bluuebunny/crossref_metadata_2025 huggingface dataset:
Copy number variation and elevated genetic diversity at immune trait loci in Atlantic and Pacific herring
Authors: Mohamadnejad Sangdehi Fahime , Jamsandekar Minal S. , Enbody Erik D. , Pettersson Mats E. , Andersson Leif
Published: October 2023

Atlantic and Pacific herring are sister species that diverged about 2 million years ago. Here we describe a genome comparison of the two species that reveal high genome-wide differentiation as expected for two distinct species but with islands of remarkably low genetic differentiation as measured by anFSTanalysis. However, this is not caused by low interspecies sequence divergence but an exceptionally high estimated intraspecies nucleotide diversity. These high diversity regions are not enriched for repeats but are highly enriched for immune trait-related genes. This enrichment includes classical immunity genes, such as immunoglobulin, T-cell receptor and major histocompatibility complex genes, but also a substantial number of genes with a role in the innate immune system. An analysis of long-read based assemblies from two Atlantic herring individuals revealed extensive copy number variation at these genomic regions, indicating that the elevated intraspecies nucleotide diversities was partially due to the cross-mapping of short reads. This study demonstrates that copy number expansion and variation is a characteristic feature of immune trait loci in herring and that this genetic diversity is likely to contribute to resistance to infectious diseases in extremely abundant species, such as the Atlantic and Pacific herring. Another important implication is that these loci are blind spots in classical genome-wide screens for genetic differentiation using short-read data, not only in herring, likely also in other species harboring qualitatively similar variation at immune trait loci.

Significance

This study has revealed an extensive copy number variation and high nucleotide diversity at genes related to the immune system in Atlantic herring. Our analysis of previously published data in teleost species indicate that this is probably a widespread pattern among vertebrates. We also document that population genetic parameters estimated using short-read sequencing data are unreliable for these regions due to their complexity. They will also appear as blind spots in genome scans for regions of genetic differentiation based onFSTstatistics due to the very high within population nucleotide diversity. We show how long-read data can be used to decipher the gene organization and genetic diversity at these regions.
Biological validation of fecal corticosterone metabolites as a non-invasive stress assessment in translocated California valley quail (Callipepla californica)
Authors: Currier Sarah A. , Whitt Jeffrey G. , Reyna Kelly S.
Published: October 2023

U.S. quail species are vulnerable to population declines as a result climate change, habitat loss, and habitat fragmentation; all of which can induce physiological stress. Additionally, population restoration techniques (PRTs), like translocations, also induce stress. Traditional stress assessments include capturing and handling birds to extract blood, methods which are inherently stressful and can compound stress analyses. However, the stress hormone corticosterone is metabolized from the blood and excreted in feces as fecal corticosterone metabolites (FCMs). FCMs have been used as a non-invasive measurement of stress in a variety of species, but must be validated for each species. The objective of this study was to biologically validate the use of FCMs as a non-invasive measurement of stress-hormone levels in California valley quail (Callipepla californica). Reference and treatment quail were acclimated for 3 wks in an outdoor aviary. Subsequently, treatment quail were subjected to a simulated, 48-h translocation, a common and stressful PRT. Fecal samples were collected every 4 h and processed using an enzyme immunoassay. Mean FCM concentrations of treatment quail (41.50 ±16.13 ng/g) were higher than reference FCM concentrations (24.07 ±10.4 ng/g). These results biologically validate the use of FCMs as a non-invasive method to assess stress hormone levels in California valley quail, demonstrate diurnal variation in quail stress levels, and confirms that quail translocations are a stressful PRT. Ultimately, this research validates a new non-invasive tool for stress measurement to advance quail research, management, and conservation.

Lay summary

This study biologically validates the use of fecal corticosterone metabolites as a non-invasive method for detecting stress in quail, demonstrates diurnal variation in quail stress levels, confirms that translocations elevate stress which likely impacts success, and establishes a new non-invasive tool for stress measurement in quail research, management, and conservation.
A Murine Delayed-Healing Model Associates Immune Response with Functional Bone Regeneration after Trauma
Authors: Patrick Matthew , Stromberg Arnold , Ahn Jaimo , Hankenson Kurt , Annamalai Ramkumar T.
Published: October 2023

Nonunion and delayed-union fractures pose a significant clinical challenge, often leading to prolonged morbidity and impaired quality of life. Fracture-induced hematoma and acute inflammation are crucial for establishing the healing cascade. However, aberrant inflammatory phenotypes can suppress healing and cause bone resorption. Elucidating these mechanisms is necessary to develop potent immunomodulatory therapies and prevent nonunion. Here, we report a delayed fracture healing model enabling the modulation of interfragmentary strain that mimics the etiology of hypertrophic nonunions to elucidate the role of dysregulated immune response in poor healing outcomes. High interfragmentary strain (>15%) was associated with larger callus volumes but delayed bone healing, increased inflammation, and inferior healing outcomes, while lower strain levels (<5%) corresponded to normal bone healing. In addition, we found distinct differences in the ossification, chondrification, and fibrosis patterns between high and low-strain groups, underscoring the significant impact of strain on the healing process. A comprehensive analysis of the systemic immune response revealed dynamic alterations in immune cell populations and factors, particularly within the early hours and days post-fracture. Several immune factors exhibited significant correlations with various functional healing outcomes, indicating their potential as predictive markers for assessing fracture healing progression. Our results also highlighted the significance of timely resolution of proinflammatory signals and the elevation of pro-regenerative immune cell phenotypes in promoting bone regeneration. Multivariate analysis revealed that CD25+ T-regulatory cells were influential in predicting proper bone healing, followed by CD206+ macrophages, underscoring the pivotal role of immune cell populations in the bone healing process. In conclusion, our study provides valuable insights into the intricate interplay between interfragmentary strain, immune response, and the ultimate outcomes of fracture healing. By shedding light on the underlying mechanisms that drive hypertrophic nonunion pathogenesis, our research lays the foundation for enhanced surgical management of nonunions and offers a promising avenue for developing targeted therapeutic interventions and personalized treatment strategies for individuals suffering from fracture nonunion.
Cell segmentation and gene imputation for imaging-based spatial transcriptomics
Authors: Zhong Yunshan , Ren Xianwen
Published: October 2023

