bluuebunny/crossref_metadata_2025 huggingface dataset:
The distribution of distances to the edge of species coexistence
Authors: Desallais Mario , Loreau Michel , Arnoldi Jean-François
Published: January 2024

In Lotka-Volterra community models, given a set of biotic interactions, recent approaches have analysed the probability of finding a set of species intrinsic growth rates (representing intraspecific demographic features) that will allow coexistence. Several metrics have been used to quantify the fragility of coexistence in the face of variations in those intrinsic growth rates (representing environmental perturbations), thus probing a notion of ‘distance’ to the edge of coexistence of the community. Here, for any set of interacting species, we derive an analytical expression for the whole distribution of distances to the edge of their coexistence. Remarkably, this distribution is entirely driven by (at most) two characteristic distances that can be directly computed from the matrix of species interactions. We illustrate on data from experimental plant communities that our results offer new ways to study the contextual role of species in maintaining coexistence, and allow us to quantify the extent to which intraspecific features and biotic interactions combine favorably (making coexistence more robust than expected), or unfavourably (making coexistence less robust than expected). Our work synthesizes different study of coexistence and proposes new, easily calculable metrics to enrich research on community persistence in the face of environmental disturbances.
Investments in photoreceptors compete with investments in optics to determine eye design
Authors: Heras Francisco J H , Laughlin Simon B
Published: January 2024

Because an animal invests in an eye’s optics and photoreceptor array to meet behavioural needs at minimum cost, optics and photoreceptors compete for resources to maximise eye performance. This competition has not previously been investigated. Its outcome depends on the relative costs and benefits of investing space, materials and energy in optics and photoreceptors. We introduce a measure of cost, specific volume in µm3sr−1, which relates to performance via optical, physiological and geometrical constraints. We model apposition compound eyes and simple (camera type) eyes to calculate the performance surface across the morphospace of eyes of given type and total cost. This surface identifies the allocation of resources that maximises efficiency and shows how efficiency reduces as eye morphology departs from optimum. Using published data, we calculate specific volumes to estimate the investments in optics and photoreceptors that insects make, and compare these with our models. We find that efficient allocation can explain three robust trends: fast flying diurnal insects allocate>50% of eye volume to photoreceptor arrays, their photoreceptors’ photosensitive waveguides (rhabdomeres, rhabdoms) are much longer than simple eyes’, and length increases systematically with spatial resolution. We conclude that photoreceptor costs often equal or exceed optical costs, therefore competition between optics and photoreceptors for resources is a major factor in eye design, and matching investments in optics and photoreceptors to maximise efficiency is a design principle. Our methodology can be developed to view the adaptive radiation of eyes through a cost:benefit lens.
SIRT1 mediates the antagonism of Wnt/β-catenin pathway by vitamin D in colon carcinoma cells
Authors: García-Martínez José Manuel , Chocarro-Calvo Ana , Martínez-Useros Javier , Regueira-Acebedo Nerea , Fernández-Aceñero María Jesús , Muñoz Alberto , Larriba María Jesús , García-Jiménez Custodia
Published: January 2024

Cancer initiation and progression result from both genetic alterations and epigenetic reprograming caused by environmental or endogenous factors which can lead to aberrant cell signalling. Most colorectal cancers (CRC) are linked to the abnormal activation of the Wnt/ β-catenin pathway, whose key feature is the accumulation of acetylated β-catenin protein within the nucleus of colon epithelial cells. Nuclear β- catenin acts as a transcriptional co-activator that alters the expression of many target genes involved in cell proliferation and invasion. The most active vitamin D metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3, calcitriol) can antagonize the over-activated Wnt/ β-catenin pathway via binding to its high affinity receptor VDR. Here, we show that the activation of the SIRT1 deacetylase by 1,25(OH)2D3-bound VDR promotes deacetylation and nuclear exclusion of β-catenin and, consequently, the downregulation of its pro-tumorigenic target genes and the inhibition of human colon carcinoma cell proliferation. Notably, orthogonal SIRT1 activation systematically drives nuclear exclusion of β-catenin, highlighting the key role of SIRT1 in CRC. Since nuclear localization of β-catenin is a critical driver of CRC initiation and progression that requires its acetylation, our results provide a mechanistic basis for the epidemiological evidence linking vitamin D deficiency and increased CRC risk and mortality.
Drivers of Bird Communities in an Urban Neighborhood Vary by Scale
Authors: Darracq Andrea , Bliznick Clay , Yeager Ray , Turner Jay , Prathiba Pradeep , Pease Jacob , Whiteman Howard , Smith Ted , Bhatnagar Aruni
Published: January 2024

