bluuebunny/crossref_metadata_2025 huggingface dataset:
Pathway-Specific Polygenic Scores Improve Cross-Ancestry Prediction of Psychosis and Clinical Outcomes
Authors: Tubbs Justin D. , Leung Perry B.M. , Zhong Yuanxin , Zhan Na , Hui Tomy C.K. , Ho Karen K.Y. , Hung Karen S.Y. , Cheung Eric F.C. , So Hon-Cheong , Lui Simon S.Y. , Sham Pak C.
Published: September 2023

Psychotic disorders are debilitating conditions with disproportionately high public health burden. Genetic studies indicate high heritability, but current polygenic scores (PGS) account for only a fraction of variance in psychosis risk. PGS often show poor portability across ancestries, performing significantly worse in non-European populations. Pathway-specific PGS (pPGS), which restrict PGS to genomic locations within distinct biological units, could lead to increased mechanistic understanding of pathways that lead to risk and improve cross-ancestry prediction by reducing noise in genetic predictors. This study examined the predictive power of genome-wide PGS and nine pathway-specific pPGS in a unique Chinese-ancestry sample of deeply-phenotyped psychosis patients and non-psychiatric controls. We found strong evidence for the involvement of schizophrenia-associated risk variants within “nervous system development” (p=2.5e-4) and “regulation of neuron differentiation” pathways (p=3.0e-4) in predicting risk for psychosis. We also found the “ion channel complex” pPGS, with weights derived from GWAS of bipolar disorder, to be strongly associated with the number of inpatient psychiatry admissions a patient experiences (p=1.5e-3) and account for a majority of the signal in the overall bipolar PGS. Importantly, although the schizophrenia genome-wide PGS alone explained only 3.7% of the variance in liability to psychosis in this Chinese ancestry sample, the addition of the schizophrenia-weighted pPGS for “nervous system development” and “regulation of neuron differentiation” increased the variance explained to 6.9%, which is on-par with the predictive power of PGS in European ancestry samples. Thus, not only can pPGS provide greater insight into mechanisms underlying genetic risk for disease and clinical outcomes, but may also improve cross-ancestry risk prediction accuracy.
Spatial and temporal relationship between focal and rotational drivers and their relationship to structural remodeling in patients with persistent AF
Authors: Honarbakhsh Shohreh , Roney Caroline , Wharmby Amy , Vidal Horrach Caterina , Hunter Ross J.
Published: September 2023

Background

Focal and rotational activations have been demonstrated in AF, but their relationship to each other and to structural remodeling remains unclear.

Methods

Patients undergoing catheter ablation for persistent AF were included. All patients underwent pulmonary vein isolation. Unipolar signals were collected to identify focal and rotational drivers using a wavefront propagation algorithm. Aim was to assess the relationship of drivers to underlying low voltage zones (LVZs; <0.5mV) and to determine whether there was a temporal (≤500ms) and spatial (≤12mm) relationship between focal and rotational drivers.

Results

In 40 patients, 86 drivers were identified (57, 66.3% focal and 29, 33.7% rotational). Rotational drivers showed co-localized to LVZs (21/29, 72.4%) whilst focal drivers did not (11/57 in LVZ, 19.3%; p<0.001). The proportion of the left atrium (LA) occupied by LVZs predicted rotational driver occurrence (AUC 0.96, 95%CI 0.90-1.00; p<0.001). In patients with a relatively healthy atrium, where the atrium was made up of ≤15% LVZs, only focal drivers were identified. Eighteen of the 21 (85.7%) rotational drivers located in LVZs also showed a temporal and spatial relationship to a focal driver. The presence of a LVZ within 12 mm of the focal driver was a strong predictor for whether a paired rotational driver would also occur in that vicinity.

Conclusions

Rotational drivers are largely confined to areas of structural remodelling and have a clear spatial and temporal relationship with focal drivers suggesting they are dependent on them. These novel mechanistic observations outline a plausible model for patient specific mechanisms maintaining AF.
Lesioned hemisphere-specific phenotypes of post-stroke fatigue emerge from motor and mood characteristics in chronic stroke
Authors: De Doncker William , Kuppuswamy Annapoorna
Published: September 2023

Post-stroke fatigue commonly presents alongside several co-morbidities. The interaction between co-morbidities and their relationship to fatigue is not known. Here we focus on physical and mood comorbidities, alongside lesion characteristics. We predict the emergence of distinct fatigue phenotypes with distinguishable physical and mood characteristics.

In this cross-sectional observational study, in 94 first time, non-depressed, moderate to minimally impaired chronic stroke survivors, the relationship between measures of motor function (Grip strength, Nine Hole Peg Test time), motor cortical excitability (Resting Motor Threshold), Hospital Anxiety and Depression Scale scores and Fatigue Severity Scale – 7 scores age, gender and side of stroke was established using Spearman’s rank correlation. Mood and motor variables were then entered into k-means clustering algorithm to identify number of unique clusters, if any. Post-hoc pairwise comparisons followed by corrections for multiple comparisons was performed to characterise differences between clusters in the variables included in k-means clustering.

Clustering analysis revealed a 4-cluster model to be the winning model (average silhouette score of 0.311). There was no significant difference in FSS-7 scores between the 4 high-fatigue clusters. 2 clusters consisted of only left hemispheric strokes, and the remaining two were exclusively right hemisphere strokes. Factors that differentiated hemisphere-specific clusters was the level of depressive symptoms and anxiety. Motor characteristics distinguished the low-depressive left from right hemispheric clusters.