Imaging-based spatial transcriptomics technologies are revolutionary tools for biomedical investigation, but the power is currently limited by small number of measured genes and tricky cell segmentation. Here we introduce RedeFISH to simultaneously conduct cell segmentation and gene imputation for imaging-based spatial transcriptomics with the aid of single-cell RNA sequencing data. Extensive benchmarking across various spatial platforms and tissue types shows the validity and power of the cell-segmented, whole-transcriptome spatial data generated by RedeFISH.
Effects of chronic lithium treatment on neuronal excitability and GABAergic transmission in anAnk3mutant mouse model
Authors: Caballero-Florán René N. , Nelson Andrew D. , Min Lia , Jenkins Paul M.
Published: October 2023

Bipolar disorder (BD) is a common psychiatric disease that can lead to psychosocial disability, decreased quality of life, and high risk for suicide. Genome-wide association studies have shown that theANK3gene is a significant risk factor for BD, but the mechanisms involved in BD pathophysiology are not yet fully understood. Previous work has shown that ankyrin-G, the protein encoded byANK3, stabilizes inhibitory synapses in vivo through its interaction with the GABAAreceptor-associated protein (GABARAP). We generated a mouse model with a missense p.W1989R mutation inAnk3, that abolishes the interaction between ankyrin-G and GABARAP, which leads to reduced inhibitory signaling in the somatosensory cortex and increased pyramidal cell excitability. Humans with the same mutation exhibit BD symptoms, which can be attenuated with lithium therapy. In this study, we describe that chronic treatment ofAnk3p.W1989R mice with lithium normalizes neuronal excitability in cortical pyramidal neurons and increases inhibitory GABAergic postsynaptic currents. The same outcome in inhibitory transmission was observed when mice were treated with the GSK-3β inhibitor Tideglusib. These results suggest that lithium treatment modulates the excitability of pyramidal neurons in the cerebral cortex by increasing GABAergic neurotransmission, likely via GSK-3 inhibition. In addition to the importance of these findings regardingANK3variants as a risk factor for BD development, this study may have significant implications for treating other psychiatric disorders associated with alterations in inhibitory signaling, such as schizophrenia, autism spectrum disorder, and major depressive disorder.
Identification of potential Auxin Response Candidate genes for soybean rapid canopy coverage through comparative evolution and expression analysis
Authors: Neres Deisiany F. , Taylor Joseph S. , Bryant John A. , Bargmann Bastiaan O. R. , Wright R. Clay
Published: October 2023

Glycine max, soybean, is an abundantly cultivated crop worldwide. Efforts have been made over the past decades to improve soybean production in traditional and organic agriculture, driven by growing demand for soybean-based products. Rapid canopy cover development (RCC) increases soybean yields and suppresses early-season weeds.

Genome-wide association studies have found natural variants associated with RCC, however causal mechanisms are unclear. Auxin modulates plant growth and development and has been implicated in RCC traits. Therefore, modulation of auxin regulatory genes may enhance RCC. Here, we focus on the use of genomic tools and existing datasets to identify auxin signaling pathway RCC candidate genes, using a comparative phylogenetics and expression analysis approach.

We identified genes encoding 14 TIR1/AFB auxin receptors, 61 Aux/IAA auxin co-receptors and transcriptional co-repressors, and 55 ARF auxin response factors in the soybean genome. We used Bayesian phylogenetic inference to identify soybean orthologs ofArabidopsis thalianagenes, and defined an ortholog naming system for these genes. To further define potential auxin signaling candidate genes for RCC, we examined tissue-level expression of these genes in existing datasets and identified highly expressed auxin signaling genes in apical tissues early in development. We identified at least 4TIR1/AFB, 8Aux/IAA, and 8ARFgenes with highly specific expression in one or more RCC-associated tissues. We hypothesize that modulating the function of these genes through gene editing or traditional breeding will have the highest likelihood of affecting RCC while minimizing pleiotropic effects.
Phylogenomics reveals the deep ocean as an accelerator for evolutionary diversification in anglerfishes
Authors: Miller Elizabeth Christina , Faucher Rose , Hart Pamela B. , Rincon-Sandoval Melissa , Santaquiteria Aintzane , White William T. , Baldwin Carole C. , Miya Masaki , Betancur-R Ricardo , Tornabene Luke , Evans Kory , Arcila Dahiana
Published: October 2023