Given the accelerated pace of global biodiversity loss and rapid urbanization, it is becoming increasingly urgent to identify ways to minimize the costs and maximize the benefits of urban environments for wild flora and fauna. For instance, it has been estimated that 48% of all bird species are experiencing population declines. One of the main drivers of these declines is habitat loss and degradation associated with urbanization. Increased urbanization necessitates a better understanding of how to conserve birds in urban areas. Although relationships between urbanization and bird communities have been explored extensively, few studies have been conducted in residential neighborhoods, and the influence of urban environmental conditions, particularly air pollution, on bird communities remains unclear. In this study, we examined relationships between bird community metrics and environmental measures related to vegetation and air pollution within a residential neighborhood at multiple spatial scales. We found that bird species richness and the average number of native species were positively related to greenness (as measured by the normalized difference vegetation index; NDVI) within 50 m, and negatively associated with ambient levels of NO2at 200 m. Similarly, we found the Hill-Shannon diversity index was positively associated with canopy cover, but negatively associated with NO2at 200 m. The average number of invasive bird species, however, was negatively correlated with canopy cover at 50 m. The average number of native birds was negatively related to ultrafine particle (<100 nm in diameter) concentration. Unlike native bird abundances, invasive bird abundances were not sensitive to NO2or ultrafine particles. Thus, our research suggests that reductions in air pollution, in combination with greening efforts that increase NDVI and canopy cover via the restoration of vegetation within urban neighborhoods, are likely to increase bird diversity and the abundances of native birds while reducing the abundance of invasive birds.
Phenotype-specific melanoma uptake of fatty acid from human adipocytes activates AXL and CAV1-dependent β-catenin nuclear accumulation
Authors: Chocarro-Calvo Ana , Jociles-Ortega Miguel , García-Martinez José Manuel , Louphrasitthiphol Pakavarin , Garcia Yurena Vivas , Ramírez-Sánchez Ana , Chauhan Jagat , Fiuza M Carmen , Duran Manuel , García-Jiménez Custodia , Goding Colin R.
Published: January 2024

Phenotypic diversity of cancer cells within tumors generated through bi-directional interactions with the tumor microenvironment has emerged as a major driver of disease progression and therapy resistance. Nutrient availability plays a critical role in determining phenotype, but whether specific nutrients elicit different responses on distinct phenotypes is poorly understood. Here we show, using melanoma as a model, that only MITFLowundifferentiated cells, but not MITFHighcells, are competent to drive lipolysis in human adipocytes. In contrast to MITFHighmelanomas, adipocyte-derived free fatty acids are taken up by undifferentiated MITFLowcells via a fatty acid transporter (FATP)-independent mechanism. Importantly, oleic acid (OA), a monounsaturated long chain fatty acid abundant in adipose tissue and lymph, reprograms MITFLowundifferentiated melanoma cells to a highly invasive state by ligand-independent activation of AXL, a receptor tyrosine kinase associated with therapy resistance in a wide range of cancers. AXL activation by OA then drives SRC-dependent formation and nuclear translocation of a β-catenin-CAV1 complex. The results highlight how a specific nutritional input drives phenotype-specific activation of a pro-metastasis program with implications for FATP-targeted therapies.
crossNN: an explainable framework for cross-platform DNA methylation-based classification of cancer
Authors: Yuan Dongsheng , Jugas Robin , Pokorna Petra , Sterba Jaroslav , Slaby Ondrej , Schmid Simone , Siewert Christin , Osberg Brendan , Capper David , Zeiner Pia , Weber Katharina , Harter Patrick , Jabareen Nabil , Mackowiak Sebastian , Ishaque Naveed , Eils Roland , Lukassen Sören , Euskirchen Philipp
Published: January 2024

DNA methylation-based classification of brain tumors has emerged as a powerful and indispensable diagnostic technique. Initial implementations have used methylation microarrays for data generation, but different sequencing approaches are increasingly used. Most current classifiers, however, rely on a fixed methylation feature space, rendering them incompatible with other platforms, especially different flavors of DNA sequencing. Here, we describe crossNN, a neural network-based machine learning framework which can accurately classify tumor entities using DNA methylation profiles obtained from different platforms and with different epigenome coverage and sequencing depth. It outperforms other deep- and shallow machine learning models with respect to precision as well as simplicity and computational requirements while still being fully explainable. Validation in a large cohort of >1,900 tumors profiled using different microarray and sequencing platforms, including low-pass nanopore and targeted bisulfite sequencing, demonstrates the robustness and scalability of the model.
Dual-domain joint learning reconstruction method (JLRM) combined with physical process for spectral computed tomography
Authors: Ma Genwei , Zhao Xing
Published: January 2024

Spectral computed tomography (SCT) is an powerful imaging modality with broad applications and advantages such as contrast enhancement, artifact reduction, and material differentiation. The positive process or data collected process of SCT is a nonlinear physical process existing scatter and noise, which make it is an extremely ill-posed inverse problem in mathematics. In this paper, we propose a dual-domain iterative network combining a joint learning reconstruction method (JLRM) with a physical process. Specifically, a physical module network is constructed according to the SCT physical process to accurately describe this forward process, which makes the nonlinear use of the traditional mathematical iterative algorithm effective and stable. Additionally, we build a residualto-residual strategy with an attention mechanism to overcome the slow speed of the traditional mathematical iterative algorithm. We have verified the feasibility of the method through our winning submission to the AAPM DL-spectral CT challenge, and demonstrated that high-accuracy also basis material decomposition results can be achieved with noisy data.
Estimated genetics prevalence of early-onset Parkinson’s disease caused byPRKNmutations
Authors: Diogo Dorothée , Wong Emily H.M. , DeBoever Christopher , Qu Wei , Lee Jonghun , Crawford Stephen , Hioki Takeshi , Padmanabhan Jaya , Prilutsky Daria , Proetzel Gabriele
Published: January 2024

Background

Estimating the prevalence of rare diseases is challenging due to very limited natural history studies, lack of studies in diverse populations, and frequent under or misdiagnosis. We leveraged human genetics to estimate the genetic prevalence (eGP) of familial Parkinson’s disease (PD) caused by biallelic pathogenic variants in theParkin(PRKN) gene (PRKN-PD).