The significant differences in side of stroke, and the differential relationship between mood and motor function in the 4 clusters reveals the heterogenous nature of post-stroke fatigue, which is amenable to categorisation. Such categorisation is critical for understanding the interactions between post-stroke fatigue and its presenting comorbid deficits, with significant implications for development of context/category specific interventions.
Comparing peptide identifications by FAIMS versus quadrupole gas-phase fractionation
Authors: Faivre Danielle A. , McGann Christopher D. , Merrihew Gennifer E. , Schweppe Devin K. , MacCoss Michael J.
Published: September 2023

High-field asymmetric waveform ion mobility spectrometry (FAIMS) coupled to liquid chromatography-mass spectrometry (LC-MS) has been shown to increase peptide and protein detections compared to LC-MS/MS alone. However, FAIMS has not been compared to other methods of gas-phase fractionation, such as quadrupole gas-phase fractionation, which could increase our understanding of the mechanisms of improvement. The goal of this work was to assess whether FAIMS improves peptide identifications because 1) gas-phase fractionation enables the analysis of less abundant signals by excluding more abundant precursors from filling the ion trap, 2) the use of FAIMS reduces co-isolation of peptides during the MS/MS process resulting in a reduction of chimeric spectra, or 3) a combination of both. To investigate these hypotheses, pooled human brain tissue samples were measured in triplicate using FAIMS gas-phase fractionation, quadrupole gas-phase fractionation, or no gas-phase fractionation on two Thermo Eclipse Tribrid Mass Spectrometers. On both instruments, our data confirmed prior observations that FAIMS increased the number of peptides identified. We further demonstrated that the main benefit of FAIMS is due to the reduced co-isolation of persistent peptide precursor ions, which results in a decrease in chimeric spectra.
Long-term severe hypoxia adaptation induces non-canonical EMT and a novel Wilms Tumor 1 (WT1) isoform
Authors: Quenneville Jordan , Feghaly Albert , Tual Margaux , Major François , Gagnon Etienne
Published: September 2023

The majority of cancer deaths are caused by solid tumors, where the four most prevalent cancers (breast, lung, colorectal and prostate) account for more than 60% of all cases (1). Tumor cell heterogeneity driven by variable cancer microenvironments, such as hypoxia, is a key determinant of therapeutic outcome. We developed a novel culture protocol, termed the Long-Term Hypoxia (LTHY) time course, to recapitulate the gradual development of severe hypoxia seenin vivo, to mimic conditions observed in primary tumors. Cells subjected to LTHY underwent a non-canonical epithelial to mesenchymal transition (EMT) based on miRNA and mRNA signatures as well as displayed EMT-like morphological changes. Concomitant to this, we report production of a novel truncated isoform of WT1 transcription factor (tWt1), a non-canonical EMT driver, with expression driven by a yet undescribed intronic promoter through hypoxia-responsive elements (HREs). We further demonstrated that tWt1 initiates translation from an intron-derived start codon, retains proper subcellular localization, DNA binding, and its human ortholog negatively predicts long-term patient survival. Our study demonstrates the importance of culture conditions that better mimic those observed in cancers, especially with regards to hypoxia, and identifies a novel isoform of WT1 which correlates with poor long-term survival in ovarian cancer.
Endonucleolytic RNA cleavage drives changes in gene expression during the innate immune response
Authors: Karasik Agnes , Lorenzi Hernan A. , DePass Andrew V. , Guydosh Nicholas R.
Published: September 2023

Viral infection triggers several dsRNA sensors that lead to changes in gene expression in the cell. One of these sensors activates an endonuclease, RNase L, that cleaves single stranded RNA. However, how the resultant widespread RNA fragmentation affects gene expression is not fully understood. Here we show that this fragmentation induces the Ribotoxic Stress Response via ZAKα, potentially through ribosome collisions. The p38 and JNK pathways that are activated as part of this response promote outcomes that inhibit the virus, such as programmed cell death. We also show that RNase L limits the translation of stress-responsive genes, including antiviralIFITmRNAs andGADD34that encodes an antagonist of the Integrated Stress Response. Intriguingly, we found the activity of the generic endonuclease, RNase A, recapitulates many of the same molecular phenotypes as activated RNase L, demonstrating how widespread RNA cleavage can evoke an antiviral program.

Highlights

Activated RNase L acts with dsRNA-sensing pathways to promote cell signaling

RNA fragmentation induces transcription through ZAKα signaling

Activation of RNase L modulates levels of eIF2α phosphorylation

Translation of theGADD34andIFITmRNAs is inhibited by active RNase L
Natural genetic variation quantitatively regulates heart rate and dimension
Authors: Gierten Jakob , Welz Bettina , Fitzgerald Tomas , Thumberger Thomas , Hummel Oliver , Leger Adrien , Weber Philipp , Hassel David , Hübner Norbert , Birney Ewan , Wittbrodt Joachim
Published: September 2023