Colonization of a novel habitat is often followed by radiation in the wake of ecological opportunity. Alternatively, some habitats should be inherently more constraining than others if the challenges of that environment have few evolutionary solutions. We examined the push-and-pull of these factors on evolution following habitat transitions, using anglerfishes (Lophiiformes) as a model. Deep-sea fishes are notoriously difficult to study, and poor sampling has limited progress thus far. Here we present a new phylogeny of anglerfishes with unprecedented taxonomic sampling (1,092 loci and 40% of species), combined with three-dimensional phenotypic data from museum specimens obtained with micro-CT scanning. We use these datasets to examine the tempo and mode of phenotypic and lineage diversification using phylogenetic comparative methods, comparing lineages in shallow and deep benthic versus bathypelagic habitats. Our results show that anglerfishes represent a surprising case where the bathypelagic lineage has greater taxonomic and phenotypic diversity than coastal benthic relatives. This defies expectations based on ecological principles since the bathypelagic zone is the most homogeneous habitat on Earth. Deep-sea anglerfishes experienced rapid lineage diversification concomitant with colonization of the bathypelagic zone from a continental slope ancestor. They display the highest body, skull and jaw shape disparity across lophiiforms. In contrast, reef-associated taxa show strong constraints on shape and low evolutionary rates, contradicting patterns suggested by other shallow marine fishes. We found that Lophiiformes as a whole evolved under an early burst model with subclades occupying distinct body shapes. We further discuss to what extent the bathypelagic clade is a secondary adaptive radiation, or if its diversity can be explained by non-adaptive processes.
Diagnostic Accuracy of GPT Multimodal Analysis on USMLE Questions Including Text and Visuals
Authors: Sorin Vera , Glicksberg Benjamin S. , Barash Yiftach , Konen Eli , Nadkarni Girish , Klang Eyal
Published: October 2023

Objective

Large Language Models (LLMs) have demonstrated proficiency in free-text analysis in healthcare. With recent advancements, GPT-4 now has the capability to analyze both text and accompanying images. The aim of this study was to evaluate the performance of the multimodal GPT-4 in analyzing medical images using USMLE questions that incorporate visuals.

Methods

We analyzed GPT-4’s performance on 55 USMLE sample questions across the three steps. In separate chat instances we provided the model with each question both with and without the images. We calculated accuracy with and without the images provided.

Results

GPT-4 achieved an accuracy of 80.0% with images and 65.0% without. No cases existed where the model answered correctly without images and incorrectly with them. Performance varied across USMLE steps and was significantly better for questions with figures compared to graphs.

Conclusion

GPT-4 demonstrated an ability to analyze medical images from USMLE questions, including graphs and figures. A multimodal LLM in healthcare could potentially accelerate both patient care and research, by integrating visual data and text in analysis processes.
Agent-based Model for Microbial Populations Exposed to Radiation (AMMPER) simulates yeast growth for deep-space experiments
Authors: Singh Amrita , Santa Maria Sergio R. , Gentry Diana M. , Liddell Lauren C. , Lera Matthew P. , Lee Jessica A.
Published: October 2023

Space radiation poses a substantial health risk to humans traveling beyond Earth’s orbit to the Moon and Mars. As microbes come with us to space as model organisms for studying radiation effects, a computational model simulating those effects on microorganisms could enable us to better design and interpret those experiments. Here we present Agent-based Model for Microbial Populations Exposed to Radiation (AMMPER), which simulates the effects of protons, a major component of deep-space radiation, on budding yeast (Saccharomyces cerevisiae) growth. The model combines radiation track structure data from the RITRACKS package with novel algorithms for cell replication, motion, damage, and repair. We demonstrate that AMMPER qualitatively reproduces the effects of 150 MeV proton radiation on growth rate, but not lag time, of wild type and DNA repair mutant yeast strains. The variance in AMMPER’s results is consistent with the variance in experimental results, suggesting that AMMPER can recapitulate the stochasticity of empirical experiments. Finally, we used AMMPER to predict responses to deep space radiation that may be tested in future experiments. A user-friendly, open-source, extendable Python package for studying the relationship between single-particle radiation events and population-level responses, AMMPER can facilitate the basic research necessary to ensure safe and sustainable exploration of deep space.
Local cortical network stimulation as a concept for focal epilepsy treatment
Authors: van Blooijs D. , van der Stoel M.D. , Huiskamp G.J.M. , Demuru M. , Ramsey N.F. , Leijten F.S.S.
Published: October 2023

Background

Electrical stimulation therapy for epilepsy patients is applied either to the epileptogenic region or to a larger network (e.g. with deep brain stimulation).

Objective/hypothesis

Responses to single pulse electrical stimuli (SPES) reveal potential stimulation sites that target the epileptogenic region for cortical network stimulation therapy.

Methods

We applied SPES to ten epilepsy patients who underwent intracranial electrocorticography recordings for pre-surgical evaluation. We detected cortico-cortical evoked potentials (CCEPs) in response electrodes after stimulating other pairs of electrodes, revealing effective connections. We calculated event-related spectral perturbation (ERSP) plots in all response electrodes after stimulating other electrode pairs. We detected interictal epileptic discharges (IEDs) before and after each single pulse and calculated the logarithmic IED ratio.