Methods

We curated the reportedPRKN-PD pathogenic variants and obtained the heterozygous carrier frequencies of these variants from gnomAD and the Japanese Multi-omics reference panel (jMorp). We used the carrier frequencies to estimate the eGP ofPRKN-PD in eight genetic ancestries.

Results

Non-Japanese East Asians presented the highest eGP ofPRKN-PD (24 per 100,000 individuals, 95% CI=4-165 per 100,000 individuals), followed by Non-Finnish Europeans (22 in 100,000 individuals, 95% CI = 11-64 per 100,000 individuals). Based on the proportions of races and ethnicities, we estimated the eGP in the USA and the world-wide eGP to be 18 per 100,000 individuals (95% CI=7-68 per 100,000 individuals). and 13 per 100,000 individuals (95% CI=3-70 per 100,000 individuals), respectively. These estimates were significantly reduced when excluding structural variants (world-wide eGP=2 per 100,000 individuals, 95% CI=1-5 per 100,000 individuals).

Conclusions

This is the first study estimating thePRKN-PD genetic prevalence. Our results suggest that the prevalence of the disease may be higher than previously reported, highlighting potential underdiagnosis. We also demonstrate the importance of carefully considering the known genetic epidemiology of each disease, and its limitations, when using the approach applied in this study to estimate the disease genetic prevalence.
The Concept of Stroma AReactive Invasion Front Areas (SARIFA) as a New Prognostic Biomarker for Lipid-driven Cancers Holds True in Pancreatic Ductal Adenocarcinoma
Authors: Grochowski Przemyslaw , Grosser Bianca , Sommer Florian , Probst Andreas , Waidhauser Johanna , Schenkirsch Gerhard , Reitsam Nic G. , Märkl Bruno
Published: January 2024

Background

Pancreatic ductal adenocarcinoma (PDAC) is a ‘difficult-to-treat’ entity. To forecast its prognosis, we introduced a new biomarker, SARIFA (stroma areactive invasion front areas), which are an area at the tumour invasion front lacking desmoplastic stroma reaction upon malignant invasion in the surrounding tissue, leading to direct contact between tumour cells and adipocytes. SARIFA showed its significance in gastric and colorectal carcinoma, revealing lipid metabolism alternations that promote tumour progression.

Methods

We reviewed the SARIFA status of 174 PDAC cases on all available H&E-stained tumour slides from archival Whipple-resection specimens. SARIFA positivity was defined as SARIFA detection in at least 66% of the available slides. To investigate alterations in tumour metabolism and microenvironment, we performed immunohistochemical staining for FABP4, CD36 and CD68. To verify and quantify a supposed delipidation of adipocytes, adipose tissue was digitally morphometrised.

Results

In total, 54 cases (31%) were classified as SARIFA positive and 120 (69%) as SARIFA negative. Patients with SARIFA-positive PDAC showed a significantly worse overall survival compared with SARIFA-negative cases (median overall survival: 9.9 months vs. 18.0 months, HR: 1.558 (1.081–2.247), 95% CI, p = 0.018), which was independent from other prognostic markers (p = 0.014). At the invasion front of SARIFA-positive PDAC, we observed significantly higher expression of FABP4 (p<0.0001) and higher concentrations of CD68+macrophages (p=0.031) related to a higher risk of tumour progression. CD36 staining showed no significant expression differences. The adipocyte areas at the invasion front were significantly smaller, with mean values of 4021 ± 1058 µm2and 1812 ± 1008 µm2for the SARIFA-positive and -negative cases, respectively. The area differences between the SARIFA-positive invasion front area and the other three parameters were highly significant (p < 0.001)

Conclusions

SARIFA is a promising prognostic biomarker for PDAC. Its assessment is characterised by simplicity and low effort. The mechanisms behind SARIFA suggest a tumour-promoting increased lipid metabolism and altered immune background, both showing new therapeutic avenues.
Health services provided at the time of abortion in the US: a scoping review of the qualitative and quantitative evidence
Authors: Mahoney Katherine M , Bravo Licia , McAllister Arden , Bogar Kacie , Hennessey Sean , Schreiber Courtney A. , Abernathy Alice
Published: January 2024

Objectives

While it is well documented that abortion access is associated with improved health, pregnancy-related, and socioeconomic outcomes, the association between abortion access and other reproductive health outcomes is less well described. Abortion-providing clinics also offer preventative reproductive health services. We conducted a scoping review to ascertain the extent to which preventive reproductive healthcare services (contraception, sexually transmitted infection testing and treatment, cervical cancer screening) are affected by abortion access in the United States.

Methods

Researchers screened articles and extracted data from PubMed, Embase, Scopus and CINAHL. We excluded articles that did not link abortion to contraception, sexually transmitted infection testing and treatment and cervical cancer screening; or took place outside the US.

Results

5,359 papers were screened, 74 were included for full text review. Sixty-five were about contraception, seven on STIs, one on cervical cancer screening, and one on other services. The association between policies that restrict or protect abortion access and preventative health services has not been studied on a national scale. Drivers of variation were: insurance and billing policies; regulatory requirements of abortion-providing facilities, lack of staff training in clinics that did not specialize in abortion care; and limited follow up after abortion.

Conclusions

Abortion--providing clinics are a highly utilized access point for reproductive health services. More research is needed to determine the public health impact of constrained abortion access on contraceptive use, STI rates and cervical cancer in regions where many abortion-providing clinics have closed.