The polygenic contribution to heart development and function along the health-disease continuum remains unresolved. To gain insight into the genetic basis of quantitative cardiac phenotypes, we utilize highly inbred Japanese rice fish models,Oryzias latipes, andOryzias sakaizumii. Employing automated quantification of embryonic heart rates as core metric, we profiled phenotype variability across five inbred strains. We observed maximal phenotypic contrast between individuals of the HO5 and the HdrR strain. HO5 showed elevated heart rates associated with embryonic ventricular hypoplasia and impaired adult cardiac function. This contrast served as the basis for genome-wide mapping. In a segregation population of 1192 HO5 x HdrR F2 embryos, we mapped 59 loci (173 genes) associated with heart rate. Experimental validation of the top 12 candidate genes in loss-of-function models revealed their causal and distinct impact on heart rate, development, ventricle size, and arrhythmia. Our study uncovers new diagnostic and therapeutic targets for developmental and electrophysiological cardiac diseases and provides a novel scalable approach to investigate the intricate genetic architecture of the vertebrate heart.

One-Sentence Summary

Key loci for vertebrate heart function mapped and validated, highlighting diagnostic and potential therapeutic targets for cardiac disorders.
Therapeutic mitigation of measles-like immune amnesia and exacerbated disease after prior respiratory virus infections in ferrets
Authors: Cox Robert M , Wolf Josef D , Lieberman Nicole A , Lieber Carolin M , Kang Hae-Ji , Sticher Zachary M , Yoon Jeong-Joong , Andrews Meghan K , Govindarajan Mugunthan , Krueger Rebecca E , Sobolik Elizabeth B. , Natchus Michael G , Gewirtz Andrew T , deSwart Rik , Kolykhalov Alexander A , Hekmatyar Khan , Sakamoto Kaori , Greninger Alexander L , Plemper Richard K
Published: September 2023

After years of the COVID-19 pandemic, over 40 million children worldwide are at risk of measles due to delayed vaccination1and temporary SARS-CoV-2 viral dominance2. Acute measles has a case-fatality rate of ∼1%, but most morbidity and mortality arise post-measles due to destruction of pre-existing immune memory by lymphotropic measles virus (MeV)3,4, a paramyxovirus of theMorbillivirusgenus. MeV-induced immune amnesia is not mitigated by post-exposure vaccination and the impact of unrelated respiratory virus disease history on measles severity has not been defined. We used a lethal canine distemper virus (CDV)-ferret model as surrogate for human morbillivirus disease5and employed the orally efficacious broad-spectrum paramyxovirus polymerase inhibitor GHP-883096to establish measles treatment paradigms. Applying a receptor tropism-intact recombinant CDV with low lethality, we providein vivoconfirmation of the morbillivirus immune amnesia hypothesis and reveal an 8-day advantage of antiviral treatment versus therapeutic vaccination in preserving immune memory. Infection of ferrets with non-lethal influenza A virus (IAV) A/CA/07/2009 (H1N1) or respiratory syncytial virus (RSV) four weeks prior to CDV caused exacerbated CDV disease that rapidly advanced to fatal hemorrhagic pneumonia associated with lung onslaught by commensal bacteria. RNAseq of BAL samples and lung tissue identified CDV-induced expression of trefoil factor (TFF) peptides, which was absent in animals pre-infected with IAV, thus highlighting that immune priming by unrelated respiratory viruses influences morbillivirus infection outcome. Non-invasive pulmonary ferret MRI revealed that severe outcomes of consecutive IAV/CDV infections were prevented by oral GHP-88309 treatment even when initiated after peak clinical signs of CDV. These findings validate the morbillivirus immune amnesia hypothesis, define treatment paradigms for measles, identify prior disease history as risk factor for exacerbated morbillivirus disease, and demonstrate that treating morbillivirus infection with direct-acting oral antivirals provides therapeutic benefit regardless of whether the time window to mitigate primary clinical signs of infection has closed.
Regulation of Oocyte Meiotic Maturation: Unraveling the Interplay between PKA Inhibition and Cdk1 Activation
Authors: Santoni Martina , Sekhsoukh Nabil , Castella Sandrine , Le Tran , Miot Marika , Daldello Enrico Maria
Published: September 2023

Oocyte meiosis is arrested at the first prophase stage, until hormonal stimulation triggers progression into the meiotic divisions. This process, called meiotic maturation, depends on extensive post-transcriptional events. In all vertebrates, two bottleneck events orchestrate meiosis resumption: first, the inhibition of PKA and, second, the activation of Cdk1, the master regulator of eukaryotic cell division. However, the molecular events occurring between these two steps are almost unknown. To address this issue, we took advantage of a Cdk1 inhibitor to identify the early events that depend on PKA downregulation and occur independently of Cdk1 activity. Unexpectedly, we show that accumulation of Cyclin B1 and Mos, the kinase responsible for MAPK activation in oocytes, are regulated in an opposing manner by a two-step mechanism. PKA downregulation induces first the accumulation of Cyclin B1 without any increase of its translation, independently of Cdk1 activation. Subsequently, the rate of Cyclin B1 translation increases in response to Cdk1 activation. In contrast, Mos translation begins downstream PKA inhibition, but the protein does not accumulate until Cdk1 is activated. These intertwined regulations create the positive feedback loops required for the full activation of Cdk1. Additionally, we show that two consecutive waves of translation occur during the G2-M transition, the first induced by PKA inhibition and the second by Cdk1 activation. Finally, we demonstrate that Arpp19, the only known early substrate of PKA inXenopusoocytes, is not involved in the control of these early events. This study reveals that PKA downregulation promotes multiple molecular pathways that converge on the activation of Cdk1 to induce the G2/M transition in vertebrate oocytes.
Differential susceptibility of human microglia HMC3 cells and brain microvascular endothelial HBEC-5i cells to Mayaro and Una virus infection
Authors: Campos Dalkiria , Sugasti-Salazar Madelaine , Galán-Jurado Paola Elaine , Valdés-Torres Patricia , Zegarra Dalel , González-Santamaría José
Published: September 2023

