bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulation of Stemness and Differentiation Regulators by Valproic Acid in Medulloblastoma Neurospheres
Authors: Freire Natália Hogetop , Herlinger Alice Laschuk , Vanini Julia , Dalmolin Matheus , Fernandes Marcelo A. C. , Nör Carolina , Ramaswamy Vijay , Brunetto de Farias Caroline , Brunetto André Tesainer , Brunetto Algemir Lunardi , Gregianin Lauro José , da Cunha Jaeger Mariane , Taylor Michael D. , Roesler Rafael
Published: September 2024

Changes in epigenetic processes such as histone acetylation are proposed as key events influencing cancer cell function and the initiation and progression of pediatric brain tumors. Valproic acid (VPA) is an antiepileptic drug that acts partially by inhibiting histone deacetylases (HDACs) and could be repurposed as an epigenetic anticancer therapy. Here, we show that VPA reduced medulloblastoma (MB) cell viability and led to cell cycle arrest. These effects were accompanied by enhanced H3K9 histone acetylation (H3K9ac) and decreased expression of theMYConcogene. VPA impaired the expansion of MB neurospheres enriched in stemness markers and reducedMYCwhile increasingTP53expression in these neurospheres. In addition, VPA induced morphological changes consistent with neuronal differentiation and the increased expression of differentiation marker genesTUBB3andENO2. The expression of stemness genesSOX2,NES, andPRTGwas differentially affected by VPA in MB cells with differentTP53status. VPA increased H3K9 occupancy of the promoter region ofTP53. Among the genes regulated by VPA, the stemness regulatorsMYCandNESshowed an association with patient survival in specific MB subgroups. Our results indicate that VPA may exert antitumor effects in MB by influencing histone acetylation, which may result in the modulation of stemness, neuronal differentiation, and the expression of genes associated with patient prognosis in specific molecular subgroups. Importantly, the actions of VPA in MB cells and neurospheres include a reduction in the expression ofMYCand an increase inTP53.
Clustering individuals using INMTD: a novel versatile multi-view embedding framework integrating omics and imaging data
Authors: Li Zuqi , Windels Sam F. L. , Malod-Dognin Noël , Weinberg Seth M. , Marazita Mary L. , Walsh Susan , Shriver Mark D. , Fardo David W. , Claes Peter , Pržulj Nataša , Van Steen Kristel
Published: September 2024

Motivation

Combining omics and images, can lead to a more comprehensive clustering of individuals than classic single-view approaches. Among the various approaches for multi-view clustering, nonnegative matrix tri-factorization (NMTF) and nonnegative Tucker decomposition (NTD) are advantageous in learning low-rank embeddings with promising interpretability. Besides, there is a need to handle unwanted drivers of clusterings (i.e. confounders).

Results

In this work, we introduce a novel multi-view clustering method based on NMTF and NTD, named INMTD, that integrates omics and 3D imaging data to derive unconfounded subgroups of individuals. In the application to real-life facial-genomic data, INMTD generated biologically relevant embeddings for individuals, genetics and facial morphology. By removing confounded embedding vectors, we derived an unconfounded clustering with better internal and external quality; the genetic and facial annotations of each derived subgroup highlighted distinctive characteristics. In conclusion, INMTD can effectively integrate omics data and 3D images for unconfounded clustering with biologically meaningful interpretation.

Availability and implementation

https://github.com/ZuqiLi/INMTD
Impact of complex spatial population structure on early and long-term adaptation in rugged fitness landscapes
Authors: Servajean Richard , Alexandre Arthur , Bitbol Anne-Florence
Published: September 2024

We study how rugged fitness landscapes are explored by spatially structured populations with demes on the nodes of a graph, connected by migrations. In the weak mutation and rare migration regime, we find that, in most landscapes, migration asymmetries associated with some suppression of natural selection allow the population to reach higher fitness peaks first. In this sense, suppression of selection can make early adaptation more efficient. However, the time it takes to reach the first fitness peak is then increased. We also find that suppression of selection tends to enhance finite-size effects. Finite structures can adapt more efficiently than very large ones, especially in high-dimensional fitness landscapes. We extend our study to frequent migrations, suggesting that our conclusions hold in this regime. We then investigate the impact of spatial structure with rare migrations on long-term evolution by studying the steady state of the population with weak mutation, and introducing an associated steady-state effective population size. We find that suppression of selection is associated to small steady-state effective population sizes, and thus to small average steady-state fitnesses.
An optimized pipeline for high-throughput bulk RNA-Seq deconvolution illustrates the impact of obesity and weight loss on cell composition of human adipose tissue
Authors: Ahn Cheehoon , Divoux Adeline , Zhou Mingqi , Seldin Marcus M , Sparks Lauren M , Whytock Katie L
Published: September 2024