We analyzed whether power suppression in the ERSP occurred in a response electrode when connected with the stimulus pair. We analyzed whether a larger change in IED ratio was accompanied by power suppression in the response electrode or when this electrode was connected with the stimulus pair.

Results

We found that SPES has a neuromodulatory effect measured as: 1) the relationship of a CCEP and power suppression, 2) a larger change in IED rate when a CCEP was present, 3) a decrease in IED rate when power suppression was observed.

Conclusion(s)

Results suggest that stimulation in an area connected to the epileptogenic region can modulate IEDs in this region. SPES might provide a template for localizing a stimulation site outside the epileptogenic region for electrical stimulation treatment of epilepsy.

Highlights

Stimulation of an electrode pair can suppress power in an electrode on connected tissue.

Stimulation of an electrode pair changes IED rate in an electrode on connected tissue.

A decrease in IED rate was accompanied by power suppression.

SPES indicates potential stimulation sites for neurostimulation therapy in epilepsy.
Nationwide population-based infection- and vaccine-induced SARS-CoV-2 seroprevalence in Germany at the end of 2021
Authors: Mercuri Elisabetta , Schmid Lorenz , Poethko-Müller Christina , Schlaud Martin , Kußmaul Cânâ , Ordonez-Cruickshank Ana , Haller Sebastian , Rexroth Ute , Hamouda Osamah , Schaade Lars , Wieler Lothar H. , Gößwald Antje , Schaffrath Rosario Angelika ,   the RKI-SOEP-2 Study Group
Published: October 2023

Background

The first wave of the Corona Monitoring Nationwide (RKI-SOEP) Study drawn from the German Socio-Economic Panel proved a low pre-vaccine SARS-CoV-2 seroprevalence in the German adult population of 2.1%.

Methods

In this second wave of the study (RKI-SOEP-2, November 2021-March 2022), we used combined serological and self-reported data on infection and vaccination to estimate the prevalence of SARS-CoV-2-specific anti-spike and/or anti-nucleocapsid IgG antibodies (combined seroprevalence), past infection, and basic immunization in individuals aged 14+.

Findings

Combined seroprevalence was 90.7% (95% CI 89.7% - 91.6%) without correction for antibody waning and 94.6% (95% CI 93.6% - 95.7%) with correction. While 1 in 10 individuals had been infected (9.9%, 95% CI 9.0% - 10.9%), 9 in 10 had at least a basic immunization (90%, 95% CI 88.9%-90.9%). Population-weighted estimates differed by age, region, and socioeconomic deprivation. Infection-induced seroprevalence with correction for antibody waning was 1.55 (95% CI 1.3 - 1.8) times higher than the cumulative proportion based on national surveillance data.

Interpretation

At the beginning of the SARS-CoV-2-Omicron wave, the vast majority of the population had been vaccinated, infected, or both. Our results show how large-scale vaccination, but not a high infection rate, was able to fill the immunity gap, especially in older individuals (aged 65+) who are known to be at higher risk of severe COVID-19. Our data point towards a targeted demographically and regionally stratified mitigation strategy, to optimize future pandemic mitigation efforts.
Lipid-lowering therapy for patients with arterial hypertension and concomitant chronic obstructive pulmonary disease in a south American cohort
Authors: Lobo Diego , Bermudez Santiago , Dulcey Sarmiento Luis Andrés , Gomez Jaime , Hernandez Carlos , Theran Leon Juan Sebastián , Caltagirone Raimondo , Amaya Maria Camila , Estévez Gómez Maria Juliana , Acevedo Peña Diego Andrey , Castillo Goyeneche Silvia Fernanda , Arias Anderson Felipe , Blanco Edgar , Ciliberti Maria , Calderon Silvia , Gutierrez Emily , Lizcano Angie , Bacca Lizeth , Martinez Juan Camilo
Published: October 2023

Introduction

to assess the lipid-lowering effect, the effect on endothelial function, oxidative stress of Rosuvastatin at a dose of 40 mg in patients with dyslipidemia, arterial hypertension (AH) and chronic obstructive pulmonary disease (COPD) initially, over time after 4 weeks and 12 months of treatment.

Material and methods

The prospective study included 33 patients (mean age 60 [54;61] years) with hypertension, COPD and dyslipidemia. The laboratory examination consisted of determining the lipid spectrum and the level of lipid peroxidation products (LPO). To assess the tolerability of the prescribed therapy, creatinine, bilirubin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were studied. To assess endothelial function, an endothelium-dependent vasodilation test (EDVD) was performed. Rosuvastatin at a dose of 40 mg was prescribed as lipid-lowering therapy. Initially, after 12 months, an ultrasound duplex scanning of the carotid arteries was performed to assess the presence of atherosclerotic plaques (AP) in the lumen of the vessel. The study was approved by the Local Ethics Committee of the Andes University in Merida, Venezuela (protocol No. 10 of December 25, 2017).

Results

after 4 weeks of treatment with Rosuvastatin at a dose of 40 mg, there was a significant decrease in total cholesterol levels by 26%, low-density lipoproteins (LDL) by 33%, triglycerides (TG) by 19%, while high-density lipoproteins (HDL) increased by 18%. Improvements in endothelial dysfunction (ED) and lipid peroxidation were observed during treatment with Rosuvastatin. Treatment with Rosuvastatin at a dose of 40 mg did not cause adverse reactions in patients.