Mayaro (MAYV) and Una (UNAV) are emerging alphaviruses circulating in the Americas. Earlier reports have revealed that MAYV infects different human cell lines, including synovial and dermal fibroblasts, chondrocytes, osteoblasts, astrocytes and pericytes, as well as neural progenitor cells. In this study we evaluated the susceptibility of immortalized human microglia HMC3 cells and brain microvascular endothelial HBEC-5i cells to MAYV and UNAV infection. Cytopathic effects, cell viability, viral progeny yields, and the presence of E1 and nsP1 proteins in HMC3 and HBEC-5i cells infected with several MAYV or UNAV strains were assessed using an inverted microscope, MTT assay, plaque-forming assays, and immunofluorescence or Western blot, respectively. Finally, the expression of immune response genes was analyzed using qRT-PCR. MAYV and UNAV demonstrated strong cytopathic effects and significantly reduced cell viability in HMC3 cells. Moreover, the HMC3 cells were efficiently infected regardless of the virus strains tested, and E1 and nsP1 viral proteins were detected. In contrast, only MAYV appeared to infect HBEC-5i cells, and minimal effects on cell morphology or viability were observed. Furthermore, the MAYV titer and viral protein levels were substantially lower in the infected HBEC-5i cells when compared to those of the infected microglia cells. Finally, unlike UNAV, MAYV elicited a strong expression of specific interferon-stimulated genes in microglia cells, along with pro-inflammatory cytokines implicated in the immune response. Collectively, these findings demonstrate that MAYV and UNAV are capable of infecting relevant human brain cells.
Ancient DNA supports that the evolution of Skin Tone in East Asians intensified after their split with Native Americans
Authors: Ferrando-Bernal Manuel
Published: September 2023

Skin tone has been deeply studied in European populations both using modern and ancient DNA. However, other populations are underrepresented in such studies. One such population is East Asians, for which, interestingly, it has been claimed to evolve light skin tones in parallel to Europeans. Moreover, it is not clear whether this happened before or after their split from Native Americans. Over the last few years, several studies have sequenced hundreds of ancient genomes belonging to East Asians ancient populations. Additionally, some variants have been associated with light skin in East Asians. To shed some light, I applied a Polygenic Risk Score for some of the variants associated with light skin, in 237 modern Native Americans and East Asian individuals and in more than 700 East Asians ancient samples. The results suggest that this phenotype may have started to evolve in the ancestors of East Asians and Native Americans but intensified after their split.
Propagation of human respiratory syncytial virus in cells derived from the black flying fox (Pteropus alecto)
Authors: Tan Timothy , Tan Boon Huan , Sugrue Richard
Published: September 2023

The propagation of human respiratory syncytial virus (hRSV) was evaluated in thePteropus alectokidney (PaKi) cell line. At 20 hrs post-infection, immunoblotting of hRSV-infected PaKi cell lysates with anti-G, anti-N, anti-P and anti-M2-1 indicated expression of the respective virus proteins of the correct size. The hRSV-infected PaKi cell were also stained using anti-F, anti-G, anti-N, anti-P and anti-M2-1 and imaged using immunofluorescence microscopy, which confirmed high levels of virus infection, and the presence of numerous virus filaments and virus-induced inclusion bodies. PaKi cell monolayers also supported multiple cycle infection when hRSV was used to infect PaKi cells using a low multiplicity of infection. These data indicate that prior adaptation of hRSV was not required for its propagation in the PaKi cell line, and suggests that PaKi cell line is a suitable cell model system with which to examine virus-host interactions involving RSV infection in fruit bats.
Genetic basis of variation in thermal developmental plasticity forDrosophila melanogasterbody pigmentation
Authors: Lafuente E , Duneau D , Beldade P
Published: September 2023

Seasonal differences in insect pigmentation are attributed to the influence of ambient temperature on pigmentation development. This thermal plasticity is adaptive and heritable, thereby capable of evolving. However, the specific genes contributing to the variation in plasticity that can drive its evolution remain largely unknown. To address this, we analyzed pigmentation and pigmentation plasticity inDrosophila melanogaster. We measured two components of pigmentation in the thorax and abdomen: overall darkness and the proportion of length covered by darker pattern elements (a trident in the thorax and bands in the abdomen) in females from two developmental temperatures (17°C or 28°C) and 191 genotypes. Using a GWAS approach to identify the genetic basis of variation in pigmentation and its response to temperature, we identified numerous dispersed QTLs, including some mapping to melanogenesis genes (yellow,ebony, andtan). Remarkably, we observed limited overlap between QTLs for variation within specific temperatures and those influencing thermal plasticity, as well as minimal overlap between plasticity QTLs across pigmentation components and across body parts. For most traits, consistent with selection favoring the retention of plasticity, we found that lower plasticity alleles were often at lower frequencies. The functional analysis of selected candidate QTLs and pigmentation genes largely confirmed their contributions to variation in pigmentation and/or pigmentation plasticity. Overall, our study reveals the existence and underlying basis of extensive and trait-specific genetic variation for pigmentation and pigmentation plasticity, offering a rich reservoir of raw material for natural selection to shape the independent evolution of these traits.
Molecular analysis of archival diagnostic prostate cancer biopsies identifies genomic similarities in cases with progression post-radiotherapy, and those withde novometastatic disease
Authors: Charlton P , O’Reilly D , Philippou Y , Rao SR , Lamb AD , Mills IG , Higgins G , Hamdy FC , Verrill C , Buffa FM , Bryant RJ
Published: September 2023