Cellular heterogeneity of human adipose tissue, is linked to the pathophysiology of obesity and may impact the response to energy restriction and changes in fat mass. Here, we provide an optimized pipeline to estimate cellular composition in human abdominal subcutaneous adipose tissue (ASAT) from publicly available bulk RNA-Seq using signature profiles from our previously published full-length single nuclei (sn)RNA-Seq of the same depot. Individuals with obesity had greater proportions of macrophages and lower proportions of adipocyte sub-populations and vascular cells compared with lean individuals. Two months of diet-induced weight loss (DIWL) increased the estimated proportions of macrophages; however, two years of DIWL reduced the estimated proportions of macrophages, thereby suggesting a bi-phasic nature of cellular remodeling of ASAT during weight loss. Our optimized high-throughput pipeline facilitates the assessment of composition changes of highly characterized cell types in large numbers of ASAT samples using low-cost bulk RNA-Seq. Our data reveal novel changes in cellular heterogeneity and its association with cardiometabolic health in humans with obesity and following weight loss.

Lead contact

Katie Whytock (Katie.Whytock@adventhealth.com)
A comparative assessment of self-limiting genetic control strategies for population suppression
Authors: Han Yue , Champer Jackson
Published: September 2024

Genetic control strategies are promising solutions for control of pest populations and invasive species. Methods utilizing repeated releases of males such as Sterile Insect Technique (SIT), Release of Insects carrying a Dominant Lethal (RIDL), self-limiting gene drives, and gene disruptors are highly controllable methods, ensuring biosafety. Although models of these strategies have been built, detailed comparisons are lacking, particularly for some of the newer strategies. Here, we conducted a thorough comparative assessment of self-limiting genetic control strategies by individual-based simulation models. Specifically, we find that repeated releases greatly enhance suppression power of weak and self-limiting gene drives, enabling population elimination with even low efficiency and high fitness costs. Moreover, dominant female sterility further strengthens self-limiting systems that can either use gene drive or disruptors that target genes without a mechanism to bias their own inheritance. Some of these strategies are highly persistent, resulting in relatively low release ratios even when released males suffer high fitness costs. To quantitively evaluate different strategies independent from ecological impact, we proposed constant-population genetic load, which achieves over 95% accuracy in predicting simulation outcomes for most strategies, though it is not as precise in a few frequency-dependent systems. Our results suggest that many new self-limiting strategies are safe, flexible, and more cost-effective than traditional SIT and RIDL, and thus have great potential for population suppression of insects and other pests.
High-Throughput Empirical and Virtual Screening to Discover Novel Inhibitors of Polyploid Giant Cancer Cells in Breast Cancer
Authors: Ma Yushu , Shih Chien-Hung , Cheng Jinxiong , Chen Hsiao-Chun , Wang Li-Ju , Tan Yanhao , Chiu Yu-Chiao , Chen Yu-Chih
Published: September 2024