Implications

Attention should be paid to changing trends in contraceptive use, STI rates and cervical cancer as abortion-providing clinics close, this may reduce access to reproductive health services broadly.
Sex-specific effects of Birth Weight on Longitudinal Behavioural Outcomes; a Mendelian Randomisation Approach using Polygenic Scores
Authors: Byg Lars Meinertz , Wang Carol , Attia John , Whitehouse Andrew , Pennell Craig
Published: January 2024

Intro

It is unclear if sex differences in behaviour arising from birth weight (BW) are genuine because of the cross-sectional nature and potential confounding in previous studies. We aimed to test if sex differences associated with birth weight phenotype were reproducible using a Mendelian randomisation approach, i.e. polygenic score for birthweight across childhood and adolescence.

Method

Utilising data from the Raine study we had 1484 genotyped participants with a total of 6446 child behaviour checklist assessments across childhood and adolescence. We used BW polygenic scores in linear mixed-effects models to predict parentally-assessed attention, aggression and social problems scales; we also derived estimates and significance for a sex-by-genotype interaction. We used a Bonferroni corrected significance threshold and tested robustness of the results with teacher assessments of behaviour as well as a second polygenic score.

Results

We found a sex-by-genotype interaction with lower BW polygenic scores (BW-PGS) associated with increased aggression in males compared to females. These findings were consistent across various analyses, including teacher assessments. Surprisingly, a lower BW-PGS showed protective effects in females, while lower BW phenotype had detrimental effects in males with evidence of a genotype-phenotype mismatch increasing aggression problems in males only.

Conclusion

This study underscores the genuine nature of behavioural sex differences arising from low BW and highlights the sex-dependent and diverging effects of environmental and genetic BW determinants.
Treatment of a genetic liver disease in mice through transient prime editor expression
Authors: Rothgangl Tanja , Ioannidi Eleonora I. , Weber Yanik , Tálas András , Böck Desirée , Matsushita Mai , Villiger Elina Andrea , Schmidheini Lukas , Moon Jennifer , Lin Paulo J.C. , Fan Steven H.Y. , Marquart Kim F. , Schwerdel Cornelia , Rimann Nicole , Faccin Erica , Villiger Lukas , Muramatsu Hiromi , Vadovics Máté , Cremonesi Alessio , Thöny Beat , Kopf Manfred , Häberle Johannes , Pardi Norbert , Tam Ying K. , Schwank Gerald
Published: January 2024

Prime editing is a versatile genome editing technology that does not rely on DNA double-strand break formation and homology-directed repair (HDR). This makes it a promising tool for correcting pathogenic mutations in tissues consisting predominantly of postmitotic cells, such as the liver. While recent studies have already demonstrated proof-of-concept forin vivoprime editing, the use of viral delivery vectors resulted in prolonged prime editor (PE) expression, posing challenges for clinical application. Here, we developed anin vivoprime editing approach where we delivered the pegRNA using self-complementary adeno-associated viral (scAAV) vectors and the prime editor using nucleoside-modified mRNA encapsulated in lipid nanoparticles (LNPs). This methodology led to transient expression of the PE for 48h and 26% editing at theDnmt1locus using AAV doses of 2.5×1013vector genomes (vg)/kg and a single dose of 3mg/kg mRNA-LNP. When targeting the pathogenic mutation in the Pahenu2mouse model of phenylketonuria (PKU), we achieved 4.3% gene correction using an AAV dose of 2.5×1013vg/kg and three doses of 2 mg/kg mRNA-LNP. Editing was specific to the liver and the intended locus, and was sufficient to reduce blood L-phenylalanine (Phe) levels from over 1500 µmol/l to below the therapeutic threshold of 600 µmol/l. Our study demonstrates the feasibility ofin vivogene correction in the liver with transient PE expression, bringing prime editing closer to clinical application.
Evolution of human pair bonds as a consequence of male-biased mating sex ratios?
Authors: Nitschke Matthew C. , Kumar Viney , Milliner Katrina E. , Hawkes Kristen , Kim Peter S.
Published: January 2024

Compared to our closest primate relatives, human life history involves greater longevity, which includes a distinctive postmenopausal life stage. The extension of the human lifes-pan (and continued fertility in old males) without lengthening female fertility directly changes the ratio of fertile males to fertile females, called the adult sex ratio (ASR). Additionally, this affects a more fine-grained ratio, the operational sex ratio (OSR), defined as the ratio of males to females currently able to conceive. Here, we construct an ODE model with minimal age structure, in which males compete for paternities using either a multiple-mating or mate-guarding strategy. Our focus is on investigating the differences of strategy choice between populations with chimpanzee-like and human-like life histories. By simulating the system, we determine the dominant strategy and its dependence on various parameter combinations. We introduce a new measure we call the lifetime paternity opportunities (LPO) of a given male strategy. The LPO directly calculates the payoffs of different male strategies and hence enables us to predict when strategies may shift. Our results show that an increase in OSR and ASR correlates well with a change in the dominant strategy from multiple mating to guarding.
How to measure bacterial genome plasticity? A novel time-integrated index helps gather insights on pathogens
Authors: Bellinzona Greta , Batisti Biffignandi Gherard , Baldanti Fausto , Brilli Matteo , Sassera Davide , Gaiarsa Stefano
Published: January 2024

