bluuebunny/crossref_metadata_2025 huggingface dataset:
p110α-dependent hepatocyte signaling is critical for liver gene expression and its rewiring in MASLD
Authors: Régnier Marion , Polizzi Arnaud , Fougeray Tiffany , Fougerat Anne , Perrier Prunelle , Anderson Karen , Lippi Yannick , Sarra Smati , Lukowicz Céline , Lasserre Frédéric , Fouche Edwin , Huillet Marine , Rives Clémence , Tramunt Blandine , Naylies Claire , Garcia Géraldine , Rousseau-Bacquié Elodie , Bertrand-Michel Justine , Canlet Cécile , Chevolleau-Mege Sylvie , Debrauwer Laurent , Heymes Christophe , Burcelin Rémy , Levade Thierry , Gourdy Pierre , Wahli Walter , Blum Yuna , Gamet-Payrastre Laurence , Ellero-Simatos Sandrine , Guillermet-Guibert Julie , Hawkins Phillip , Stephens Len , Postic Catherine , Montagner Alexandra , Loiseau Nicolas , Guillou Hervé
Published: January 2024

Insulin and other growth factors are key regulators of liver gene expression, including in metabolic diseases. Most of the phosphoinositide 3-kinase (PI3K) activity induced by insulin is dependent on PI3Kα. We used mice lacking p110α, the catalytic subunit of PI3Kα, to investigate its role in the regulation of liver gene expression in health and in Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD). The absence of hepatocyte PI3Kα signaling promoted glucose intolerance in lean mice and significantly regulated liver gene expression, including insulin-sensitive genes, inad libitumfeeding. Some of the defective regulation of gene expression in response to hepatocyte-restricted insulin receptor deletion was related to PI3Kα signaling. In addition, though PI3Kα deletion in hepatocytes promoted insulin resistance, it was protective against steatotic liver disease in diet-induced obesity. In the absence of hepatocyte PI3Kα, the effect of diet-induced obesity on liver gene expression was significantly altered, with changes in rhythmic gene expression in liver. Altogether, this study highlights the specific role of p110α in the control of liver gene expression in physiology and in the metabolic rewiring that occurs during MASLD.
Maternal den site fidelity of polar bears in western Hudson Bay
Authors: Klappstein Natasha , McGeachy David , Pilfold Nicholas , Lunn Nicholas , Derocher Andrew
Published: January 2024

Seasonal migrations allow to access temporally varying resources and individuals may show fidelity to specific locations. Polar bears (Ursus maritimus) are a sea ice dependent species that migrate between marine and terrestrial habitats, the latter being important for parturition and early cub rearing. However, fidelity to maternity den sites is poorly understood. We assessed polar bear maternal den site fidelity of the Western Hudson Bay subpopulation in Manitoba, Canada. Using capture and telemetry data collected between 1979−2018, we examined site fidelity from 188 maternity den locations from 78 individuals. We calculated within-individual inter-year distances between dens, and compared these to between-individual distances via non-parametric bootstrapping. We used generalised additive models to assess how maternal age, years between denning events, and sea ice conditions affected site fidelity. We found some evidence of site fidelity, as within-individual inter-year distances were smaller than between-individual den distances by approximately 18.5 km. As time between captures increased, inter-den distances also increased (ranging from approximately 25 km to 55 km), but no other variables significantly affected fidelity. Our findings suggest that western Hudson Bay polar bears show a moderate amount of fidelity to denning areas, but not necessarily to specific sites.
Arthropod community composition in urban landscapes is shaped by both environmental filtering and dispersal limitation
Authors: Roper-Edwards Indigo R. , Hurlbert Allen H.
Published: January 2024

We assessed the relative importance of environmental filtering and dispersal limitation in structuring foliage- and ground-dwelling arthropod communities in central North Carolina. We hypothesized that both the local environment and the dispersal distance between sites would predict community composition, but that dispersal distance would be more important for ground arthropods than for foliage arthropods. In both groups, variation in habitat characteristics was important in structuring communities, and the role of dispersal in structuring communities was much greater after accounting for variation in landscape connectivity. Our results demonstrate the importance of both dispersal limitation and environmental filtering in shaping community composition and emphasize the importance of variation in the landscape for modeling these forces. Examining communities of multiple arthropod groups across the same spatial gradient highlights the scale-dependence of these processes and illustrates how variation in the environment can alter the relative abundance of specialist and generalist taxa.
Feedback loop regulation between viperin and viral hemorrhagic septicemia virus through competing protein degradation pathways
Authors: Lu Xiaobing , Yi Meisheng , Hu Zhe , Yang Taoran , Zhang Wanwan , Marsh E. Neil G. , Jia Kuntong
Published: January 2024