Therapy resistance in breast cancer is increasingly attributed to polyploid giant cancer cells (PGCCs), which arise through whole-genome doubling and exhibit heightened resilience to standard treatments. Characterized by enlarged nuclei and increased DNA content, these cells tend to be dormant under therapeutic stress, driving disease relapse. Despite their critical role in resistance, strategies to effectively target PGCCs are limited, largely due to the lack of high-throughput methods for assessing their viability. Traditional assays lack the sensitivity needed to detect PGCC-specific elimination, prompting the development of novel approaches. To address this challenge, we developed a high-throughput single-cell morphological analysis workflow designed to differentiate compounds that selectively inhibit non-PGCCs, PGCCs, or both. Using this method, we screened a library of 2,726 FDA Phase 1-approved drugs, identifying promising anti-PGCC candidates, including proteasome inhibitors, FOXM1, CHK, and macrocyclic lactones. Notably, RNA-Seq analysis of cells treated with the macrocyclic lactone Pyronaridine revealed AXL inhibition as a potential strategy for targeting PGCCs. Although our single-cell morphological analysis pipeline is powerful, empirically testing all existing compounds is impractical and inefficient. To overcome this limitation, we trained a machine learning model to predict anti-PGCC efficacyin silico, integrating chemical fingerprints and compound descriptions from prior publications and databases. The model demonstrated a high correlation with experimental outcomes and predicted efficacious compounds in an expanded library of over 6,000 drugs. Among the top-ranked predictions, we experimentally validated two compounds as potent PGCC inhibitors. These findings underscore the synergistic potential of integrating high-throughput empirical screening with machine learning-based virtual screening to accelerate the discovery of novel therapies, particularly for targeting therapy-resistant PGCCs in breast cancer.
Targeting CCRL2 enhances therapeutic outcomes in a tuberculosis mouse model
Authors: Wang Tianyin , Quijada Darla , Ahmenda Taha , Castillo Jennie Ruelas , Naji Nour Sabiha , Peske J David , Karakousis Petros C. , Paul Suman , Karantanos Theodoros , Karanika Styliani
Published: September 2024

Tuberculosis (TB) remains among the leading infectious causes of death. Due to the limited number of antimicrobials in the TB drug discovery pipeline, interest has developed in host-directed approaches to improve TB treatment outcomes. C-C motif chemokine-like receptor 2 (CCRL2) is a unique seven-transmembrane domain receptor that is upregulated by inflammatory signals and mediates leucocyte migration. However, little is known about its role in the setting of TB infection. Here, we show thatMycobacterium tuberculosis(Mtb) infection increases CCRL2 protein expression in macrophages and in mouse lungs. To target selectively CCRL2-expressing cellsin vivo,we developed a novel mouse anti-CCRL2 antibody-drug conjugate (ADC) linked with the cytotoxic drug SG3249. We tested its adjunctive therapeutic efficacy against TB when combined with the first-line regimen for drug-susceptible TB (isoniazid, rifampin, pyrazinamide, ethambutol; RHZE). The anti-CCRL2 ADC treatment potentiated RHZE efficacy in Mtb-infected mice and decreased gross lung inflammation. CCRL2 expression in lung dendritic cells and alveolar macrophages was lower in mice receiving anti-CCRL2 ADC treatment + RHZE compared to those receiving RHZE alone or the control group, although the total innate cell populations did not differ across treatment groups. Interestingly, neutrophils were completely absent in the anti-CCRL2 ADC treatment + RHZE group, unlike in the other treatment groups. IFN-γ+ and IL17-Α+ T-cell responses, which are associated with optimal TB control, were also elevated in the anti-CCRL2 ADC treatment + RHZE group. Collectively, our findings suggest that CCRL2-targeting approaches may improve TB treatment outcomes, possibly through selective killing of Mtb-infected innate immune cells.
Perforin-2 is dispensable for host defense againstAspergillus fumigatusandCandida albicans
Authors: Aufiero Mariano A. , Hung Li-Yin , Herbert De’Broski R. , Hohl Tobias M.
Published: September 2024

Myeloid phagocytes are essential for antifungal immunity against pulmonaryAspergillus fumigatusand systemicCandida albicansinfections. However, the molecular mechanisms underlying fungal clearance by phagocytes remain incompletely understood. In this study, we investigated the role of perforin-2 (Mpeg1) in antifungal immunity. We found thatMpeg1-/-mice generated on a mixed C57BL/6J-DBA/2 background exhibited enhanced survival, reduced lung fungal burden, and greater neutrophil fungal killing activity compared to wild-type C57BL/6J (B6) mice, suggesting that perforin-2 may impair antifungal immune responses. However, when we comparedMpeg1-/-mice with co-housedMpeg+/+littermate controls, these differences were no longer observed, indicating that initial findings were likely influenced by differences in the murine genetic background or the microbiota composition. Furthermore, perforin-2 was dispensable for antifungal immunity duringC. albicansbloodstream infection. These results suggest that perforin-2 is not essential for host defense against fungal infections in otherwise immune competent mice and highlight the importance of generating co-housed littermate controls to minimize murine genetic and microbiota-related factors in studies of host defense mechanisms.

