bluuebunny/crossref_metadata_2025_split huggingface dataset:
EHMT2 LOSS-OF-FUNCTION ALTERATIONS CAUSE A KLEEFSTRA-LIKE SYNDROME
Authors: Martinez-Delgado Beatriz , Lopez-Martin Estrella , Kerkhof Jennifer , Baladron Beatriz , Mielu Lidia M. , Sanchez-Ponce Diana , Bada-Navarro Ariadna , Herrero-Matesanz Marina , Lopez-Jimenez Lidia , Rzasa Jessica , Rots Dmitrijs , Fernandez Marta , Hernandez-San Miguel Esther , Gomez-Mariano Gema , Marin-Reina Purificacion , Cazorla-Calleja Rosario , Alonso Javier , Kleefstra Tjitske , Posada Manuel , Bermejo-Sanchez Eva , Sadikovic Bekim , Barrero Maria J. 
Published: January 2024

ABSTRACTDysregulation of the epigenetic machinery is associated with neurodevelopmental defects in humans. Kleefstra syndrome (KS) is a neurodevelopmental syndrome caused by heterozygous alterations in the geneEHMT1that cause loss-of-function. EHTM1 and EHMT2 are highly similar histone methyltransferases that play relevant roles in development. Despite their similarity, individuals with alterations inEHMT2have never been described. Here, we describe a pediatric patient with a KS-overlapping phenotype and a single base de novo substitution inEHMT2that causes the amino acid change p.Ala1077Ser in the catalytic SET domain. This change causes a reduction in the affinity of the catalytic domain for the H3 tail and in the activity of the enzyme by three- to five-fold. DNA methylation, histone methylation and gene expression profiles suggest a significant overlap between the EHMT2 p.Ala1077Ser variant and KS. Based on this evidence we suggest that EHMT2 haploinsufficiency causes a Kleefstra-like syndrome. Although we cannot rule out dominant negative effects caused by the EHMT2 p.Ala1077Ser variant, our data and previously published data suggest that loss of EHMT2 function is probably more detrimental to cells than loss of EHMT1, explaining why individuals with alterations inEHMT2are very rare.
A large-scale online survey of patients and the general public: Preferring safe and noninvasive neuromodulation for mental health
Authors: Atkinson-Clement Cyril , Junor Andrea , Kaiser Marcus 
Published: January 2024

AbstractWhile neurotechnology provides opportunities for novel mental health interventions, preferences of patients and the general public, and the reasons for their choices are still unclear. Here, we conducted a large-scale online survey with 784 participants, half of them suffering from psychiatric and/or neurological conditions. We asked about techniques ranging from invasive (pharmaceutical drugs and brain implants) to noninvasive approaches (ultrasound, magnetic, or electric stimulation). First, participants had a low level of prior knowledge but were interested and excited about these opportunities. Second, both patients and the general population preferred focused ultrasound stimulation (first choice) while drugs and implants were ranked 3rdand 5thout of five, respectively. Finally, that preference was mainly driven by whether they perceived a technology as safe, rather than as effective. Overall, this survey identifies safety as main criterion for interventions and shows a preference for novel noninvasive approaches such as focused ultrasound neuromodulation.HighlightsFocused ultrasound is the preferred intervention for brain and mental health conditionsThe preference of techniques was consistent between healthy participants and patients suffering from brain or mental health conditions.Getting more information about different neuromodulation techniques reduced confusion and increased feelings of being excited, optimistic, and comfortable with these techniquesThe ranking of preference is linked with the perceived safety but less related with perceived efficiency of techniques indicating safety as more important criterion
Highly accurate and precise automated cup-to-disc ratio quantification for glaucoma screening
Authors: Chaurasia Abadh K , Greatbatch Connor J , Han Xikun , Gharahkhani Puya , Mackey David A , MacGregor Stuart , Craig Jamie E , Hewitt Alex W 
Published: January 2024