Purpose

It is important to identify molecular features that improve prostate cancer (PCa) risk stratification before radical treatment with curative intent. Molecular analysis of historical diagnostic formalin-fixed paraffin-embedded (FFPE) prostate biopsies from cohorts with post-radiotherapy (RT) long-term clinical follow-up has been limited. Utilizing parallel sequencing modalities, we performed a proof-of-principle sequencing analysis of historical diagnostic FFPE prostate biopsies. We compared patients with i) stable PCa post-primary or salvage RT (sPCa), ii) progressing PCa post-RT (pPCa), and iii)de novometastatic PCa (mPCa).

Experimental Design

A cohort of 19 patients with diagnostic prostate biopsies (n=6 sPCa, n=5 pPCa, n=8 mPCa) and mean 4 years 10 months follow-up (diagnosed 2009-2016) underwent nucleic acid extraction from demarcated malignancy. Samples underwent 3’RNA sequencing (3’RNAseq) (n=19), nanoString analysis (n=12) and Illumina 850k methylation (n=8) sequencing. Bioinformatic analysis was performed to coherently identify differentially expressed genes (DEGs) and methylated genomic regions (MGRs).

Results

18 of 19 samples provided useable 3’RNAseq data. Principal Component Analysis (PCA) demonstrated similar expression profiles between pPCa and mPCa cases, versus sPCa. Coherently differentially methylated probes between these groups identified ∼600 differentially MGRs. The top 50 genes with increased expression in pPCa patients were associated with reduced progression-free survival post-RT (p<0.0001) in an external cohort.

Conclusions

3’RNAseq, nanoString and 850K-methylation analyses are each achievable from historical FFPE diagnostic pre-treatment prostate biopsies, unlocking the potential to utilize large cohorts of historic clinical samples. Profiling similarities between individuals with pPCa and mPCa suggests biological similarities and historical radiological staging limitations, which warrant further investigation.
High resolution longitudinal molecular and morphological tracking of planktonic threats to salmon aquaculture: new candidates and old players
Authors: Algueró-Muñiz María , Spatharis Sofie , Dwyer Toni , de Noia Michele , Chaib Bachar , Robertson Brendan , Johnstone Calum , Welsh Jennifer , Macphee Annabell , Mazurkiewicz Marta , Bickerdike Ralph , Migaud Hervé , McGhee Clara , Præbel Kim , Llewellyn Martin
Published: September 2023

Marine-phase salmonid aquaculture is a major component of the coastal economies of Northern Europe, North America and Chile and is under threat from numerous challenges to gill health, many of which originate from the phyto- and zooplankton. Associated losses are growing as a proportion of production year on year. A first step towards mitigating losses is to characterize the biological drivers of poor gill health. Numerous planktonic species have been implicated, including toxic and siliceous microalgae, hydrozoans and scyphozoans; however, rigorous longitudinal surveys of planktonic diversity and gill health have been lacking. In the current study, we present and assess an ‘exhaustive’ identification approach combining both morphological and molecular methods (environmental DNA metabarcoding) approaches in combination with robust statistical models to identify the planktonic drivers of complex gill disease (CGD) and fish mortality. We undertook longitudinal molecular and microscopic evaluation at two marine aquaculture facilities on the west coast of Scotland using daily data collected during the 2021 growing season (March-October). Examining these two different sites, one sheltered and one exposed to the open sea, we identified new, important, and unexpected planktonic drivers (e.g. doliolids and appendicularians) of CGD and mortality and confirmed the significance of some established threats (e.g. hydrozoans and diatoms). We also explored delayed or ‘lagged’ effects of planktonic abundances on gill health and undertook a comparison of environmental DNA metabarcoding and microscopy in their ability to identify and quantify planktonic species. Our data highlight the diversity of planktonic threats to salmonid aquaculture as well as the importance of using both molecular and morphological approaches to detect those. Despite our study relying on two farm sites only, our results evidence the role of the different planktonic players on salmon gill disease; there is now an urgent need to expand systematic longitudinal molecular and morphological approach across multiple sites and over multiple years. The resultant catalogue of main biological drivers will enable early warning systems, new treatments and, ultimately, a sustainable platform for future salmonid aquaculture in the marine environment.
Characterising the metabolic rewiring of extremely slow growingKomagataella phaffii
Authors: Coltman Benjamin Luke , Rebnegger Corinna , Gasser Brigitte , Zanghellini Jürgen
Published: September 2023