IMPORTANCE

Aspergillus fumigatusis the leading cause of invasive aspergillosis (IA), which is associated with significant mortality, particularly in immunocompromised patients such as those with acute leukemia or undergoing hematopoietic stem cell transplants, where death rates reach 40-50% despite standard care. Treatments for IA remain limited and resistance to antifungals is emerging, leading the World Health Organization to recently classifyA. fumigatusas a critical priority fungal pathogen. A greater understanding of how the immune system clearsA. fumigatuscould lead to host-directed therapies that could complement our current armamentarium of antifungal drugs and improve patient outcomes. Our findings reveal that perforin-2 is not essential for antifungal immunity againstA. fumigatusin otherwise immune-competent mice and underscore the necessity of using co-housed littermate controls to avoid confounding factors in immunological studies.
Probiotic acoustic biosensors for noninvasive imaging of gut inflammation
Authors: Buss Marjorie T. , Zhu Lian , Kwon Jamie H. , Tabor Jeffrey J. , Shapiro Mikhail G.
Published: September 2024

Inflammatory bowel diseases (IBD) affect millions of people globally, result in severe symptoms, and are difficult to diagnose and monitor – often necessitating the use of invasive and costly methods such as colonoscopies or endoscopies. Engineered gut bacteria offer a promising alternative due to their ability to persist in the gastrointestinal (GI) tract and sense and respond to specific environmental signals. However, probiotics that have previously been engineered to report on inflammatory and other disease biomarkers in the Gl tract rely on fluorescent or bioluminescent reporters, whose signals cannot be resolved in situ due to the poor penetration of light in tissue. To overcome this limitation, we introduce probiotic biosensors that can be imaged in situ using ultrasound – a widely available, inexpensive imaging modality providing sub-mm spatial resolution deep inside the body. These biosensors are based on the clinically approved probiotic bacteriumE. coliNissle, which we engineered to transiently colonize the GI tract, sense inflammatory biomarkers, and respond by expressing air-filled sound-scattering protein nanostructures called gas vesicles. After optimizing biomolecular signaling circuits to respond sensitively to the biomarkers thiosulfate and tetrathionate and produce strong and stable ultrasound contrast, we validated our living biosensors in vivo by noninvasively imaging antibiotic-induced inflammation in mice. By connecting cell-based diagnostic agents to ultrasound, this “diagnostic yogurt” will make it easier, cheaper, and less painful to diagnose and monitor IBD or other GI conditions.
Application ofhsp60amplicon sequencing to characterize microbial communities associated with juvenile and adultEuprymna scolopessquid
Authors: Smith Steph , Bongrand Clotilde , Lawhorn Susannah , Ruby Edward G. , Septer Alecia N.
Published: September 2024

The symbiotic relationship betweenVibrio (Aliivibrio) fischeriand the Hawaiian bobtail squid,Euprymna scolopes, serves as a key model for understanding host-microbe interactions. Traditional culture-based methods have primarily isolatedV. fischerifrom the light organs of wild-caught squid, yet culture-independent analyses of this symbiotic microbiome remain limited. This study aims to enhance species-level resolution of bacterial communities associated withE. scolopesusinghsp60amplicon sequencing. We validated ourhsp60sequencing approach using pure cultures and mixed bacterial populations, demonstrating its ability to distinguishV. fischerifrom other closely-related vibrios and the possibility of using this approach for strain-level diversity with further optimization. This approach was applied to whole-animal juvenile squid exposed to either seawater or a clonalV. fischeriinoculum, as well as ventate samples and light organ cores from wild-caught adults.V. fischeriaccounted for the majority of the identifiable taxa for whole-animal juvenile samples and comprised 94%-99% of amplicon sequence variants (ASVs) for adult light organ core samples, confirming thatV. fischeriis the dominant, if not sole, symbiont typically associated withE. scolopeslight organs. In one ventate sample,V. fischericomprised 82% of reads, indicating the potential for non-invasive community assessments using this approach. Analysis of non-V. fischeriASVs revealed thatBradyrhizobium spp. and other members of the Rhodobacterales order are conserved across juvenile and adult samples. These findings provide insight into the presence of additional microbial associations with the squid host tissue outside of the light organ that have not been previously detected through traditional culture methods.
Mimicking mechanics: A comparison of meat and meat analogs
Authors: St. Pierre Skyler R. , Kuhl Ellen
Published: September 2024