Viperin is an antiviral protein that exhibits a remarkably broad spectrum of antiviral activity. Viperin-like proteins are found all kingdoms of life, suggesting it is an ancient component of the innate immune system. However, viruses have developed strategies to counteract viperin’s effects. Here, we describe a feedback loop between viperin and viral hemorrhagic septicemia virus (VHSV), a common fish pathogen. We show thatLateolabrax japonicusviperin (Ljviperin) is induced by both IFN-independent and IFN-dependent pathways, with the C-terminal domain ofLjviperin being important for its anti-VHSV activity.Ljviperin exerts an antiviral effect by binding both the nucleoprotein (N) and phosphoprotein (P) of VHSV and induces their degradation through the autophagy pathway, which is an evolutionarily conserved antiviral mechanism. However, counteracting viperin’s activity, N protein targets and degrades transcription factors that up-regulateLjviperin expression, interferon regulatory factor (IRF) 1 and IRF9, through ubiquitin-proteasome pathway. Together, our results reveal a previously unknown feedback loop between viperin and virus, providing potential therapeutic targets for VHSV prevention.

Importance

Viral hemorrhagic septicaemia (VHS) is a contagious disease caused by the viral hemorrhagic septicaemia virus (VHSV), which poses a threat to over 80 species of marine and freshwater fish. Currently, there are no effective treatments available for this disease. Understanding the mechanisms of VHSV-host interaction is crucial for preventing viral infections. Here, we found that, as an ancient antiviral protein, viperin degrades the N and P proteins of VHSV through the autophagy pathway. Additionally, the N protein also impacts the biological functions of IRF1 and IRF9 through the ubiquitin-proteasome pathway, leading to the suppression of viperin expression. Therefore, the N protein may serve as a potential virulence factor for the development of VHSV vaccines and screening of antiviral drugs. Our research will serve as a valuable reference for the development of strategies to prevent VHSV infections.
A bibliometric analysis of neurobiological and behavioral disturbances of cafeteria diet interventions
Authors: Lopez-Castro Alejandra
Published: January 2024

Obesity is a global epidemic mainly caused by the overconsumption of western diets, high in fat and sugars. Cafeteria diet administered to rodents is an effective model of the metabolic, neurobiological, and behavioral disturbances caused by the over consumption of western diet in humans. However, this is still an emerging research field. To provide information about the past, present and future of the research field, this study aims to explore the research field of cafeteria diet and behavior through bibliometric analysis. Original articles on cafeteria diet and behavior were obtained from Pubmed, Scopus and Web of Science databases from 2013 to Octuber 30, 2023. The R packages litsearchr, bibliometrix, sjrdata and mblm were used for descriptive and inferential statistics. Linear regression, concept mapping and trend analysis were used for relationship analysis. 85 articles included from 457 authors, 20 countries and 56 institutions were included. 46 from Pubmed, 12 from Scopus and 27 from Web of Science. The 25 topmost productive authors were from Spain, Brazil, Australia, Switzerland, and USA. 15 authors had an h-index higher than 3. The institution with the largest production of articles is the University of South Wales with 10 articles. A simple linear regression could not establish significance between the relationship between the impact factor and the number of citations received. In addition, a conceptual structure map was performed, and 5 clusters were found. Finally, by a bi-factor analysis, a trend topic established that anxiety is the term currently in trend and since 2017 in the cafeteria diet and behavior research field. The present study explores the performance of authors, countries, institutions, and journals on classical measures of scientific parameters. This helped to model multiple correspondence and trend analyses that provide a reliable source of information to direct research on cafeteria diet interventions.
Estrogen receptor-related receptor (Esrra) induces ribosomal protein Rplp1-mediated adaptive hepatic translation during prolonged starvation
Authors: Tripathi Madhulika , Gauthier Karine , Sandireddy Reddemma , Zhou Jin , Gupta Priyanka , Sakthivel Suganya , Jiemin Nah , Arul Kabilesh , Tikno Keziah , Park Sung-Hee , Wang Lijin , Ho Lena , Giguere Vincent , Ghosh Sujoy , McDonnell Donald P. , Yen Paul M. , Singh Brijesh K.
Published: January 2024