Conclusion

correction of lipid metabolism disorders in patients with hypertension and COPD by prescribing Rosuvastatin at a dose of 40 mg can quickly reduce total cholesterol, LDL and TG, positively affecting endothelial function and lipid peroxidation processes. Therapy with Rosuvastatin at a starting dose of 40 mg in patients with dyslipidemia, hypertension and COPD is safe. After 12 months of regular use of Rosuvastatin at a dose of 40 mg, regression of AB was observed.
Histomorphometric features of placentae from women having malaria and HIV coinfection with preterm births
Authors: Adam Khalil Y. , Moses Obimbo M. , Jesse Gitaka , Edwin Walong , Omondi Ogutu , Ojwang Stephen.B.O.
Published: October 2023

Background

Malaria and HIV are associated with preterm births possibly due to partial maternal vascular malperfusion resulting from altered placental angiogenesis. There is a paucity of data describing structural changes associated with malaria and HIV coinfection in the placentae of preterm births thus limiting the understanding of biological mechanisms by which preterm birth occurs.

Objectives

This study aimed to determine the differences in clinical characteristics, placental parenchymal histological, and morphometric features of the terminal villous tree among women with malaria and HIV coinfection having preterm births.

Methods

Twenty-five placentae of preterm births with malaria and HIV coinfection (cases) were randomly selected and compared to twenty-five of those without both infections (controls). Light microscopy was used to determine histological features on H&E and MT-stained sections while histomorphometric features of the terminal villous were analyzed using image analysis software. Clinical data regarding maternal age, parity, marital status, level of education, gestational age and placental weight were compared.

Results

Placental weight, villous perimeter and area were significantly lower in cases as compared to controls 454g vs. 488g, 119.32µm vs. 130.47µm, and 937.93µm2vs. 1132.88µm2respectively. Increased syncytial knots and accelerated villous maturity were significantly increased in the cases. The relative risk of development of partial maternal vascular malperfusion was 2.1 (CI: 1.26-3.49).

Conclusion

These findings suggest that malaria and HIV coinfection leads to partial maternal vascular malperfusion that may lead to chronic hypoxia in the placenta and altered weight, villous perimeter and surface area. This may represent a mechanism by which malaria and HIV infection results in pre-term births.
Systematic SARS-CoV-2 S Gene Sequencing in Wastewater Samples Enables Early Lineage Detection and Uncovers Rare Mutations in Portugal
Authors: Reis Ana C. , Pinto Daniela , Monteiro Sílvia , Santos Ricardo , Martins João Vieira , Sousa Alexandra , Páscoa Rute , Lourinho Rita , Cunha Mónica V.
Published: October 2023

As the COVID-19 pandemic reached its peak, many countries implemented genomic surveillance systems to track the evolution and transmission of SARS-CoV-2. Transition from the pandemic to the endemic phase prioritized alternative testing strategies to maintain effective epidemic surveillance at the population level, with less intensive sequencing efforts. One such promising approach was Wastewater-Based Surveillance (WBS), which offers non-invasive, cost-effective means for analysing virus trends at the sewershed level. From 2020 onwards, wastewater has been recognized as an instrumental source of information for public health, with national and international authorities exploring options to implement national wastewater surveillance systems and increasingly relying on WBS as early warning of potential pathogen outbreaks. In Portugal, several pioneer projects joined the academia, water utilities and Public Administration around WBS.

To validate WBS as an effective genomic surveillance strategy, it is crucial to collect long term performance data. In this work, we present one year of systematic SARS-CoV-2 wastewater surveillance in Portugal, representing 35% of the mainland population. We employed two complementary methods for lineage determination - allelic discrimination by RT-PCR and S gene sequencing. This combination allowed us to monitor variant evolution in near-real-time and identify low-frequency mutations.

Over the course of this year-long study, spanning from May 2022 to April 2023, we successfully tracked the dominant Omicron sub-lineages, their progression and evolution, which aligned with concurrent clinical surveillance data. Our results underscore the effectiveness of WBS as a tracking system for virus variants, with the ability to unveil mutations undetected via massive sequencing of clinical samples from Portugal, demonstrating the ability of WBS to uncover new mutations and detect rare genetic variants.

Our findings emphasize that knowledge of the genetic diversity of SARS-CoV-2 at the population level can be extended far beyond via the combination of routine clinical genomic surveillance with wastewater sequencing and genotyping.
Early screening of colorectal cancer using feature engineering with artificial intelligence-enhanced analysis of nanoscale chromatin modifications
Authors: Chang Andrew , Prabhala Sravya , Daneshkhah Ali , Lin Jianan , Subramanian Hariharan , Roy Hemant Kumar , Backman Vadim
Published: October 2023