Retentostat cultivations have enabled investigations into substrate-limited near-zero growth for a number of microbes. Quantitative physiology at these near-zero growth conditions has been widely discussed, yet characterisation of the fluxome is relatively under-reported. We investigated the rewiring of metabolism in the transition of a recombinant protein producing strain ofKomagataella phaffiito glucose-limited near-zero growth rates. We used cultivation data from a 200-fold range of growth rates and comprehensive biomass composition data to integrate growth rate dependent biomass equations, generated using a number of different approaches, into aK. phaffiigenome scale metabolic model. Here we show that a non-growth associated maintenance value of 0.65 mmolATPgCDW−1h−1and a growth-associated maintenance value oflead to accurate growth-rate predictions. In-line with its role as energy source, metabolism is rewired to increase the yield of ATP per glucose. This includes a reduction of flux through the pentose phosphate pathway, and a greater utilisation of glycolysis and the TCA cycle. Interestingly, we observed activity of an external, non-proton translocating NADH dehydrogenase in addition to the malate-aspartate shuttle. Regardless of the method used for the generation of biomass equations, a similar, yet different, growth rate dependent rewiring was predicted. As expected, these differences between the different methods were clearer at higher growth rates, where the biomass equation provides a much greater constraint than at slower growth rates. When placed on an increasingly limited glucose diet, the metabolism ofK. phaffiiadapts, enabling it to continue to drive critical processes sustaining its high viability at near-zero growth rates.
Phylogeny structures species’ interactions in experimental ecological communities
Authors: Lemos-Costa Paula , Miller Zachary R. , Allesina Stefano
Published: September 2023

The advent of molecular phylogenetics provided a new perspective on the structure and function of ecological communities. In particular, the hypothesis that traits responsible for species’ interactions are largely determined by shared evolutionary history has suggested the possibility of connecting the phylogeny of ecological communities to their functioning. However, statistical tests of this link have yielded mixed results. Here we propose a novel framework to test whether phylogeny influences the patterns of coexistence and abundance of species assemblages, and apply it to analyze data from large biodiversity-ecosystem functioning experiments. In our approach, phylogenetic trees are used to parameterize species’ interactions, which in turn determine the abundance of species in a specified assemblage. We use a maximum likelihood-based approach to score models parameterized with a given phylogenetic tree. To test whether evolutionary history structures interactions, we fit and score ensembles of randomized trees, allowing us to determine if phylogenetic information helps to predict species’ abundances. Moreover, we can determine the contribution of each branch of the tree to the likelihood, revealing particular clades in which interaction strengths are closely tied to phylogeny. We find strong evidence of phylogenetic signal across a range of published experiments and a variety of models. The flexibility of our framework permits incorporation of ecological information beyond phylogeny, such as functional groups or traits, and provides a principled way to test hypotheses about which factors shape the structure and function of ecological communities.
Reservoir ecosystems support large pools of fish biomass
Authors: Parisek Christine A. , De Castro Francine A. , Colby Jordan D. , Leidy George R. , Sadro Steve , Rypel Andrew L.
Published: September 2023

Humans increasingly dominate Earth’s natural freshwater ecosystems, and many freshwater fisheries resources are imperiled and at-risk of collapse. Yet despite this, the productive capacity of intensively modified freshwater ecosystems is rarely studied. We digitized, and provide open access to, a legacy database containing empirical fish biomass from 1,127 surveys on 301 USA reservoirs. In parallel, we developed a slate of reservoir classification schemas that were deployed to better understand distributions of biomass and secondary production. By fusing these data products, we generated a predictive capacity for understanding the scope of fisheries biomass and secondary production across all USA reservoirs. We estimate total potential fish total standing stock in USA reservoirs is 3.4 billion (B) kg, and annual secondary production is 4.5 B kg y-1. In southern USA alone, total standing stock and secondary production are 1.9 B kg and 2.5 B kg y-1, respectively. We also observe non-linear trends in reservoir fish production and biomass over time, indicating that these ecosystems are quite dynamic. Results demonstrate that reservoirs represent globally relevant pools of freshwater fisheries, in part due to their immense spatial and limnetic footprint. This study further shows that reservoir ecosystems play major roles in food security, and fisheries conservation, even though they are frequently overlooked by freshwater scientists. We encourage additional effort be expended to effectively manage reservoir environments for the good of humanity, biodiversity, and fishery conservation.

Significance Statement

Globally, many freshwater fishes and fisheries resources are imperiled and at-risk of collapse. However, previous research overwhelmingly focuses on freshwater fisheries in natural rivers and lakes. This study provides evidence that novel and reconciled ecosystems, such as reservoirs, hold massive pools of freshwater fisheries biomass and may have higher ecological value than previously thought. While dams are patently ecological catastrophes, ecosystem services including secondary fish production provided by reservoirs are nonetheless substantial. Indeed, in many locations (e.g., arid regions), reservoirs are the only remaining fisheries resource. We suggest considerable conservation management is warranted for reservoir fisheries worldwide.