Protein translation is an energy-intensive ribosome-driven process that is reduced during nutrient scarcity to conserve cellular resources. During prolonged starvation, cells selectively translate specific proteins to enhance their survival (adaptive translation); however, this process is poorly understood. Accordingly, we analyzed protein translation and mRNA transcription by multiple methodsin vitroandin vivoto investigate adaptive hepatic translation during starvation. While acute starvation suppressed protein translation in general, proteomic analysis showed that prolonged starvation selectively induced translation of lysosome and autolysosome proteins. Significantly, the expression of the orphan nuclear receptor, estrogen-related receptor alpha (Esrra) increased during prolonged starvation and served as a master regulator of this adaptive translation by transcriptionally stimulating 60S acidic ribosomal protein P1 (Rplp1) gene expression. Overexpression or siRNA knockdown of Esrra expressionin vitroorin vivoled to parallel changes in Rplp1 gene expression, lysosome/autophagy protein translation, and autophagy. Remarkably, we have found that Esrra had dual functions by not only regulating transcription but also controling adaptive translation via the Esrra/Rplp1/lysosome/autophagy pathway during prolonged starvation.
Towards a phylogenomic classification of Magnoliidae
Authors: Helmstetter Andrew J. , Ezedin Zacky , de Lírio Elton John , de Oliveira Sylvia M. , Chatrou Lars W. , Erkens Roy H.J. , Larridon Isabel , Leempoel Kevin , Maurin Olivier , Roy Shyamali , Zuntini Alexandre R. , Baker William J. , Couvreur Thomas L.P. , Forest Félix , Sauquet Hervé
Published: January 2024

Premise

Magnoliidae are a strongly supported clade of angiosperms. Previous phylogenetic studies based primarily on analyses of a limited number of mostly plastid markers have led to the current classification of magnoliids into four orders and 18 families. However, uncertainty remains regarding the placement of several families.

Methods

Here we present the first comprehensive phylogenomic analysis of Magnoliidae as a whole, sampling 235 species from 199 (74%) genera and representing all families and most previously accepted subfamilies and tribes. We analyze newly generated data from the Angiosperms353 probe set using both coalescent and concatenation analyses and testing the impact of multiple filtering and alignment strategies.

Results

While our results generally provide further support for previously established phylogenetic relationships in both magnoliids as a whole and large families including Annonaceae and Lauraceae, they also provide new evidence for previously ambiguous relationships. In particular, we find support for the position of Hydnoraceae as sister to the remainder of Piperales and, for the first time, resolve the backbone of relationships among most genera of Myristicaceae.

Conclusions

Although some of our results are limited by low gene recovery for a number of taxa and significant gene tree conflict for some relationships, this study represents a significant step towards reconstructing the evolutionary history of a major lineage of angiosperms. Based on these results, we present an updated phylogenetic classification for Magnoliidae, recognizing 21 families, summarizing previously established subfamilies and tribes, and describing new tribes for Myristicaceae.
Analysis of 193,618 trauma patient presentations in war-affected Syria from July 2013 to July 2015
Authors: Mowafi Hani , Hariri Mahmoud , Zhang Baobao , Alnahhas Houssam , Bakri Basil , Eldahan Adam , Moustafa Moustafa , Saqqur Maher , Al-Kassem Anas
Published: January 2024

Introduction

Since 2011, the Syrian war has produced a mounting toll in terms of deaths and displaced persons. We present an analysis of demographic and temporal patterns of trauma patient presentations to Syrian hospitals in non-governmental, non-Islamic State (NGNI) regions from 2013 – 2015.

Methods

We analyzed an administrative dataset of patient presentations to 95 NGNI Syrian hospitals in regions outside of Syrian government control from July 2013 – July 2015. Descriptive analysis of this secondary data is reported and logistic regression was performed to assess for factors associated with inpatient mortality.

Results

193,618 trauma patients presented to 95 NGNI hospitals from July 2013 – July 2015 (154,225 male, 79.7%; 39,393 female, 20.4%). Age information was complete for 160,237 encounters (82.8%): 0-2y: 8,257 (4.3%), 3-12y: 24,199 (12.5%), 13-18y: 22,482 (11.6%), 19-60y: 100,553 (51.9%), and elders over 60 years: 4,746 (2.5%). 59,387 patients were admitted (Ward 57,625; ICU 1,762) for an average length of stay of 3.80 days. There were 2,694 inpatient deaths (4.5% of admitted) and 4,758 patients (8.0%) required transfer to another facility for definitive care. Shrapnel (81,946; 42.3%) and blunt/crush injuries (71,477; 36.9%) were dominant injury mechanisms with an increasing proportion of these injuries over time. Inpatient mortality was most associated with extremes of age (age less than 2 aOR 2.92; age greater than 60 aOR 2.48), penetrating chest trauma (gunshot-chest aOR 6.03) and neurotrauma (blast-head aOR 13.42; blast-spine aOR 11.31; gunshot-head aOR 10.07; shrapnel-head aOR 6.34). Civilians presentations increased from 20% at start of data collection to a peak of 50% in June 2015.