Genome plasticity can be defined as the capacity of a bacterial population to swiftly gain or lose genes. The time factor plays a fundamental role for the evolutionary success of microbes, particularly when considering pathogens and their tendency to gain antimicrobial resistance factors under the pressure of the extensive use of antibiotics. Multiple metrics have been proposed to provide insights into the gene content repertoire, yet they overlook the temporal component, which has a critical role in determining the adaptation and survival of a bacterial strain. In this study, we introduce a novel index that incorporates the time dimension to assess the rate at which bacteria exchange genes, thus fitting the definition of plasticity. Opposite to available indexes, our method also takes into account the possibility of contiguous genes being transferred together in one single event. We applied our novel index to measure plasticity in three widely studied bacterial species:Klebsiella pneumoniae,Staphylococcus aureus, andEscherichia coli. Our results highlight distinctive plasticity patterns in specific sequence types and clusters, suggesting a possible correlation between heightened genome plasticity and globally recognized high-risk clones. Our approach holds promise as an index for predicting the emergence of strains of potential clinical concern, possibly allowing for timely and more effective interventions.

Impact statement

How quickly bacterial populations can acquire new functions is the key to their evolutionary success. This speed, called genome plasticity, is particularly relevant for human pathogens, especially when considering the acquisition of antimicrobial resistance. Today, the availability of large numbers of genomes from public databases makes it possible to develop a way to measure plasticity. However, none is currently available, besides indexes of gene content variability, which do not take into account the rate at which such gene content changes. In this work, we developed a plasticity index, called Flux Of Gene Segments (FOGS), and we tested it on large datasets of bacterial pathogen genomes. Interestingly, the subpopulations of the selected species that showed higher FOGS correspond to globally emerging high-risk clones. Therefore, we suggest that our index might be used not only to detect but also to predict emerging strains of human health concern.

Data summary

The authors confirm that all supporting data, code and protocols have been provided within the article or through supplementary data files.
Viral load dynamics in asymptomatic and symptomatic patients during Omicron BA.2 outbreak in Shanghai, China, 2022: a longitudinal cohort study
Authors: Ai Jingwen , Zhou Jiaxin , Li Yang , Sun Feng , Ge Shijia , Zhang Haocheng , Wu Yanpeng , Wang Yan , Zhang Yilin , Wang Hongyu , Cai Jianpeng , Zhou Xian , Wang Sen , Li Rong , Feng Zhen , Xu Xiangyanyu , Yan Xuemei , Zhao Yuchen , Zhang Juanjuan , Yu Hongjie , Zhang Wenhong
Published: January 2024

Backgrounds

The SARS-CoV-2 virus has caused global outbreaks, including the recent Omicron BA.2 wave in Shanghai in spring 2022. While, the viral load dynamic of Omicron infections with different clinical severity was still unclear.

Methods

A prospective cohort was conducted on 48,830 hospitalized COVID-19 patients in three hospitals in Shanghai, China, from 23 March and 15 May 2022. Regular nucleic acid testing was performed and the Cycle threshold (Ct) value tested by RT-PCR was used as a proxy of viral load. The viral load dynamic by different clinical severity since initial detection and the risk factors were analyzed.

Results

The study included 31% asymptomatic cases, 68% mild-moderate cases, 1% severe cases, 1.29% critical and fatal cases. 57% of patients tested positive upon admission, average Ct value remained stable with peak viral concentrations occurring at 4 days (median Ct value of 27.5), followed by a decrease with a viral shedding time (VST) of 6.1 days (IQR, 4.0-8.8 days). Omicron viral load varied by age and clinical severity, but peak Ct values occurred at similar times. Unvaccinated status, age over 60, and comorbidities were associated with higher peak viral concentrations and longer shedding durations. Asymptomatic cases had a 40% contagious probability within 6 days of detection. Mild-moderate cases and severe cases had a 27%, >50% probability of infectiousness post-symptom resolution, respectively.

Conclusion

The initial Ct value could forecast severe consequences. Unvaccinated older people with specific comorbidities are the high-risk groups associated with high viral load and long shedding duration.
Network Proteomics of the Lewy Body Dementia Brain Reveals Presynaptic Signatures Distinct from Alzheimer’s Disease
Authors: Shantaraman Anantharaman , Dammer Eric B. , Ugochukwu Obiadada , Duong Duc M. , Yin Luming , Carter E. Kathleen , Gearing Marla , Chen-Plotkin Alice , Lee Edward B. , Trojanowski John Q. , Bennett David A. , Lah James J. , Levey Allan I. , Seyfried Nicholas T. , Higginbotham Lenora
Published: January 2024

Lewy body dementia (LBD), a class of disorders comprising Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), features substantial clinical and pathological overlap with Alzheimer’s disease (AD). The identification of biomarkers unique to LBD pathophysiology could meaningfully advance its diagnosis, monitoring, and treatment. Using quantitative mass spectrometry (MS), we measured over 9,000 proteins across 138 dorsolateral prefrontal cortex (DLPFC) tissues from a University of Pennsylvania autopsy collection comprising control, Parkinson’s disease (PD), PDD, and DLB diagnoses. We then analyzed co-expression network protein alterations in those with LBD, validated these disease signatures in two independent LBD datasets, and compared these findings to those observed in network analyses of AD cases. The LBD network revealed numerous groups or “modules” of co-expressed proteins significantly altered in PDD and DLB, representing synaptic, metabolic, and inflammatory pathophysiology. A comparison of validated LBD signatures to those of AD identified distinct differences between the two diseases. Notably, synuclein-associated presynaptic modules were elevated in LBD but decreased in AD relative to controls. We also found that glial-associated matrisome signatures consistently elevated in AD were more variably altered in LBD, ultimately stratifying those LBD cases with low versus high burdens of concurrent beta-amyloid deposition. In conclusion, unbiased network proteomic analysis revealed diverse pathophysiological changes in the LBD frontal cortex distinct from alterations in AD. These results highlight the LBD brain network proteome as a promising source of biomarkers that could enhance clinical recognition and management.
ZNF827pleiotropic cardiovascular risk locus involves regulation by Nuclear factor-1
Authors: Liu Yingwei , Liu Lu , Esmael Asraa , Fustier Margaux-Alison , Georges Adrien , Bouatia-Naji Nabila
Published: January 2024

