predicted which eyes were listed subsequently for surgery. A subset of patients (N = 39) also underwent in-person follow-up testing, to confirm the accuracy of the home data.

Results
Forty-six percent of patients responded (216 eyes). No gross differences were observed between respondents and non-respondents, either in terms of age, sex, socioeconomic status, or geographic location (all P > 0.05). The home-test CS scores predicted which eyes were subsequently listed for surgery, with an AUROC {±CI95%} of 0.69 {0.61–0.76}. Predictive performance was further-improved when machine learning was used to combine CS scores with letter acuity, extracted from patients’ medical records (AUROC {±CI95%} = 0.77 {0.70–0.83}). Among 39 patients who underwent follow-up testing, home CS scores were correlated with various measures made in clinic: biometry signal-to-noise (P = 0.032), LogMAR acuity, Pelli-Robson CS and SpotChecks CS (all P < 0.001).

Conclusions
Mailing patients pen-and-paper CS tests may be a feasible, 'low-tech' way of prioritising patients on cataract waiting lists.
Safety outcomes following COVID-19 vaccination and infection in 5.1 million children in England
Authors: Copland Emma , Patone Martina , Saatci Defne , Handunnetthi Lahiru , Hirst Jennifer , Hunt David P. J. , Mills Nicholas L. , Moss Paul , Sheikh Aziz , Coupland Carol A. C. , Harnden Anthony , Robertson Chris , Hippisley-Cox Julia 
Published: May 2024

AbstractThe risk-benefit profile of COVID-19 vaccination in children remains uncertain. A self-controlled case-series study was conducted using linked data of 5.1 million children in England to compare risks of hospitalisation from vaccine safety outcomes after COVID-19 vaccination and infection. In 5-11-year-olds, we found no increased risks of adverse events 1–42 days following vaccination with BNT162b2, mRNA-1273 or ChAdOX1. In 12-17-year-olds, we estimated 3 (95%CI 0–5) and 5 (95%CI 3–6) additional cases of myocarditis per million following a first and second dose with BNT162b2, respectively. An additional 12 (95%CI 0–23) hospitalisations with epilepsy and 4 (95%CI 0–6) with demyelinating disease (in females only, mainly optic neuritis) were estimated per million following a second dose with BNT162b2. SARS-CoV-2 infection was associated with increased risks of hospitalisation from seven outcomes including multisystem inflammatory syndrome and myocarditis, but these risks were largely absent in those vaccinated prior to infection. We report a favourable safety profile of COVID-19 vaccination in under-18s.
Integrated photonic encoder for low power and high-speed image processing
Authors: Wang Xiao , Redding Brandon , Karl Nicholas , Long Christopher , Zhu Zheyuan , Skowronek James , Pang Shuo , Brady David , Sarma Raktim 
Published: May 2024

AbstractModern lens designs are capable of resolving greater than 10 gigapixels, while advances in camera frame-rate and hyperspectral imaging have made data acquisition rates of Terapixel/second a real possibility. The main bottlenecks preventing such high data-rate systems are power consumption and data storage. In this work, we show that analog photonic encoders could address this challenge, enabling high-speed image compression using orders-of-magnitude lower power than digital electronics. Our approach relies on a silicon-photonics front-end to compress raw image data, foregoing energy-intensive image conditioning and reducing data storage requirements. The compression scheme uses a passive disordered photonic structure to perform kernel-type random projections of the raw image data with minimal power consumption and low latency. A back-end neural network can then reconstruct the original images with structural similarity exceeding 90%. This scheme has the potential to process data streams exceeding Terapixel/second using less than 100 fJ/pixel, providing a path to ultra-high-resolution data and image acquisition systems.
Exposure to environmental pollutants selects for xenobiotic-degrading functions in the human gut microbiome
Authors: De Filippis Francesca , Valentino Vincenzo , Sequino Giuseppina , Borriello Giorgia , Riccardi Marita Georgia , Pierri Biancamaria , Cerino Pellegrino , Pizzolante Antonio , Pasolli Edoardo , Esposito Mauro , Limone Antonio , Ercolini Danilo 
Published: May 2024