Colonoscopy is accurate but inefficient for colorectal cancer (CRC) prevention due to the low (~7-8%) prevalence of target lesions, advanced adenomas. We leveraged rectal mucosa to identify patients who harbor CRC field carcinogenesis by evaluating chromatin 3D architecture. Supranucleosomal disordered chromatin chains (~5-20 nm, ~1 kbp) fold into chromatin packing domains (~100-200 nm, ~100–1,000 kbp). In turn, the fractal-like conformation of DNA within chromatin domains and the folding of the genome into packing domains has been shown to influence multiple facets of gene transcription, including the transcriptional plasticity of cancer cells. We deployed an optical spectroscopic nanosensing technique, chromatin-sensitive partial wave spectroscopic microscopy (csPWS), to evaluate the packing density scaling D of the chromatin chain conformation within packing domains from rectal mucosa in 256 patients with varying degrees of progression to colorectal cancer. We found average packing scaling D of chromatin domains was elevated in tumor cells, histologically normal-appearing cells 4 cm proximal to the tumor, and histologically normal-appearing rectal mucosa compared to cells from control patients (p<0.001). Nuclear D had a robust correlation with the model of 5-year risk of CRC with r2=0.94. Furthermore, rectal D was evaluated as a screening biomarker for patients with advanced adenomas presenting an AUC of 0.85 and 85% sensitivity and specificity. Artificial Intelligence (AI)-enhanced csPWS improved diagnostic performance with AUC=0.90. Considering the low sensitivity of existing CRC tests, including liquid biopsies, to early-stage cancers our work highlights the potential of chromatin biomarkers of field carcinogenesis in detecting early, significant precancerous colon lesions.
Nucleoprotein reassortment enhanced transmissibility of H3 1990.4.a clade influenza A virus in swine
Authors: Thomas Megan N. , Ciacci Zanella Giovana , Cowan Brianna , Caceres C. Joaquin , Rajao Daniela S. , Perez Daniel R. , Gauger Phillip C. , Vincent Baker Amy L. , Anderson Tavis K.
Published: October 2023

The increased detection of H3 C-IVA (1990.4.a) clade influenza A viruses (IAV) in U.S. swine in 2019 was associated with a reassortment event to acquire an H1N1pdm09 lineage nucleoprotein (pdmNP) gene, replacing a TRIG lineage NP (trigNP). We hypothesized that acquiring the pdmNP conferred a selective advantage over prior circulating H3 viruses with a trigNP. To investigate the role of the NP reassortment in transmission, we identified two contemporary 1990.4.a representative strains (NC/19 and MN/18) with different evolutionary origins of the NP gene. A reverse genetics system was used to generate wild-type (wt) strains and to swap the pdm and TRIG lineage NP genes, generating four viruses: wtNC/19-pdmNP, NC/19-trigNP, wtMN/18-trigNP, MN/18-pdmNP. Pathogenicity and transmission of the four viruses were compared in pigs. All four viruses infected 10 primary pigs and transmitted to 5 indirect contact pigs per group. Pigs infected via contact with MN/18-pdmNP shed virus two days earlier than pigs infected with wtMN/18-trigNP. The inverse did not occur for wtNC/19-pdmNP and NC/19-trigNP. These data suggest that reassortment to acquire a pdmNP gene improved transmission efficiency in the 1990.4.a, but this is likely a multigenic trait. Replacing a trigNP gene alone may not diminish the transmission of a wild-type virus sampled from the swine population. This study demonstrates how reassortment and subsequent evolutionary change of internal genes can result in more transmissible viruses that impact the detection frequency of specific HA clades. Thus, rapidly identifying novel reassortants paired with dominant HA/NA may improve prediction of strains to include in vaccines.

Importance

Influenza A viruses (IAV) are composed of eight non-continuous gene segments that can reassort during coinfection of a host, creating new combinations. Some gene combinations may convey a selective advantage and be paired together preferentially. A reassortment event was detected in swine in the United States that involved the exchange of two lineages of nucleoprotein (NP) genes (trigNP to pdmNP) that became a predominant genotype detected in surveillance. Using a transmission study, we demonstrated that exchanging the trigNP for a pdmNP caused the virus to shed from the nose at higher levels and transmit to other pigs more rapidly. Replacing a pdmNP with a trigNP did not hinder transmission, suggesting that transmission efficiency depends on interactions between multiple genes. This demonstrates how reassortment alters IAV transmission and that reassortment events can provide an explanation for why genetically related viruses with different internal gene combinations experience rapid fluxes in detection frequency.
Uncultivated DPANN archaea are ubiquitous inhabitants of global oxygen deficient zones with diverse metabolic potential
Authors: Zhang Irene H. , Borer Benedict , Zhao Rui , Wilbert Steven , Newman Dianne K. , Babbin Andrew R.
Published: October 2023

Archaea belonging to the DPANN superphylum have been found within an expanding number of environments and perform a variety of biogeochemical roles, including contributing to carbon, sulfur, and nitrogen cycling. Generally characterized by ultrasmall cell sizes and reduced genomes, DPANN archaea may form mutualistic, commensal, or parasitic interactions with various archaeal and bacterial hosts, influencing the ecology and functioning of microbial communities. While DPANN archaea reportedly comprise 15–26% of the archaeal community within marine oxygen deficient zone (ODZ) water columns, little is known about their metabolic capabilities in these ecosystems. We report 33 novel metagenome-assembled genomes belonging to DPANN phyla Nanoarchaeota, Pacearchaeota, Woesarchaeota, Undinarchaeota, Iainarchaeota, and SpSt-1190 from pelagic ODZs in the Eastern Tropical North Pacific and Arabian Sea. We find these archaea to be permanent, stable residents of all 3 major ODZs only within anoxic depths, comprising up to 1% of the total microbial community and up to 25–50% of archaea. ODZ DPANN appear capable of diverse metabolic functions, including fermentation, organic carbon scavenging, and the cycling of sulfur, hydrogen, and methane. Within a majority of ODZ DPANN, we identify a gene homologous to nitrous oxide reductase. Modeling analyses indicate the feasibility of a nitrous oxide reduction metabolism for host-attached symbionts, and the small genome sizes and reduced metabolic capabilities of most DPANN MAGs suggest host-associated lifestyles within ODZs.