Introduction

SCAD (spontaneous coronary artery dissection) is a form of myocardial infarction that disproportionately affects young women. SCAD is caused by the formation of a hematoma within coronary artery wall, resulting in its blockage. Sixteen SCAD susceptibility loci are currently known, includingZNF827gene locus on chromosome 4. Several common genetic variations withinZNF827are also linked to coronary artery disease (CAD), systolic blood pressure (SBP), and ascending aortic diameter. The molecular processes driving these genetic connections, however, are unknown.

Methods

We performed fine-mapping and genetic colocalization analysis atZNF827locus on multiple GWAS signals and quantitative expression traits. We explored the regulatory function of sequences of interest using a luciferase reporter system in rat smooth muscle cells. We used siRNA to knockdown the expression of gene and assessed transcriptomic changes through bulk RNA-Seq.

Results

The genetic association signals for SCAD, CAD, blood pressure, and aorta dimensions could all be explained by a single causal variant. We identified rs13128814 as the most likely causative variant. This variant overlaps epigenetic regulatory markers specifically active in vascular SMCs and fibroblasts. A 1kb region containing the SCAD-risk allele (A) of rs13128814 variant had a transcriptional activation impact, while the protective allele (G) had no effect.In silicopredictions found nuclear factor 1 (NF1) transcription factors preferentially bind to the A allele of rs13128814. We found that overexpressing NFIA (Nuclear Factor 1 A-Type) activated transcription in this area. SCAD association andZNF827eQTL colocalization in various vascular tissues suggested the latter as a plausible target gene in this locus. Knockdown of ZNF827 in iPSC-derived SMCs and fibroblasts, followed by RNA-seq, identified a large number of dysregulated genes, including multiple genes involved in cardiovascular disease.

Conclusion

Our findings inZNF827locus support the hypothesis that the rs13128814 variant, which may affect the binding of NF1 family transcription factors and causeZNF827expression to be deregulated, is the molecular mechanism underpinning the relationship of theZNF827locus with numerous cardiovascular disorders.ZNF827acts as a regulator of gene expression in vascular SMCs and fibroblasts. Further investigation ofZNF827function in vascular tissue will be required to understand the implications of its dysregulation on cardiovascular physiopathology.
A high coverage Mesolithic aurochs genome and effective leveraging of ancient cattle genomes using whole genome imputation
Authors: Erven Jolijn A.M , Scheu Amelie , Verdugo Marta Pereira , Cassidy Lara , Chen Ningbo , Gehlen Birgit , Street Martin , Madsen Ole , Mullin Victoria E
Published: January 2024

Ancient genomic analyses are often restricted to utilising pseudo-haploid data due to low genome coverage. Leveraging low coverage data by imputation to calculate phased diploid genotypes that enable haplotype-based interrogation and SNP calling at unsequenced positions is highly desirable. This has not been investigated for ancient cattle genomes despite these being compelling subjects for archaeological, evolutionary and economic reasons. Here we test this approach by sequencing a Mesolithic European aurochs (18.49x; 9852-9376 calBC), an Early Medieval European cow (18.69x; 427-580 calAD), and combine these with published individuals; two ancient and three modern. We downsample these genomes (0.25x, 0.5x, 1.0x, 2.0x) and impute diploid genotypes, utilising a reference panel of 171 published modern cattle genomes that we curated for 21.7 million (Mn) phased single-nucleotide polymorphisms (SNPs). We recover high densities of correct calls with an accuracy of >99.1% at variant sites for the lowest downsample depth of 0.25x, increasing to >99.5% for 2.0x (transversions only, minor allele frequency (MAF) ≥2.5%). The recovery of SNPs correlates with coverage, on average 58% of sites are recovered for 0.25x increasing to 87% for 2.0x, utilising an average of 3.5 million (Mn) transversions (MAF ≥2.5%), even in the aurochs which is temporally and morphologically distinct from the reference panel. Our imputed genomes behave similarly to directly called data in allele-frequency-based analyses; for example consistently identifying runs of homozygosity >2mb, including a long homozygous region in the Mesolithic European aurochs.
Wnt/β-catenin signaling improves oxidative metabolism in skeletal muscle of obese ob/ob mice
Authors: Christodoulou-Vafeiadou Eleni , Lepeigneux Céline , Naviere Aurore , Pujol Julien , Benhamed Fadila , Maire Pascal , Guillet-Deniau Isabelle
Published: January 2024

Background

Canonical Wnt signaling is involved in many physiological and pathological states. As it regulates lipid metabolism and glucose homeostasis, its misregulation may lead to the development of diabetes and obesity. We have already reported that activation of the Wnt/β-catenin canonical signaling pathway increased insulin sensitivity and prevented lipid deposits in rat skeletal muscle through a reciprocal regulation of Wnt10b and the lipogenic factor SREBP-1c.