ABSTRACTObjectiveAn enlarged cup-to-disc ratio (CDR) is a hallmark of glaucomatous optic neuropathy. Manual assessment of CDR may be inaccurate and time-consuming. Herein we sought to develop and validate a deep-learning-based algorithm to automatically determine CDR from fundus images.DesignAlgorithm development for estimating CDR using fundus data from a population-based observational study.ParticipantsA total of 184,580 fundus images from the UK Biobank, Drishti_GS, and EyePACS.Main Outcome MeasuresThe area under the receiver operating characteristic curve (AUROC) and coefficient of determination (R2).MethodsFastAI and PyTorch libraries were used to train a convolutional neural network-based model on fundus images from the UK Biobank. Models were constructed to determine image gradability (classification analysis) as well as to estimate CDR (regression analysis). The best-performing model was then validated for use in glaucoma screening using a multiethnic dataset from EyePACS and Drishti_GS.ResultsOur gradability model vgg19_bn achieved an accuracy of 97.13% on a validation set of 16,045 images, with 99.26% precision and AUROC of 96.56%. Using regression analysis, our best-performing model (trained on the vgg19_bn architecture) attained an R2of 0.8561 (95% CI: 0.8560-0.8562), while the mean squared error was 0.4714 (95% CI: 0.4712-0.4716) and mean absolute error was 0.5379 (95% CI: 0.5378-0.5380) on a validation set of 12,183 images for determining CDR (0-9.5 scale with a 0.5 interval). The regression point was converted into classification metrics using a tolerance of 2 for 20 classes; the classification metrics achieved an accuracy of 99.35%. The EyePACS dataset (98172 healthy, 3270 glaucoma) was then used to externally validate the model for glaucoma diagnosis, with an accuracy, sensitivity and specificity of 82.49%, 72.02% and 82.83%, respectively.ConclusionsOur models were precise in determining image gradability and estimating CDR in a time-efficient manner. Although our AI-derived CDR estimates achieve high accuracy, the CDR threshold for glaucoma screening will vary depending on other clinical parameters.PrecisDeep-learning-based models can accurately diagnose and monitor glaucoma progression through automated CDR assessment. However, the CDR threshold for glaucoma screening may vary depending on other clinical parameters.
Joint Association of Polygenic Risk and Social Determinants of Health with Coronary Heart Disease in the United States
Authors: Norland Kristjan , Schaid Daniel J. , Naderian Mohammadreza , Na Jie , Kullo Iftikhar J. 
Published: January 2024

AbstractBackgroundThe joint effects of polygenic risk and social determinants of health (SDOH) on coronary heart disease (CHD) in the United States are unknown.MethodsIn 67,256 All of Us (AoU) participants with available SDOH data, we ascertained self-reported race/ethnicity and calculated a polygenic risk score for CHD (PRSCHD). We used 90 SDOH survey questions to develop an SDOH score for CHD (SDOHCHD). We assessed the distribution of SDOHCHDacross self-reported races and US states. We tested the joint association of SDOHCHDand PRSCHDwith CHD in regression models that included clinical risk factors.ResultsSDOHCHDwas highest in self-reported black and Hispanic people. Self-reporting as black was associated with higher odds of CHD but not after adjustment for SDOHCHD. Median SDOHCHDvalues varied by US state and were associated with heart disease mortality. A 1-SD increase in SDOHCHDwas associated with CHD (OR=1.36; 95% CI, 1.29 to 1.46) and incident CHD (HR=1.73; 95% CI, 1.27 to 2.35) in models that included PRSCHDand clinical risk factors. Among people in the top 20% of PRSCHD, CHD prevalence was 4.8% and 7.8% in the bottom and top 20% of SDOHCHD, respectively.ConclusionsIncreased odds of CHD in self-reported black people are likely due to higher SDOH burden. SDOH and PRS were independently associated with CHD in the US. Our findings emphasize the need to consider both PRS and SDOH for equitable disease risk assessment.
First-in-human imaging with [89Zr]Zr-DFO-SC16.56 anti-DLL3 antibody in patients with high-grade neuroendocrine tumors of the lung and prostate
Authors: Tendler Salomon , Dunphy Mark P. , Agee Matthew , O’Donoghue Joseph , Aly Rania G. , Choudhury Noura J. , Kesner Adam , Kirov Assen , Mauguen Audrey , Baine Marina K. , Schoder Heiko , Weber Wolfgang A , Rekhtman Natasha , Lyashchenko Serge K. , Bodei Lisa , Morris Michael J. , Lewis Jason S. , Rudin Charles M. , Poirier John T. 
Published: January 2024