Importance

Archaea from the DPANN superphylum have diverse metabolic capabilities and participate in multiple biogeochemical cycles. While metagenomics and enrichments have revealed that many DPANN are characterized by ultrasmall genomes, few biosynthetic genes, and episymbiotic lifestyles, much remains unknown about their biology. We report 33 new DPANN metagenome-assembled genomes originating from the 3 global marine oxygen deficient zones (ODZs), the first from these regions. We survey DPANN abundance and distribution within the ODZ water column, investigate their biosynthetic capabilities, and report potential roles in the cycling of organic carbon, methane, and nitrogen. We test the hypothesis that nitrous oxide reductases found within several ODZ DPANN genomes may enable ultrasmall episymbionts to serve as nitrous oxide consumers when attached to a host nitrous oxide producer. Our results indicate DPANN archaea as ubiquitous residents within the anoxic core of ODZs with the potential to produce or consume key compounds.
Identifying cellular RNA-binding proteins during infection uncovers a role for MKRN2 in influenza mRNA trafficking
Authors: Bonazza Stefano , Coutts Hannah , Sukumar Swathi , Turkington Hannah , Courtney David G
Published: October 2023

Utilisation of RNA-binding proteins (RBPs) is an important aspect of post-transcriptional regulation of viral RNA. Viruses such as influenza A viruses (IAV) interact with RBPs to regulate processes including splicing, nuclear export and trafficking, while also encoding RBPs within their genomes, such as NP and NS1. But with almost 1000 RBPs encoded within the human genome it is still unclear what role, if any, many of these proteins play during viral replication. Using the RNA interactome capture (RIC) technique, we isolated RBPs from IAV infected cells to unravel the RBPome of mRNAs from IAV infected human cells. This led to the identification of one particular RBP, MKRN2, that associates with and positively regulates IAV mRNA. Through further validation, we determined that MKRN2 is involved in the nuclear-cytoplasmic trafficking of IAV mRNA likely through an association with the RNA export mediator GLE1. In the absence of MKRN2, IAV mRNAs accumulate in the nucleus of infected cells, which we suspect leads to their degradation by the nuclear RNA exosome complex. MKRN2, therefore, appears to be required for the efficient nuclear export of IAV mRNAs in human cells.
Vascular abnormalities in heart and brain are associated with cardiovascular and neurological symptoms in a novel mouse model for Williams syndrome
Authors: el Azzouzi Hamid , Bosman Laurens W.J. , Kros Lieke , van Vliet Nicole , Ridwan Yanto , Dijkhuizen Stéphanie , Sabel-Goedknegt Erika , Generowicz Bastian S. , Novello Manuele , Kretschmann Emma , Snoeren Morrisen , Broere Danique , Caliandro Rocco , Koekkoek Sebastiaan K.E. , Kruizinga Pieter , van Dis Vera , Zhou Haibo , Yang Hui , Zhou Changyang , van der Pluijm Ingrid , Essers Jeroen , De Zeeuw Chris I.
Published: October 2023

Williams syndrome is a developmental disorder caused by a microdeletion entailing loss of a single copy of 25-27 genes on chromosome 7q11.23. Patients with Williams syndrome suffer from cardiovascular and neuropsychological symptoms. So far, the structural abnormalities of the cardiovascular system in Williams syndrome have been attributed to the loss of a copy of the elastin (ELN) gene. In contrast, the neuropsychological consequences of Williams syndrome, including motor deficits, hypersociability and cognitive impairments, have been mainly attributed to altered expression of transcription factors like LIMK1, GTF2I and GTF2IRD1, while the potential secondary impact of altered cerebrovascular function has been largely ignored. To study the relation between the mutation underlying Williams syndrome and vascularization of not only the heart but also that of the brain, we generated a mouse model with a relatively long microdeletion, including theNcf1gene to reduce the confounding impact of hypertension. The affected mice had an elongated and tortuous aorta, but unlike inElnhaploinsufficient mice, there were no signs of structural cardiac hypertrophy. Our Williams syndrome mice had similar structural abnormalities in their coronary and brain vessels, showing disorganized extracellular matrices of the vessel walls. Moreover, our mouse model faithfully replicated both cardiovascular and neurological symptoms of Williams syndrome, highlighting that accurate non-invasive evaluation of complex vascular abnormalities is feasible. Altogether, we present evidence for vascular malformations that are similar in heart and brain, suggesting that cardiovascular and neurological symptoms can both by impacted by changes in the vascular structure in patients with Williams syndrome.
The LexA-RecA* structure reveals a lock-and-key mechanism for SOS activation
Authors: Cory Michael B. , Li Allen , Hurley Christina M. , Carman Peter J. , Pumroy Ruth A. , Hostetler Zachary M. , Venkatesh Yarra , Gupta Kushol , James Petersson E. , Kohli Rahul M.
Published: October 2023