Results

Here we have studied the role of Wnt/β-catenin canonical signaling in skeletal muscle of genetically obese and diabetic (ob/ob)mice and their control ob/+ mice. We showed thatWnt10bandSREBP-1cexpressions were conversely regulated in cultured mouse myoblasts isolated from lean ob/+ or obese ob/ob mice. Activation of the Wnt/β-catenin pathway using Wnt10b overexpression or the selective GSK3 inhibitor 6-Bromo-indirubin-3’oxime (BIO) was sufficient to decrease lipogenic genes expression in cultured myoblasts isolated from control and obese mice. In vivo, we performed direct electrotransfection of Wnt10b cDNA or BIO injections inTibialis Anterior(TA) muscles of ob/ob and ob/+ mice. Both up-regulatedWnt10bgene expression and down-regulatedSREBP-1cexpression. Canonical Wnt signaling increased slow Myosin Heavy Chain-I (MHC-I) oxidative fiber number as well as fast Myosin Heavy Chain-IIA (MHC-IIA) oxidative fiber number, while decreasing fast glycolytic fiber number in TA muscle. In addition, Wnt signaling increased mitochondrial oxidative metabolism and respiratory reserve capacity by 2- and 3-fold in myotubes cultured from ob/ob and ob/+ mice muscles respectively. Surprisingly, the activation of the Wnt pathway was sufficient to reduce hyperglycemia by 30% within 3 weeks in ob/ob mice.

Conclusions

Our results show that activation of Wnt/β-catenin signaling in skeletal muscle induced a shift towards a more oxidative metabolism in myofibers, thus mimicking the effects of exercise training. Wnt10b could be a valuable candidate to develop therapeutic drugs for the treatment of obesity and/or type 2 diabetes.
Two paralogous PHD finger proteins participate inParamecium tetraurelia’s natural genome editing
Authors: Häußermann Lilia , Singh Aditi , Swart Estienne C.
Published: January 2024

The unicellular eukaryoteParamecium tetraureliacontains functionally distinct nuclei: germline micronuclei (MICs) and a somatic macronucleus (MAC). During sexual reproduction, the MIC genome is reorganized into a new MAC genome and the old MAC is lost. Almost 45,000 unique Internal Eliminated Sequences (IESs) distributed throughout the genome require precise excision to guarantee a functional new MAC genome. Here, we characterize a pair of paralogous PHD finger proteins involved in DNA elimination. DevPF1, the early-expressed paralog, is present in only some of the gametic and post-zygotic nuclei during meiosis. Both DevPF1 and DevPF2 localize in the new developing MACs, where IESs excision occurs. InDevPF2knockdown (KD) long IESs are preferentially retained and late-expressed small RNAs decrease; no length preference for retained IESs was observed inDevPF1-KD and development-specific small RNAs were abolished. The expression of at least two genes from the new MAC with roles in genome reorganization seems to be influenced byDevPF1-andDevPF2-KD. Thus, both PHD fingers are crucial for new MAC genome development, with distinct functions, potentially via regulation of non-coding and coding transcription in the MICs and new MACs.
F420reduction as a cellular driver for anaerobic ethanotrophy
Authors: Lemaire Olivier N , Wegener Gunter , Wagner Tristan
Published: January 2024

The anaerobic ethane oxidation performed by seafloor archaea and sulfate-reducing partner bacteria involves largely uncharted biochemistry. This study deciphers the molecular basis of the CO2-generating steps by characterizing the native archaeal enzymes isolated from a thermophilic enrichment culture. While other microorganisms couple these steps to ferredoxin reduction, we found that the CO-dehydrogenase and the formylmethanofuran-dehydrogenase are bound to an F420-reductase module. The crystal structures of these multi-metalloenzyme complexes revealed a [4Fe-4S]-cluster networks electronic bridges coupling C1-oxidation to F420-reduction. Accordingly, both systems exhibit robust F420-reductase activities, which are not detected in methanogenic or methanotrophic relative organisms. We speculate that the whole catabolism of these archaea is reoriented towards F420-reduction, which facilitates the electron transfer to the sulfate-reducing partner, therefore representing the driving force of ethanotrophy.
FLUAV RAM-IGIP: A modified live influenza virus vaccine that enhances humoral and mucosal responses against influenza
Authors: Joaquín Cáceres C. , Claire Gay L. , Jain Aarti , Mejías Teresa D. , Cardenas Matias , Seibert Brittany , Faccin Flavio Cargnin , Cowan Brianna , Geiger Ginger , Baker Amy Vincent , Carnaccini Silvia , Huw Davies D. , Rajao Daniela S. , Perez Daniel R.
Published: January 2024