Conclusion

The Syrian war has resulted in large volumes of trauma patients and significant mortality at NGNI Syrian hospitals. Mortality was most associated with neurotrauma and penetrating chest trauma. There was an increasing trend over time towards blunt/crush and shrapnel injuries consistent with the transition to the widespread use of aerial bombardment with resultant explosions and building collapse. Civilians including children and the elderly represent high proportions of the injured in NGNI Syrian hospitals. Additional work is needed to improve documentation of clinical service and to assess outcomes of care to improve quality of services provided to Syrian war trauma patients.
Discovery and validation of plasma-based protein biomarkers for the aetiological distinction of bacterial and non-bacterial febrile infections in African children
Authors: Waeni Jacqueline M , Chege Timothy K , Gicheru Elijah T , Mutunga Martin , Njunge James , O’Connor Daniel , Sande Charles J
Published: January 2024

Background

In many low resource settings, the clinical management of children with febrile infections is hindered by poor access to diagnostic tools to determine whether the cause of an infection is bacterial, viral or parasitic. As a result, many clinicians resort to the default prescription of antibiotics as a safety precaution, contributing to the alarming spread of antimicrobial resistance. Commonly used biomarkers for identification of bacterial sepsis such as CRP lack aetiological specificity and are frequently elevated by non-bacterial infections including malaria. We set out to discover and validate new biomarkers for the characterization of the microbial aetiology of febrile acute infections in Kenyan children.

Methods

We recruited a discovery cohort comprising of children who had been admitted to hospital with a variety of severe acute infections. Diagnostic identification of viral infections was done using a 15-target virus PCR panel, bacterial infections were identified using blood culture while malaria infections were identified by microscopy. Using mass spectrometry analysis, we identified a set of 76 plasma proteins whose abundance varied significantly by the microbial aetiology of infection and used machine learning to generate a shortlist of candidate biomarkers that had the highest diagnostic performance in distinguishing aetiologies. To validate these candidate biomarkers, we recruited a separate validation cohort where the plasma levels of the shortlisted biomarkers were assayed among children with different infectious aetiologies using a custom protein microarray.

Results

In the discovery study, six candidate biomarkers whose plasma abundance was significantly different in children with bacterial and viral infections were shortlisted by random forest for cross-cohort validation (AGT, HRG, LBP, PON1, SERPINA1, SERPINA3). In the validation study, we found that of the six biomarkers, only AGT compared favourably to CRP and identified febrile bacterial infections with a sensitivity of 72.4% (95% CI 48.4% - 83.6%) compared to CRP which distinguished febrile bacterial infections with a sensitivity of 69.5% (30.8% - 88.2%). Plasma AGT was superior to CRP in distinguishing children with febrile bacterial infections from those with febrile malaria episodes, with a sensitivity of 72.5% (40% - 84.6%) for AGT and 26% (15% - 32.8%) for CRP.

Conclusions

We report the discovery of AGT, as a sensitive plasma biomarker for the identification of febrile bacterial infections among African children living in a malaria endemic setting.
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

Dysregulation 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

While 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.

Highlights

Focused ultrasound is the preferred intervention for brain and mental health conditions

The 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 techniques

The 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

Objective

An 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.

Design

Algorithm development for estimating CDR using fundus data from a population-based observational study.

Participants

A total of 184,580 fundus images from the UK Biobank, Drishti_GS, and EyePACS.

Main Outcome Measures

The area under the receiver operating characteristic curve (AUROC) and coefficient of determination (R2).

Methods

FastAI 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.

Results

Our 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.

Conclusions

Our 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.

Precis

Deep-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

Background

The joint effects of polygenic risk and social determinants of health (SDOH) on coronary heart disease (CHD) in the United States are unknown.

Methods

In 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.

Results

SDOHCHDwas 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.

Conclusions

Increased 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

Background

Delta-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.

Methods

We 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).

Findings

Imaging 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.

Interpretation

DLL3 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.