The texture of meat is one of the most important features to mimic when developing meat analogs. Both protein source and processing method impact the texture of the final product. We can distinguish three types of mechanical tests to quantify the textural differences between meat and meat analogs: puncture-type, rheological torsion tests, and classical mechanical tests of tension, compression, and bending. Here we compile the shear force and stiffness values of whole and comminuted meats and meat analogs from the two most popular tests for meat, the Warner-Bratzler shear test and the double-compression texture profile analysis. Our results suggest that, with the right fine-tuning, today’s meat analogs are well capable of mimicking the mechanics of real meat. While Warner-Bratzler shear tests and texture profile analysis provide valuable information about the tenderness and sensory perception of meat, both tests suffer from a lack of standardization, which limits cross-study comparisons. Here we provide guidelines to standardize meat testing and report the meat stiffness as the single most informative mechanical parameter. Collecting big standardized data and sharing them with the community at large could empower researchers to harness the power of generative artificial intelligence to inform the systematic development of meat analogs with desired mechanical properties and functions, taste and sensory perception.
Maternal genetic affinities of Koṅkaṇī population in the southwest coast of India
Authors: Sequeira Jaison Jeevan , Kumar Lomous , van Driem George , Thangaraj Kumarasamy , Mustak Mohammed S
Published: September 2024

Koṅkaṇ region on the west coast of India is a hotspot of culture, folklore and ethnolinguistic diversity. The genetic landscape of this region remains understudied. The present study features Koṅkaṇī population residing along the Koṅkaṇ Malabar coast. We have sequenced complete mitogenomes of 85 and the hypervariable region of 210 Koṅkaṇī individuals to understand the maternal gene pool of this region. Comparative analysis of the over 5000 mitogenomes revealed that the Koṅkaṇī population clustered at a convergence point on the PCA plot, presumably due to a diverse maternal gene pool with both autochthonous and West Eurasian components. A distinct clustering pattern was observed within the subgroups of Sārasvata and non-Sārasvata Koṅkaṇī groups, indicating unique ancestral maternal lineages in them. This distinction is majorly due to the N macrohaplogroup lineages found in this population. We observe low haplotype and nucleotide diversity in Citrapur Sārasvata Brahmins (CSB), Rājāpur Sārasvata Brahmins (RSB), Khārvi and Kuḍubi compared to Gauḍa Sārasvata Brahmins (GSB) and Roman Catholics. The assimilation of both pre and post Last Glacial Maximum (LGM) haplogroups like M57, M36, M37, M3, M30, R8 and U2 in the Koṅkaṇī population suggests active movement and settlement along the Koṅkaṇ region on the west coast of India since the Late Pleistocene through the Holocene.
IGF2BP3 Promotes Autophagy-Mediated TNBC Metastasis via M6A-Dependent, Cap-Independent c-Met Translation
Authors: Wang Ziwen , Li Yihan , Cai Mengyuan , Zhang Xu , Xu Ruoxi , Yang Haiyan , Huang Yuzhou , Shi Liang , Wei Jifu , Ding Qiang
Published: September 2024

Tumor metastasis involves a series of complex processes and is a major challenge in clinical treatment. The cooperation of epigenetic modifications and metabolic adaptations endows tumor cells with dynamic adaptations for survival in variable environments, which is crucial for tumor metastasis and worth exploring in depth. In this study, we found IGF2BP3 could link epigenetic modification and metabolic adaptation in promoting autophagy-mediated triple-negative breast cancer (TNBC) metastasis. As a TNBC specifically high expressed N6-methyladenosine (m6A) binding protein, IGF2BP3 could bind to the m6A motif of c-Met mRNA, regulating autophagy-mediated epithelial-to-mesenchymal transition (EMT) progress by c-Met/PI3K/AKT/mTOR pathway. Moreover, through the recruitment of eIF4G2 as a collaborator, IGF2BP3 induced the changes in c-Met protein expression not by affecting mRNA stability, but by facilitating its mRNA translation initiation in an m6A-dependent and cap-independent manner. In conclusion, our study extended the role of IGF2BP3 in autophagy mediated TNBC metastasis, found IGF2BP3 could bind to the m6A motif on the 5′, 3′-UTR of c-Met mRNA to facilitate its translation in a cap-independent manner.
Characterization of motor function recovery using muscle synergies in stroke patients undergoing upper limb rehabilitation
Authors: Pregnolato Giorgia , Severini Giacomo , Maistrello Lorenza , Rimini Daniele , Lencioni Tiziana , Carpinella Ilaria , Ferrarin Maurizio , Jonsdottir Johanna , Cheung Vincent C. K. , Turolla Andrea
Published: September 2024