AbstractEnvironmental pollutants from different chemical families may reach the gut microbiome, where they can be metabolized and transformed. However, how our gut symbionts respond to the exposure to environmental pollution is still underexplored. In this observational, cohort study, we aim to investigate the influence of environmental pollution on the gut microbiome composition and potential activity by shotgun metagenomics. We select as a case study a population living in a highly polluted area in Campania region (Southern Italy), proposed as an ideal field for exposomic studies and we compare the fecal microbiome of 359 subjects living in areas with high, medium and low environmental pollution. We highlight changes in gut microbiome composition and functionality that were driven by pollution exposure. Subjects from highly polluted areas show higher blood concentrations of dioxin and heavy metals, as well as an increase in microbial genes related to degradation and/or resistance to these molecules. Here we demonstrate the dramatic effect that environmental xenobiotics have on gut microbial communities, shaping their composition and boosting the selection of strains with degrading capacity. The gut microbiome can be considered as a pivotal player in the environment-health interaction that may contribute to detoxifying toxic compounds and should be taken into account when developing risk assessment models. The study was registered at ClinicalTrials.gov with the identifier NCT05976126.
Proton-coupled transport mechanism of the efflux pump NorA
Authors: Li Jianping , Li Yan , Koide Akiko , Kuang Huihui , Torres Victor J. , Koide Shohei , Wang Da-Neng , Traaseth Nathaniel J. 
Published: May 2024

AbstractEfflux pump antiporters confer drug resistance to bacteria by coupling proton import with the expulsion of antibiotics from the cytoplasm. Despite efforts there remains a lack of understanding as to how acid/base chemistry drives drug efflux. Here, we uncover the proton-coupling mechanism of the Staphylococcus aureus efflux pump NorA by elucidating structures in various protonation states of two essential acidic residues using cryo-EM. Protonation of Glu222 and Asp307 within the C-terminal domain stabilized the inward-occluded conformation by forming hydrogen bonds between the acidic residues and a single helix within the N-terminal domain responsible for occluding the substrate binding pocket. Remarkably, deprotonation of both Glu222 and Asp307 is needed to release interdomain tethering interactions, leading to opening of the pocket for antibiotic entry. Hence, the two acidic residues serve as a “belt and suspenders” protection mechanism to prevent simultaneous binding of protons and drug that enforce NorA coupling stoichiometry and confer antibiotic resistance.
Proximal protein landscapes of the type I interferon signaling cascade reveal negative regulation by PJA2
Authors: Schiefer Samira , Hale Benjamin G. 
Published: May 2024

AbstractDeciphering the intricate dynamic events governing type I interferon (IFN) signaling is critical to unravel key regulatory mechanisms in host antiviral defense. Here, we leverage TurboID-based proximity labeling coupled with affinity purification-mass spectrometry to comprehensively map the proximal human proteomes of all seven canonical type I IFN signaling cascade members under basal and IFN-stimulated conditions. This uncovers a network of 103 high-confidence proteins in close proximity to the core members IFNAR1, IFNAR2, JAK1, TYK2, STAT1, STAT2, and IRF9, and validates several known constitutive protein assemblies, while also revealing novel stimulus-dependent and -independent associations between key signaling molecules. Functional screening further identifies PJA2 as a negative regulator of IFN signaling via its E3 ubiquitin ligase activity. Mechanistically, PJA2 interacts with TYK2 and JAK1, promotes their non-degradative ubiquitination, and limits the activating phosphorylation of TYK2 thereby restraining downstream STAT signaling. Our high-resolution proximal protein landscapes provide global insights into the type I IFN signaling network, and serve as a valuable resource for future exploration of its functional complexities.
A tipping point in stable isotope composition of Antarctic meteoric waters during Cenozoic glaciation
Authors: Dallai Luigi , Sharp Zachary D. 
Published: May 2024