Data Deposition

Code is available on GitHub (https://github.com/caparisek/res_biomass_USA; DOI 10.5281/zenodo.8316696). All data and reservoir classifications are available on Zenodo (DOI 10.5281/zenodo.8317007). Furthermore, data will also be deposited in the Environmental Data Initiative repository upon acceptance of this manuscript.
WITHDRAWN: Comparison of the effects of methylene blue with adrenaline and Marcaine with adrenaline on pain control after hemorrhoidectomy
Authors: Azhough Ramin , Dashti Mohammad Reza , Taher Sahar , Jalali Pooya
Published: September 2023

Withdrawal Statement

The authors have withdrawn their manuscript owing to Improve the article. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Prospective exploration of a prognostic biomarker of nivolumab for head and neck cancer patients (BIONEXT)
Authors: Sato Kuniaki , Toh Satoshi , Murakami Taku , Nakano Takafumi , Hongo Takahiro , Matsuo Mioko , Hashimoto Kazuki , Sugasawa Masashi , Yamasaki Keisuke , Ueki Yushi , Nakashima Torahiko , Uryu Hideoki , Ono Takeharu , Umeno Hirohito , Ueda Tsutomu , Kano Satoshi , Tsukahara Kiyoaki , Watanabe Akihito , Ota Ichiro , Monden Nobuya , Iwae Shigemichi , Maruo Takashi , Asada Yukinori , Hanai Nobuhiro , Sano Daisuke , Ozawa Hiroyuki , Asakage Takahiro , Fukusumi Takahito , Masuda Muneyuki
Published: September 2023

BACKGROUND

Nivolumab paved a new way in the treatment of patients with recurrent or metastatic (RM) head and neck squamous cell carcinoma (RM-HNSCC). However, the limited rates of long-term survivors (< 20%) demand a robust prognostic biomarker. This nationwide multi-centric prospective study aimed to identify a plasma exosome (PEX) mRNA signature, which serves as a companion diagnostic of nivolumab and provides a biological clue to develop effective therapies for a majority of non-survivors.

METHODS

Pre-treatment plasmas (N= 104) of RM-HNSCC patients were subjected to comprehensive PEX mRNA analyses for prognostic marker discovery and validation. In parallel, paired treatment-naïve tumor and plasma samples (N= 20) were assayed to elucidate biological implications of the PEX mRNA signature.

RESULTS

A combination of 6 candidate PEX mRNAs plus neutrophil-to-lymphocyte ratio precisely distinguished non-survivors from >2-year survivors (2-year OS; 0% vs 57.7%;P= 0.000124) with a high hazard ratio of 2.878 (95% CI 1.639-5.055;P= 0.0002348). In paired samples, PEXHLA-EmRNA (a non-survivor-predicting marker) was positively corelated with overexpression of HLA-E protein (P= 0.0191) and the dense population of tumor-infiltrating NK cells (P= 0.024) in the corresponding tumor, suggesting the HLA-E-NKG2A immune checkpoint may inhibit the antitumor effect of PD-1blockade in patients with high PEXHLA-EmRNA.

CONCLUSION

The PEX mRNA signature could be useful as a companion diagnostic of nivolumab. The combination of an anti-NKG2A antibody (i.e., monalizumab) and nivolumab may serve as a treatment option for non-survivors predicted by a RT-qPCR-based pre-treatment measurement of PEX mRNAs.

TRIAL REGISTRATION

This study is registered to the UMIN Clinical Trial Registry: UMIN000037029.

FUNDING

This study is partly funded by JSPS KAKENHI (Grant number JP 21436707 to MM) and Sota memorial fund to MM. PEXmRNA analyses were conducted by Showa Denko America Materials. CReS Kyushu organized sample collection and transfer, and conducted clinical data management with funding provided by Ono and Bristol-Myers Squibb.

Graphical abstract
The potential clinical impact and cost-effectiveness of the updated COVID-19 mRNA Fall 2023 vaccines in the United States
Authors: Kohli M , Maschio M , Joshi K , Lee A , Fust K , Beck E , Van de Velde N , Weinstein MC
Published: September 2023

Objectives

To assess the potential clinical impact and cost-effectiveness of COVID-19 mRNA vaccines updated for Fall 2023 in adults ≥18 years over a 1-year analytic time horizon (September 2023-August 2024).

Methods

A compartmental Susceptible-Exposed-Infected-Recovered model was updated to reflect COVID-19 in summer 2023. Numbers of symptomatic infections, COVID-19 related hospitalizations and deaths, and costs and quality-adjusted life-years (QALYs) gained were calculated using a decision tree model. The incremental cost-effectiveness ratio (ICER) of a Moderna updated mRNA Fall 2023 vaccine (Moderna Fall Campaign) was compared to no additional vaccination. Potential differences between the Moderna and the Pfizer-BioNTech Fall 2023 vaccines were examined.

Results

Base case results suggest the Moderna Fall Campaign would decrease the expected 64.2 million symptomatic infections by 7.2 million (11%) to 57.0 million. COVID-19-related hospitalizations and deaths are expected to decline by 343,000 (–29%) and 50,500 (–33%), respectively. The Moderna Fall Campaign would increase QALYs by 740,880 and healthcare costs by $5.7 billion relative to No Vaccine, yielding an ICER of $7,700 per QALY gained. Using a societal cost perspective, the ICER is $2,100. Sensitivity analyses suggest that vaccine effectiveness, COVID-19 incidence, hospitalization rates and costs drive cost-effectiveness. With a relative vaccine effectiveness (rVE) of Moderna versus Pfizer-BioNTech of 5.1% for infection and 9.8% for hospitalization, use of the Moderna vaccine is expected to prevent 24,000 more hospitalizations and 3,300 more deaths than the Pfizer-BioNTech vaccine.