In stroke rehabilitation, muscle synergies have been investigated to provide information on the level of upper limb motor impairment, but not yet for explaining motor recovery after therapy. In this study, we analysed muscle synergies parameters extracted from 62 people with stroke who underwent a specific upper limb treatment (20 sessions, 1h/day, 5d/week, 4 weeks) consisting of virtual reality, robotic or conventional treatment. Overall, participants improved upper limb motor function (Fugl-Meyer Assessment Upper Extremity-FMA-UE: Δ= 7.14 ± 7.46, p< 0.001) but the number of muscle synergies of the impaired side (N-aff) did not change after treatment (N-aff: T0= 8.8 ± 1.5; T1=8.7 ± 1.4; p=0.374). Then, we stratified the sample into Responder (No.=34) and Non-Responder (No.=28) participants, based on the Minimal Clinical Important Difference value of FMA-UE (Δ >5 points). We investigated merging and fractionation indexes in both subgroups and only the Responder subgroup significantly decreased the percentage of merged muscle synergies (p=0.004). No significant changes in the fractionation index resulted in either subgroup.

Finally, we identified vocabularies of affected upper limb motor synergies, before (No. 13 synergies) and after treatment (No. 14 synergies), and in unaffected upper limb (No. 16 synergies). We identified upper limb motor functions associated with each muscle synergy in each vocabulary based on the muscles represented in the muscle synergy. There were no differences in motor functions characterizing Responder patients. However, after therapy, both Responder and Non-Responder subgroups were characterized by the same distribution of motor functions across muscle synergies observed in the unaffected limb.

Trial registration

The trial is registered in ClinicalTrial.gov, identifier numberNCT03530358(https://clinicaltrials.gov/study/NCT03530358).

Key messages

Rehabilitation therapy for the upper limb induces reduction of muscle synergies merging in people with stroke expressing clinically important improvement of motor function. This muscular pattern is in accordance with motor control mechanisms underpinning functional recovery.

Motor function of the affected upper limb at baseline did not characterize the muscular profile of patients responding to rehabilitation treatment (Responder).

After therapy, all patients regardless the amount of motor function improvement (i.e., Responder, Non-Responder) express a muscular profile of the affected upper limb like the unaffected upper limb.
Examining Age-Dependent Patterns in Academic Bullying Behaviors
Authors: Moss Sherry E. , Mahmoudi Morteza
Published: September 2024

Academic bullying is a pervasive and longstanding issue that negatively affects all fields of science. While influential factors such as scientific discipline, sex, and ethnicity have been investigated, the impact of perpetrators’ age on the contextual behaviors of academic bullying has not been thoroughly studied. Our cross-sectional global survey of academic bullying, involving 2,390 participants, provides evidence that age significantly influences the contextual behaviors of academic bullying. Our results revealed that the youngest perpetrators (aged 25-35) exhibit significantly less abusive behavior compared to other age categories (36 and older). Additionally, the lowest percentage of abusive behavior was observed in the youngest group, while the highest was found in the older groups (aged 56-65). Our comprehensive analysis on the potential influence of the perpetrator’s academic position, ethnicity, or sex on their age group revealed no significant impact. These findings have strong implications for the development of more customized academic bullying training, policy development, and monitoring strategies, ultimately benefiting the scientific community at large in many aspects including evolution of science and improving the mental health of the academic workforce.
Precise interpretation and prioritization of sequence variants with Onkopus for supporting molecular tumor boards
Authors: Kurz Nadine S. , Kornrumpf Kevin , Tucholski Tim , Drofenik Klara , König Alexander , Beißbarth Tim , Dönitz Jürgen
Published: September 2024