The bacterial SOS response plays a key role in adaptation to DNA damage, including that caused by antibiotics. SOS induction begins when activated RecA*, an oligomeric nucleoprotein filament formed on single-stranded DNA, binds to and stimulates autoproteolysis of the repressor LexA. Here, we present the structure of the complete SOS signal complex, constituting full-length LexA bound to RecA*. We uncover an extensive interface unexpectedly including the LexA DNA-binding domain, providing a new molecular rationale for ordered SOS response gene induction. Furthermore, we find that the interface involves three RecA monomers, with a single residue in the central monomer acting as a molecular key, inserting into an allosteric binding pocket to induce LexA cleavage. Given the pro-mutagenic nature of SOS activation, our structural and mechanistic insights provide a foundation for developing new therapeutics to slow the evolution of antibiotic resistance.
Peptide-mimetic treatment ofPseudomonas aeruginosain a mouse model of respiratory infection
Authors: Moule Madeleine G. , Benjamin Aaron B. , Buger Melanie L. , Herlan Claudine , Lebedev Maxim , Lin Jennifer S. , Koster Kent J. , Wavare Neha , Adams Leslie G. , Bräse Stefan , Barron Annelise E. , Cirillo Jeffrey D.
Published: October 2023

The rise of drug resistance has become a global crisis, with >1 million deaths due to resistant bacterial infections each year.Pseudomonas aeruginosa,in particular, remains a serious problem with limited solutions due to complex resistance mechanisms that now lead to more than 32,000 multidrug-resistant (MDR) infections and over 2,000 deaths annually. While the emergence of resistant bacteria has become concerningly common, identification of useful new drug classes has been limited over the past 40+ years. We found that a potential novel therapeutic, the peptide-mimetic TM5, is effective at killingP. aeruginosaand displays sufficiently low toxicity for mammalian cells to allow for use in treatment of infections. Interestingly, TM5 killsP. aeruginosamore rapidly than traditional antibiotics, within 30-60 minutesin vitro, and is effective against a range of clinical isolates.In vivo, TM5 significantly reduced bacterial load in the lungs within 24 hours compared to untreated mice and demonstrated few adverse effects. Taken together, these observations suggest that TM5 shows promise as an alternative therapy for MDRP. aeruginosarespiratory infections.
Maternal immunization with distinct influenza vaccine platforms elicits unique antibody profiles that impact the protection of offspring
Authors: Vazquez-Pagan Ana , Roubidoux Ericka Kirkpatrick , Cherry Sean , Livingston Brandi , Bub Theresa , Lazure Lauren , Sharp Bridgett , Confer Thomas , Brigleb Pamela H. , Honce Rebekah , Whitt Kendall T. , Johnson Melissa , Meliopoulos Victoria , Schultz-Cherry Stacey
Published: October 2023

Pregnant women and infants are considered high-risk groups for increased influenza disease severity. While influenza virus vaccines are recommended during pregnancy, infants cannot be vaccinated until at least six months of age. Passive transfer of maternal antibodies (matAbs) becomes vital for the infant’s protection. Here, we employed an ultrasound-based timed-pregnancy murine model and examined matAb responses to distinct influenza vaccine platforms and influenza A virus (IAV) infection in dams and their offspring. We demonstrate vaccinating dams with a live-attenuated influenza virus (LAIV) vaccine or recombinant hemagglutinin (rHA) proteins administered with adjuvant resulted in enhanced and long-lasting immunity and protection from influenza in offspring. In contrast, a trivalent split-inactivated vaccine (TIV) afforded limited protection in our model. By cross-fostering pups, we show the timing of antibody transfer from vaccinated dams to their offspring (prenatal versus postnatal) can shape the antibody profile depending on the vaccine platform. Our studies provide information on how distinct influenza vaccines lead to immunogenicity and efficacy during pregnancy, impact the protection of their offspring, and detail roles for IgG1 and IgG2c in the development of vaccine administration during pregnancy that stimulate and measure expression of both antibody subclasses.
Inequality and redistribution: evidence from Scandinavian and Mediterranean countries
Authors: Claveria Oscar , Sorić Petar
Published: October 2023

Purpose

The purpose of this paper is to investigate the adjustment of government redistributive policies in Scandinavian and Mediterranean countries following changes in income inequality over the period 1980–2021.

Design/methodology/approach

The authors first modelled the time-varying dynamics between income inequality and redistribution and then used a non-linear framework to test for the existence of asymmetries and cointegration in their long-run relationship. The authors used two complementary measures of inequality – the share of total income accruing to top percentile income holders and the ratio of the share of total income accruing to top decile income holders divided by that accumulated by the bottom 50% – and computed redistribution as the difference between the two inequality indicators before and after taxes and transfers.

Findings

The authors found that the sign of the relationship between income inequality and redistribution is mostly positive and time-varying. Overall, the authors also found evidence that the impact of increases in inequality on redistributive measures is higher than that of decreases. Finally, the authors obtained a significant long-run relationship between both variables in all countries except Denmark and Spain. These results hold for both Scandinavian and Mediterranean countries.

Originality/value

To the best of the authors’ knowledge, this is the first paper to account for the potential existence of non-linearities and to examine the asymmetries in the adjustment of redistributive policies to increases in income inequality using alternative income inequality metrics.