SUMMARYBackgroundDelta-like ligand 3 (DLL3) is aberrantly expressed on the cell surface in many neuroendocrine cancers including small cell lung cancer (SCLC) and neuroendocrine prostate cancer (NEPC). Several therapeutic agents targeting DLL3 are in active clinical development. Molecular imaging of DLL3 would enable non-invasive diagnostic assessment to inform the use of DLL3-targeting therapeutics or to assess disease treatment response.MethodsWe conducted a first-in-human immuno-positron emission tomography (immunoPET) imaging study of [89Zr]Zr-DFO-SC16.56, composed of the anti-DLL3 antibody SC16.56 conjugated to desferrioxamine (DFO) and the positron-emitting radionuclide zirconium-89, in 18 patients with neuroendocrine cancers. An initial cohort of three patients received 1–2 mCi of [89Zr]Zr-DFO-SC16.56 at a total mass dose of 2·5 mg and underwent serial PET and computed tomography (CT) imaging over the course of one week. Radiotracer clearance, tumor uptake, and radiation dosimetry were estimated. An expansion cohort of 15 additional patients were imaged using the initial activity and mass dose. Retrospectively collected tumor biopsies were assessed for DLL3 by immunohistochemistry (IHC) (n = 16).FindingsImaging of the initial 3 SCLC patients demonstrated strong tumor-specific uptake of [89Zr]Zr-DFO-SC16.56, with similar tumor: background ratios at days 3, 4, and 7 post-injection. Serum clearance was bi-phasic with an estimated terminal clearance half-time of 119 h. The sites of highest background tracer uptake were blood pool and liver. The normal tissue receiving the highest radiation dose was liver; 1·8 mGy/MBq, and the effective dose was 0.49 mSv/MBq. Tumoral uptake varied both between and within patients, and across anatomic sites, with a wide range in SUVmax (from 3·3 to 66·7). Tumor uptake by [89Zr]Zr-DFO-SC16.56 was associated with protein expression in all cases. Two non-avid DLL3 NEPC cases by PET scanning demonstrated the lowest DLL3 expression by tumor immunohistochemistry. Only one patient had a grade 1 allergic reaction, while no grade ≥2 adverse events noted.InterpretationDLL3 PET imaging of patients with neuroendocrine cancers is safe and feasible. These results demonstrate the potential utility of [89Zr]Zr-DFO-SC16.56 for non-invasive in vivo detection of DLL3-expressing malignancies.FundingSupported by NIH R01CA213448 (JTP), R35 CA263816 (CMR), U24 CA213274 (CMR), R35 CA232130 (JSL), and a Prostate Cancer Foundation TACTICAL Award (JSL), Scannell foundation. The Radiochemistry and Molecular Imaging Probes Core Facility is supported by NIH P30 CA08748.
Complex trait associations in rare diseases and impacts on Mendelian variant interpretation
Authors: Smail Craig , Ge Bing , Keever-Keigher Marissa R. , Schwendinger-Schreck Carl , Cheung Warren , Johnston Jeffrey J. , Barrett Cassandra ,   Genomic Answers for Kids Consortium, Feldman Keith , Cohen Ana S.A. , Farrow Emily G. , Thiffault Isabelle , Grundberg Elin , Pastinen Tomi 
Published: January 2024

AbstractEmerging evidence implicates common genetic variation – aggregated into polygenic scores (PGS) – impacting the onset and phenotypic presentation of rare diseases. In this study, we quantified individual polygenic liability for 1,151 previously published PGS in a cohort of 2,374 probands enrolled in the Genomic Answers for Kids (GA4K) rare disease study, revealing widespread associations between rare disease phenotypes and PGSs for common complex diseases and traits, blood protein levels, and brain and other organ morphological measurements. We observed increased polygenic burden in probands with variants of unknown significance (VUS) compared to unaffected carrier parents. We further observed an enrichment in overlap between diagnostic and candidate rare disease genes and large-effect PGS genes. Overall, our study supports and expands on previous findings of complex trait associations in rare disease phenotypes and provides a framework for identifying novel candidate rare disease genes and in understanding variable penetrance of candidate Mendelian disease variants.
Brain transcriptomics reveals features of the host response after dengue virus type I infection induced central nervous system injury in AGB6 mice
Authors: Yu Ning , Chen Shigang , Liu Yumeng , Wang Peng , Wang Longlong , Hu Ningning , Zhang He , Li Xiao , Lu Huijun , Jin Ningyi 
Published: January 2024