One of the major challenges in precision medicine is the identification of pathogenic, actionable variants and the selection of personalized treatments. We present Onkopus, a variant interpretation framework, based on a modular architecture, for interpreting and prioritizing genetic alterations in cancer patients. We show that aggregation and harmonization of clinical databases, coupled with querying of these databases to varying associated biomarkers, can increase the number of identified therapeutic options. We present a protein analysis of mutated sites and show that protein characteristics can provide potential indicators for the functional impairment of variants of unknown significance. Variant interpretation systems like Onkopus have the potential to significantly enhance the performance of personalized treatments, as they reduce the time required for variant interpretation and manual evaluation of personalized treatments, while maintaining reproducibility and traceability. We provide a free public instance of Onkopus athttps://mtb.bioinf.med.uni-goettingen.de/onkopus.
High-throughput bacterial aggregation analysis in droplets
Authors: Saar-Abroi Merili , Lindpere Karoliine , Olman Triini , Sulp Fenella Lucia , Kiir Katri , Sanka Immanuel , Bartkova Simona , Scheler Ott
Published: September 2024

The communal lifestyle of bacteria manifested as bacterial aggregation and potential biofilm formation is posing as a significant contributor to antimicrobial resistance. A key approach to adress the emerging pandemic is to implement novel techniques that enhance the precision and speed of analysis in various microbiological experiments.

Droplet-based platforms coupled with image analysis techniques exhibit great potential in advancing the precision of investigating bacterial behaviour and increasing the speed of microbiological experiments. As most of the image analysis techniques require advanced programming skills or implement high-priced fees, open-source software interweaving user-friendly interface is in great demand.

In this paper, we introduce two image analysis pipelines constructed in CellProfiler™ to quantify bacterial aggregation responding to a presence of microplastics as well as suboptimal concentrations of antibiotics in droplets.
Respiratory shedding of infectious SARS-CoV-2 Omicron XBB.1.41.1 lineage with increased evolutionary rate among captive white-tailed deer
Authors: Ferreira Francisco C. , Pervin Tahmina , Tang Wendy , Hediger Joseph , Thomas Logan , Cook Walter , Cherry Michael , Neuman Benjamin W. , Hamer Gabriel L. , Hamer Sarah A.
Published: September 2024

White-tailed deer (Odocoileus virginianus) have high value for research, conservation, agriculture and recreation, and may be important SARS-CoV-2 reservoirs with unknown human health implications. In November 2023, we sampled 15 female deer in a captive facility in central Texas, USA. All individuals had neutralizing antibodies against SARS-CoV-2 and 11 had RT-qPCR-positive respiratory swabs; one also had a positive rectal swab. Six of 11 respiratory swabs yielded infectious virus with replication kinetics of most samples displaying lower growth 24-48 h post infectionin vitrowhen compared to Omicron lineages isolated from humans in Texas in the same period. However, virus growth was similar between groups by 72 h, suggesting no strong attenuation of deer-derived virus. All deer viruses clustered in XBB Omicron clade, with more mutations than expected compared to contemporaneous viruses in humans, suggesting that crossing the species barrier to deer was accompanied by a high substitution rate.
Sedentary life accelerates epigenetic ageing in King penguins
Authors: Cristofari Robin , Davis Leyla , Bardon Gaël , Nitta Fernandes Flávia A. , Figueroa Maria Elena , Franzenburg Sören , Gauthier-Clerc Michel , Grande Francesco , Heidrich Richard , Hukkanen Mikaela , Le Maho Yvon , Ollikainen Miina , Paciello Elodie , Rampal Patrick , Stenseth Nils C , Trucchi Emiliano , Zahn Sandrine , Le Bohec Céline , Meyer Britta S.
Published: September 2024

Introductory paragraph

Advances in medicine and food security have contributed to an increase in human lifespan1. Yet, the associated rise in sedentary behaviour and in obesity2,3already threatens these gains4. Indeed, a growing body of evidence supports the central role of nutrient sensing and energy management pathways in regulating ageing rate and healthspan5,6, but the diversity of human lifestyles challenges our ability to identify the genetic and epigenetic drivers of this age acceleration. Here, we examine how the transition of wild King penguins to zoo husbandry can closely mimic the shift to a Western lifestyle in humans, and shed light on evolutionarily conserved epigenetic changes in responses to sedentary conditions. We show that, just like modern humans, zoo-housed King penguins experience an extended lifespan, but this comes at the cost of accelerated epigenetic ageing throughout life. This accelerated ageing is associated with differential methylation in key growth and maintenance pathways including the mTOR and PI3K/Akt networks, as well as in specific pathways of lipid-rich diet adaptation and heart-function. Our results demonstrate the deeply conserved link between sedentary behaviour and food availability on the one hand, and age acceleration on the other. Such evolutionary evidence may in turn help us to improve risk detection and, ultimately, therapeutics for lifestyle-induced age acceleration in humans7.
Exploring the Biological Mechanisms of Severe COVID-19 in the Elderly: Insights from an Aged Mouse Model
Authors: Ma Li , Lin Xian , Xu Meng , Ke Xianliang , Liu Di , Chen Quanjiao
Published: September 2024