Funding

Supported 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

Emerging 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

Dengue 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

Molecular 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.
Mechanosensitive genomic enhancers potentiate the cellular response to matrix stiffness
Authors: Cosgrove Brian D. , Bounds Lexi R. , Taylor Carson Key , Su Alan L. , Rizzo Anthony J. , Barrera Alejandro , Crawford Gregory E. , Hoffman Brenton D. , Gersbach Charles A.
Published: January 2024

Epigenetic control of cellular transcription and phenotype is influenced by changes in the cellular microenvironment, yet how mechanical cues from these microenvironments precisely influence epigenetic state to regulate transcription remains largely unmapped. Here, we combine genome-wide epigenome profiling, epigenome editing, and phenotypic and single-cell RNA-seq CRISPR screening to identify a new class of genomic enhancers that responds to the mechanical microenvironment. These ‘mechanoenhancers’ could be active on either soft or stiff extracellular matrix contexts, and regulated transcription to influence critical cell functions including apoptosis, mechanotransduction, proliferation, and migration. Epigenetic editing of mechanoenhancers on rigid materials tuned gene expression to levels observed on softer materials, thereby reprogramming the cellular response to the mechanical microenvironment. These editing approaches may enable the precise alteration of mechanically-driven disease states.
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

Eukaryotic 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

Apicomplexans 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

Salmonella 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.

Importance

Salmonella 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.
An almost chromosome-level assembly and annotation of theAlectoris rufagenome
Authors: Eleiwa Abderrahmane , Nadal Jesus , Vilaprinyo Ester , Marin-Sanguino Alberto , Sorribas Albert , Basallo Oriol , Lucido Abel , Richart Cristobal , Pena Romi , Ros-Freixedes Roger , Usie Anabel , Alves Rui
Published: January 2024

The red-legged partridge,Alectoris rufa(n=38 chromosomes) plays a crucial role in the ecosystem of southwestern Europe, and understanding its genetics is vital for conservation and management. Here we sequence, assemble, and annotate a highly contiguous and nearly complete version of it genome (115 scaffolds, L90=23). This assembly contains 96.9% (8078 out of 8332) orthologous genes from the BUSCO aves_odb10 dataset of single copy orthologous genes. We identify RNA and protein genes, 95% of which with functional annotation. This near-chromosome level assembly revealed significant chromosome rearrangements compared to quail (Coturnix japonica) and chicken (Gallus gallus), suggesting thatA. rufaandC. japonicadiverged 21 M-years ago and that their common ancestor diverged fromG. gallus37 M-years ago. The reported assembly is a significant step towards a complete reference genome forA. rufa, contributing to facilitate comparative avian genomics, and providing a valuable resource for future research and conservation efforts for the red-legged partridge.
Fast and improved neutrino reconstruction in multineutrino final states with conditional normalizing flows
Authors: Raine John Andrew , Leigh Matthew , Zoch Knut , Golling Tobias
Published: January 2024

In this work we introduce ν2-flows, an extension of the ν-flows method to final states containing multiple neutrinos. The architecture can natively scale for all combinations of object types and multiplicities in the final state for any desired neutrino multiplicities. In tt¯ dilepton events, the momenta of both neutrinos and correlations between them are reconstructed more accurately than when using the most popular standard analytical techniques, and solutions are found for all events. Inference time is significantly faster than competing methods, and can be reduced further by evaluating in parallel on graphics processing units. We apply ν2-flows to tt¯ dilepton events and show that the per-bin uncertainties in unfolded distributions is much closer to the limit of performance set by perfect neutrino reconstruction than standard techniques. For the chosen double differential observables ν2-flows results in improved statistical precision for each bin by a factor of 1.5 to 2 in comparison to the neutrino weighting method and up to a factor of four in comparison to the ellipse approach.

Published by the American Physical Society
2024
Spatial inversion symmetry breaking of vortex current in a biased-ladder superfluid
Authors: Huang Weijie , Yao Yao
Published: January 2024

We investigate the quench dynamics of interacting bosons on a two-leg ladder in the presence of a uniform Abelian gauge field. The model hosts a variety of emergent quantum phases, and we focus on the superfluid biased-ladder phase breaking the Z2 symmetry of two legs. We observe an asymmetric spreading of vortex current and particle density, i.e., the vortices propagate ballistically on the right and dissolve during the propagation on the left, indicating spontaneous breaking of the spatial inversion symmetry. By decreasing the repulsion strength, it is found that the ballistic propagating vortices are more robust than the dissolving ones on the other side.

Published by the American Physical Society
2024