Current influenza A vaccines fall short, leaving both humans and animals vulnerable. To address this issue, we have developed attenuated modified live virus (MLV) vaccines against influenza using genome rearrangement techniques targeting the internal gene segments of FLUAV. The rearranged M2 (RAM) strategy involves cloning the M2 ORF downstream of the PB1 ORF in segment 2 and incorporating multiple early stop codons within the M2 ORF in segment 7. Additionally, the IgA-inducing protein (IGIP) coding region was inserted into the HA segment to further attenuate the virus and enhance protective mucosal responses. RAM-IGIP viruses exhibit similar growth rates to wild type (WT) viruses in vitro and remain stable during multiple passages in cells and embryonated eggs. The safety, immunogenicity, and protective efficacy of the RAM-IGIP MLV vaccine against the prototypical 2009 pandemic H1N1 strain A/California/04/2009 (H1N1) (Ca/04) were evaluated in Balb/c mice and compared to a prototypic cold-adapted live attenuated virus vaccine. The results demonstrate that the RAM-IGIP virus exhibits attenuated virulence in vivo. Mice vaccinated with RAM-IGIP and subsequently challenged with an aggressive lethal dose of the Ca/04 strain exhibited complete protection. Analysis of the humoral immune response revealed that the inclusion of IGIP enhanced the production of neutralizing antibodies and augmented the antibody-dependent cellular cytotoxicity response. Similarly, the RAM-IGIP potentiated the mucosal immune response against various FLUAV subtypes. Moreover, increased antibodies against NP and NA responses were observed. These findings support the development of MLVs utilizing genome rearrangement strategies in conjunction with the incorporation of immunomodulators.

IMPORTANCE

Current influenza vaccines offer suboptimal protection, leaving both humans and animals vulnerable. Our novel attenuated MLV vaccine, built by rearranging FLUAV genome segments and incorporating the IgA-inducing protein, shows promising results. This RAM-IGIP vaccine exhibits safe attenuation, robust immune responses, and complete protection against lethal viral challenge in mice. Its ability to stimulate broad-spectrum humoral and mucosal immunity against diverse FLUAV subtypes makes it a highly promising candidate for improved influenza vaccines.
Overloading And unpacKing (OAK) - droplet-based combinatorial indexing for ultra-high throughput single-cell multiomic profiling
Authors: Wu Bing , Bennett Hayley M. , Ye Xin , Sridhar Akshayalakshmi , Eidenschenk Celine , Everett Christine , Nazarova Evgeniya V. , Chen Hsu-Hsin , Kim Ivana K. , Deangelis Margaret , Owen Leah A. , Chen Cynthia , Lau Julia , Shi Minyi , Lund Jessica M. , Xavier-Magalhaes Ana , Patel Neha , Liang Yuxin , Modrusan Zora , Darmanis Spyros
Published: January 2024

Multiomic profiling of single cells by sequencing is a powerful technique for investigating cellular diversity in complex biological systems. Although the existing droplet-based microfluidic methods have advanced single-cell sequencing, they produce a plethora of cell-free droplets and underutilize barcoding capacities due to their low cell concentration prerequisites. Meanwhile, combinatorial indexing on microplates can index cells in a more effective way; however, it requires time-consuming and laborious protocols involving multiple splitting and pooling steps. Addressing these constraints, we have developed “Overloading And unpacKing” (OAK). With reduced labor intensity, OAK can provide cost-effective multiomic profiling for hundreds of thousands of cells, offering detection sensitivity on par with commercial droplet-based methods. To demonstrate OAK’s versatility, we conducted single-cell RNA sequencing (scRNA-Seq) as well as joint single-nucleus RNA sequencing (snRNA-Seq) and single-nucleus Assay for Transposase Accessible Chromatin with sequencing (snATAC-Seq) using cell lines. We further showcased OAK’s performance on more complex samples, includingin vitrodifferentiated bronchial epithelial cells and primary retinal tissues. Finally, we examined transcriptomic responses of 408,000 melanoma cells across around 1,000 starting lineages over a 90-day treatment with a RAF inhibitor, belvarafenib. We discovered a rare cell population (0.12%) that underwent a sequence of transcriptomic changes, resulting in belvarafenib resistance. Ultra-high throughput, broad compatibility with diverse molecular modalities, high detection sensitivity, and simplified experimental procedures distinguish OAK from previous methods, and render OAK a powerful tool for large-scale analysis of molecular signatures, even for rare cells.
MSK1 absence hinders BDNF-dependent striatal neurodevelopment and leads to schizophrenia symptoms
Authors: Varela-Andrés Natalia , Cebrián-León Alejandro , Hernández-del Caño Carlos , Fernández del Campo Inés S. , García-Losada Sandra , Martín-Ávila Noelia , Arévalo Juan Carlos , Merchán Miguel A. , Sánchez-Martín Manuel , Deogracias Rubén
Published: January 2024

Brain-derived neurotrophic factor (BDNF) plays a critical role in postnatal development by modulating the architecture of specific neuronal populations and brain areas. However, the precise molecular program controlling this differential responsiveness to BDNF is still unclear. In the present study, we describe that this program is governed by the restricted expression of the mitogen- and stress-activated protein kinase-1 (MSK1) in GABAergic neurons. Also, we show that whileMsk1expression declines in cortical interneurons along early postnatal development, its expression in striatal neurons increases until adulthood. Utilizing a novel MSK1 loss-of-function mouse model, we reveal its essential role in postnatal growth of the striatum, as it interacts with and modulates the BDNF-dependent phosphorylation of the methyl-CpG binding protein-2 (MeCP2). Furthermore, these mutant mice exhibit an altered transcription pattern of genes involved in the control of the dopamine and GABAergic signalling pathways. Consequently, MSK1 knockout mice behaviour is markedly altered, showing social dysfunction, altered anxiety- and depressive-like responses unequally manifested in males and females. These results elucidate how disruptions in the BDNF/MSK1 pathway impact GABAergic neurite outgrowth and contribute to behaviours reminiscent of schizophrenia in humans.