ABSTRACTDengue viruses are the causative agents of dengue fever, dengue hemorrhagic fever, and dengue shock syndrome, which are mainly transmitted by Aedes aegypti and Aedes albopictus mosquitoes, and cost billions of dollars annually in medical and mosquito control. It is estimated that up to 20% of dengue virus infections affect the brain. The incidence of DENV infection of the nervous system is increasing, suggesting that more people are at risk for neurological complications of the infection. Currently, understanding the pathogenic mechanisms of dengue virus infection of the nervous system is hampered by the lack of suitable small animal models. Here, we analyzed the pathogenicity of dengue virus in type I and type Ⅱ interferon receptor-deficient mice by intraperitoneal inoculation of DENV-I. Infected mice showed such neurological symptoms as opisthotonus, hunching, ataxia, and paralysis of one or both hind limbs. Viremia can be detected 3 days after infection. The virus showed evident brain tropism post-inoculation and viral loads peaked at 14 days post-inoculation in infected mice brain. Significant histopathologic changes were observed in brain tissue (hippocampal region and cerebral cortex). Immunohistochemistry and fluorescence showed clear fluorescent signals. Hematological analysis showed hemorrhage and hemoconcentration in DENV-I infected mice. Subsequently, brain tissue transcriptome sequencing was performed to assess host response characteristics in DENV-I infected AGB6 mice. Functional enrichment analysis and analysis of significantly differentially expressed genes (DEGs) were used to identify the key molecular mechanisms of brain tissue injury. Transcriptional patterns in brain tissue suggest that aberrant expression of pro-inflammatory cytokines induces antiviral responses to dengue virus and tissue damage. Combined with the KEGG results, it was hypothesized that the probable cause of the neurological damage affecting the neurological system and hindlimb paralysis was the marked enrichment of upregulated DEGs in the cytokine-cytokine receptor interaction signaling pathway. Screening of hub genes and their characterization by qPCR and ELISA, it was hypothesized that IL-6 and IFN-γ might be the key factors in dengue virus-induced neurological manifestations.
Heterotrophic prokaryotes internal carbon recycling compensates mismatches between phytoplankton production and heterotrophic prokaryotic consumption
Authors: Eigemann Falk , Tait Karen , Temperton Ben , Hellweger Ferdi L. 
Published: January 2024

AbstractMolecular observational tools are great for characterizing the composition and genetic endowment of microbial communities, but cannot measure fluxes, which are critical for the understanding of ecosystems. To overcome these limitations, we use a mechanistic inference approach to estimate dissolved organic carbon (DOC) production and consumption by phytoplankton operational taxonomic units (OTUs) and heterotrophic prokaryotic amplicon sequences variants (ASVs), and infer carbon fluxes between members of this microbial community from Western English Channel (WEC) time-series data. Our analyses focus on phytoplankton spring and summer blooms, as well as bacteria summer blooms. In spring blooms, phytoplankton DOC production exceeds heterotrophic prokaryotic consumption, but in bacterial summer blooms heterotrophic prokaryotes consume almost 3 times more DOC than produced by the phytoplankton. This mismatch is compensated by heterotrophic prokaryotic DOC release by death, presumably viral lysis. In both types of summer blooms, large amounts of the DOC liberated by heterotrophic prokaryotes are reused, i.e. internally recycled, and fluxes between different heterotrophic prokaryotes are at the same level as fluxes between phytoplankton and heterotrophic prokaryotes. Contextualized, internal recycling accounts for approximately 75% and 30% of the estimated net primary production (0.16 vs 0.22 and 0.08 vs 0.29 µmol l-1d-1) in bacteria and phytoplankton summer blooms, respectively, and thus represents a major component of the WEC carbon cycle. We conclude that internal recycling compensates mismatches between phytoplankton DOC production and heterotrophic prokaryotic consumption, and encourage future analyses on aquatic carbon cycles to consider fluxes between heterotrophic prokaryotes, i.e. internal recycling.
Cell Cycle Regulation has Shaped Budding Yeast Replication Origin Structure and Function
Authors: Lim Chew Theng , Miller Thomas C.R. , Tan Kang Wei , Talele Saurabh , Early Anne , East Philip , Sánchez Humberto , Dekker Nynke H. , Costa Alessandro , Diffley John F.X. 
Published: January 2024

SummaryEukaryotic DNA replication initiates from multiple genomic loci known as origins. At budding yeast origins like ARS1, a double hexamer (DH) of the MCM replicative helicase is assembled by Origin Recognition Complex (ORC), Cdc6 and Cdt1 via sequential hexamer loading from two opposed ORC binding sites. Cyclin Dependent Kinase (CDK) inhibits DH assembly, which prevents re-replication by restricting helicase loading to G1 phase. Here we show that an intrinsically disordered region (IDR) in the Orc2 subunit promotes interaction between ORC and the first loaded, closed-ring MCM hexamer (the MO intermediate); CDK phosphorylation of this IDR blocks MO formation and DH assembly. We show that MO functions by stabilising ORC at the lower affinity binding sites required for second hexamer loading. Origins comprising two high affinity ORC sites can assemble DH efficiently without MO by independently loading single hexamers; these origins escape CDK inhibitionin vitroandin vivo. Our work reveals mechanistic plasticity in MCM loading with implications for understanding how CDK regulation has shaped yeast origin evolution and how natural origins might escape cell cycle regulation. We also identify key steps common to loading pathways, with implications for understanding how MCM is loaded in other eukaryotes.
A new and widespread group of fish apicomplexan parasites
Authors: Bonacolta Anthony M , Krause Joana , Smit Nico J , Sikkel Paul , del Campo Javier 
Published: January 2024