AbstractTriple oxygen isotopes of Cenozoic intrusive rocks emplaced along the Ross Sea coastline in Antarctica, reveal that meteoric-hydrothermal waters imprinted their stable isotope composition on mineral phases, leaving a clear record of oxygen and hydrogen isotope variations during the establishment of the polar cap. Calculated O- and H-isotope compositions of meteoric waters vary from −9 ± 2‰ and −92 ± 5‰ at 40 ± 0.6 Ma, to −30 and −234 ± 5‰ at 34 ± 1.9 Ma, and intersect the modern Global Meteoric Water Line. These isotopic variations likely depict the combined variations in temperature, humidity, and moisture source regions, resulting from rearrangement of oceanic currents and atmospheric cooling during the onset of continental ice cap. Here, we report a paleo-climatic proxy based on triple oxygen geochemistry of crystalline rocks that reveals changes in the hydrological cycle. We discuss the magnitude of temperature changes at high latitudes during the Eocene-Oligocene climatic transition.
Dynamic movement of the Golgi unit and its glycosylation enzyme zones
Authors: Harada Akihiro , Kunii Masataka , Kurokawa Kazuo , Sumi Takuya , Kanda Satoshi , Zhang Yu , Nadanaka Satomi , Hirosawa Koichiro M. , Tokunaga Kazuaki , Tojima Takuro , Taniguchi Manabu , Moriwaki Kenta , Yoshimura Shin-ichiro , Yamamoto-Hino Miki , Goto Satoshi , Katagiri Toyomasa , Kume Satoshi , Hayashi-Nishino Mitsuko , Nakano Miyako , Miyoshi Eiji , Suzuki Kenichi G. N. , Kitagawa Hiroshi , Nakano Akihiko 
Published: May 2024

AbstractKnowledge on the distribution and dynamics of glycosylation enzymes in the Golgi is essential for better understanding this modification. Here, using a combination of CRISPR/Cas9 knockin technology and super-resolution microscopy, we show that the Golgi complex is assembled by a number of small ‘Golgi units’ that have 1-3 μm in diameter. Each Golgi unit contains small domains of glycosylation enzymes which we call ‘zones’. The zones of N- and O-glycosylation enzymes are colocalised. However, they are less colocalised with the zones of a glycosaminoglycan synthesizing enzyme. Golgi units change shapes dynamically and the zones of glycosylation enzymes rapidly move near the rim of the unit. Photobleaching analysis indicates that a glycosaminoglycan synthesizing enzyme moves between units. Depletion of giantin dissociates units and prevents the movement of glycosaminoglycan synthesizing enzymes, which leads to insufficient glycosaminoglycan synthesis. Thus, we show the structure-function relationship of the Golgi and its implications in human pathogenesis.
AI-enabled Lorentz microscopy for quantitative imaging of nanoscale magnetic spin textures
Authors: McCray Arthur R. C. , Zhou Tao , Kandel Saugat , Petford-Long Amanda , Cherukara Mathew J. , Phatak Charudatta 
Published: May 2024

AbstractThe manipulation and control of nanoscale magnetic spin textures are of rising interest as they are potential foundational units in next-generation computing paradigms. Achieving this requires a quantitative understanding of the spin texture behavior under external stimuli using in situ experiments. Lorentz transmission electron microscopy (LTEM) enables real-space imaging of spin textures at the nanoscale, but quantitative characterization of in situ data is extremely challenging. Here, we present an AI-enabled phase-retrieval method based on integrating a generative deep image prior with an image formation forward model for LTEM. Our approach uses a single out-of-focus image for phase retrieval and achieves significantly higher accuracy and robustness to noise compared to existing methods. Furthermore, our method is capable of isolating sample heterogeneities from magnetic contrast, as shown by application to simulated and experimental data. This approach allows quantitative phase reconstruction of in situ data and can also enable near real-time quantitative magnetic imaging.