Limitations and Conclusions

As COVID-19 becomes endemic, future incidence, including patterns of infection, are highly uncertain. Vaccine effectiveness of Fall 2023 vaccines is unknown, and it is unclear when a new variant that evades natural or vaccine immunity will emerge. Despite these limitations, the Moderna Fall 2023 vaccine can be considered cost-effective relative to no vaccine.
Prediction of fall-risk factors specific to the old-age Indian population
Authors: Sharma Abhinav , Sharma Mehul , Sharma Ashish Arunkumar
Published: September 2023

Background/Objectives

The health care infrastructure of India, designed to treat acute problems, can benefit from preventive medicine-based policies that address chronic and non-communicable issues of relevance to India’s growing elderly population. Unintentional fall related injuries are one such issue whose economic burden can be streamlined with proper preventative public health policies. It is imperative that fall-risk factors specific to the Indian population be identified and analyzed for use in geriatric falls-risk assessment. We aim to determine factors predictive of falls in the aging Indian population in this study using Wave 1 data from the World Health Organization Study on Global Ageing and Adult Health (WHO SAGE) in India.

Methods

Cross-sectional analysis of results from WHO SAGE Wave 1 was conducted. Multivariate analysis was used to determine risk factors of falls specific to the Indian population in adults over the age of 50. Prediction models were created and evaluated using these risk factors and their performances were evaluated. SAGE Wave 1 India was implemented in six states that together provided nationally representative samples. Multistage stratified sampling was used to select these states and systematic sampling was used to select households from villages and urban districts within these states. Data from all individuals over the age of 50 in selected households was compiled for analysis.

Findings

34 fall risk factors specific to the Indian population were determined. The model that did not weigh the factors was determined as the best model for possible use in clinically assessing old-age adults at risk for falling. Furthermore, 6 risk factors in the Indian census were used to identify falls risks hotspots on a district-level map of India.

Conclusion

This analysis can be used in public health policy recommendations and can form a basis for assessing and addressing falls-risk issues in India.
Identification of Potential EGFR Inhibitors for Type 2 Diabetes and Pancreatic Cancer Treatment: A Computational Approach
Authors: Romero Ricardo
Published: September 2023

This study conducted a differential gene expression analysis in two independent studies of type 2 diabetes using pancreatic samples, specifically Langerhans cells. Through protein-protein interaction network analysis, the Epidermal Growth Factor Receptor (EGFR) emerged as the top hub gene among the upregulated genes in both studies. Furthermore, functional enrichment analysis revealed the involvement of EGFR in pancreatic cancer signaling pathways, indicating its potential role beyond diabetes.

To identify potential EGFR inhibitors, a virtual screening approach was employed using tyrosine kinase inhibitors. Two separate deep learning classification models were developed and trained on distinct sets of ligands, one for predicting bioactivity and the other for assessing toxicity. The ligands underwent rigorous filtering based on binding energies and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties.

This filtering process resulted in the identification of nine hits that demonstrated promising characteristics in terms of both bioactivity and druglikeness, making them viable candidates for further development as EGFR inhibitors.

To evaluate the performance of the identified hits, approved drugs including Afatinib, Almonertinib, Erlotinib, Gefitinib, and Osimertinib were used as controls. Notably, the finalist compounds consistently outperformed the control drugs across all evaluated parameters, indicating their superior potential as EGFR inhibitors.

This study provides valuable insights into the molecular mechanisms underlying type 2 diabetes by highlighting the significant role of EGFR and its potential association with pancreatic cancer signaling pathways. Moreover, the identified hits from the virtual screening represent promising candidates for further investigation and development of improved drugs targeting EGFR.
Economic analysis of disease and control of multi-field epidemics in agriculture
Authors: Mikaberidze Alexey , Gokhale Chaitanya S. , Bargués-Ribera Maria , Verma Prateek
Published: September 2023

Epidemics of plant diseases are estimated to cause significant economic losses in crop production. Fungicide applications are widely used to control crop diseases but incur substantial indirect costs. One essential class of indirect costs arises due to the evolution of fungicide resistance. This indirect cost must be estimated reliably to design economic policy for more sustainable use of fungicides. Such estimation is difficult because the cost depends on economic parameters and the epidemiological/evolutionary properties of crop pathogens. Even a conceptual framework for such estimation is missing. To address this problem, we combined a spatially implicit mathematical model of crop epidemics with an economic analysis at the landscape scale. We investigated how the net economic return from a landscape depends on the proportion of fungicide-treated fields. We discovered a pattern of accelerating (or decelerating) returns, contrary to expected diminishing returns. Next, we calculated the economic cost of the evolution of fungicide resistance as the difference between the optimal net return of the landscape in the absence and presence of resistance. We found that this cost depends strongly on the fungicide price, the degree of resistance, the pathogen’s basic reproduction number and the yield loss due to disease. Surprisingly, the cost declines with the fungicide price and exhibits a non-monotonic pattern as a function of the basic reproduction number. Hence, to calculate the cost, we must estimate these parameters robustly, incorporating variations in environmental conditions, crop varieties and the genetic composition of pathogen populations. Appropriate estimation of the cost of resistance evolution can inform economic policy, design dynamic fungicide pricing, and encourage more sustainable use of fungicides.