SummaryApicomplexans are obligate intracellular parasites which have evolved from a free-living, phototrophic ancestor. Well-known representatives includePlasmodium, the causative agent of malaria, and the gregarines which infect a vast number of marine invertebrates. Apicomplexans have been reported from marine environmental samples in high numbers1, with several clades of Apicomplexan-Related Lineages (ARLs) having been described from environmental sequencing data (SSU rRNA metabarcoding)2. The most notable of these being the corallicolids (previously known as ARL-V) which possess chlorophyll-biosynthesis genes in their relic chloroplast (apicoplast) and are geographically wide-spread and abundant symbionts of anthozoans3.Ophioblennius macclurei, the redlip blenny, along with other tropical reef fishes, is known to be infected byHaemogregarina-like andHaemohormidium-like parasites4; however previous phylogenetic work using the 18S rRNA genes shows these parasites to be distinct from where they are classified morphologically5,6and instead related to the Coccidia. Hybrid genomic sequencing incorporating Oxford Nanopore Technologies long reads and Illumina short reads of apicomplexan-infectedO. macclureiblood was carried out to retrieve more genetic information on these parasites. Using this approach, we were able to recover the entire rRNA operon of this apicomplexan parasite along with the complete mitochondrion and apicoplast genomes. Phylogenetic analyses using this new genomic information consistently place these fish-infecting apicomplexans, hereby informally named ichthyocolids, sister to the corallicolids within Coccidia. The apicoplast genome did not contain chlorophyll biosynthesis genes, providing evidence for another independent loss of this pathway within Apicomplexa. Based on the 16S rRNA gene found in the apicoplast, this group corresponds to the previously described ARL-VI. Screening of fish microbiome studies using the plastid 16S rRNA gene shows these parasites to be geographically and taxonomically widespread in fish species across the globe with potentially major implications for commercial fisheries and oceanic food webs.
Sensitivity of dairy calfSalmonella entericaserotype Cerro isolates to infection-relevant stressors
Authors: Raabis Sarah M. , Westerman Trina L. , Cruz Eddy , Deblois Courtney L. , Suen Garret , Elfenbein Johanna R. 
Published: January 2024

AbstractSalmonella entericaserotype Cerro (S.Cerro) is an emergingSalmonellaserotype isolated from cattle, but the association ofS.Cerro with disease is not well understood. While comparative genomic analyses of bovineS.Cerro isolates have indicated mutations in elements associated with virulence, the correlation ofS.Cerro fecal shedding with clinical disease in cattle varies between epidemiologic studies. The primary objective of this study was to characterize the infection-relevant phenotypes ofS.Cerro fecal isolates obtained from neonatal calves born on a dairy farm in Wisconsin, USA. TheS.Cerro isolates varied in biofilm production and sensitivity to the bile salt deoxycholate. AllS.Cerro isolates were sensitive to sodium hypochlorite, hydrogen peroxide, and acidic shock. However,S.Cerro isolates were resistant to nitric oxide stress. TwoS. Cerro isolates were unable to compete withS.Typhimurium during infection of calf ligated intestinal loops, indicating decreased fitnessin vivo. Together, our data suggest thatS.Cerro is sensitive to some innate antimicrobial defenses present in the gut, many of which are also used to controlSalmonellain the environment. The observed phenotypic variation inS.Cerro isolates from a single farm suggest phenotypic plasticity that could impact infectious potential, transmission, and persistence on a farm.ImportanceSalmonella entericais a zoonotic pathogen that threatens both human and animal health.Salmonella entericaserotype Cerro is being isolated from cattle at increasing frequency over the past two decades, however its association with clinical disease is unclear. The goal of this study was to characterize infection-relevant phenotypes ofS.Cerro isolates obtained from dairy calves from a single farm. Our work shows that there can be variation among temporally-relatedS.Cerro isolates and that these isolates are sensitive to killing by toxic compounds of the innate immune system and those used for environmental control ofSalmonella. This work contributes to our understanding of the pathogenic potential of the emerging pathogenS. Cerro.