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global health crisis, particularly affecting the elderly, who are more susceptible to severe outcomes. However, definitive parameters or mechanisms underlying the severity of COVID-19 in elderly people remain confused. Thus, this study seeks to elucidate the mechanism behind the increased vulnerability of elderly individuals to severe COVID-19. We employed an aged mouse model with a mouse-adapted SARS-CoV-2 strain to mimic the severe symptoms observed in elderly patients with COVID-19. Comprehensive analyses of the whole lung were performed using transcriptome and proteome sequencing, comparing data from aged and young mice. For transcriptome analysis, bulk RNA sequencing was conducted using an Illumina sequencing platform. Proteomic analysis was performed using mass spectrometry following protein extraction, digestion, and peptide labeling. We analyzed the transcriptome and proteome profiles of young and aged mice and discovered that aged mice exhibited elevated baseline levels of inflammation and tissue damage repair. After SARS-CoV-2 infection, aged mice showed increased antiviral and inflammatory responses; however, these responses were weaker than those in young mice, with significant complement and coagulation cascade responses. In summary, our study demonstrates that the increased vulnerability of the elderly to severe COVID-19 can be attributed to an attenuated antiviral response and the overactivation of complement and coagulation cascades.
Transcriptomic and histological characterization of telocytes in the human dorsal root ganglion
Authors: Haberberger Rainer V , Matusica Dusan , Shiers Stephanie , Sankaranarayanan Ishwarya , Price Theodore J
Published: September 2024

Telocytes are interstitial cells with long processes that cover distances in tissues and likely coordinate interacts with other cell types. Though present in central and peripheral neuronal tissues, their role remains unclear. Dorsal root ganglia (DRG) house pseudounipolar afferent neurons responsible for signals such as temperature, proprioception and nociception. This study aimed to investigate the presence and function of telocytes in human DRG by investigating their transcriptional profile, location and ultrastructure.

Sequencing data revealed CD34 and PDGFRA expressing cells comprise roughly 1.5-3% of DRG cells. Combined expression ofCD34andPDGFRAis a putative marker gene set for telocytes. Further analysis identified nine subclusters with enriched cluster-specific genes. KEGG and GO pathway analysis suggested vascular, immune and connective tissue associated putative telocyte subtypes. Over 3000 potential receptor-ligand interactions between sensory neurons and theseCD34andPDGFRAexpressing putative telocytes were identified using a ligand-receptors interactome platform. Immunohisto-chemistry showed CD34+ telocytes in the endoneural space of DRGs, next to neuron-satellite complexes, in perivascular spaces and in the endoneural space between nerve fibre bundles, consistent with pathway analysis. Transmission electron microscopy (TEM) confirmed their location identifying characteristic elongated nucleus, long and thin telopods containing vesicles, surrounded by a basal lamina. This is the first study that provides gene expression analysis of telocytes in complex human tissue such as the DRG, highlighting functional differences based on tissue location with no significant ultrastructural variation.

Key points

uman DRGs containCD34/PDGFRA+ putative telocytes that can be subgrouped in nine clusters based on gene expression

The DRGs contain CD34+ telocytes in close proximity to neuron-satellite complexes, blood vessels and nerve fibre bundles.

The basic features of telocytes with elongated nuclei and thin telopods do not differ between locations.
Genomic analyses of recently emerging clades of mpox virus reveal gene deletion and single nucleotide polymorphisms that correlate with altered virulence and transmission
Authors: Kumar Ankeet , Jhanwar Pratima , B Roohani , Gulati Amulya , Tatu Utpal
Published: September 2024

Mpox virus (MPXV) has consistently caused human infections since the first reported case in 1970, with the initial outbreaks primarily attributed to sporadic zoonotic transmissions. In recent years, an increase in human-to-human transmission has been observed, particularly during the 2022 outbreak caused by Clade IIb, which was declared a public health emergency by WHO. In 2024, the emergence of Clade Ib from Africa raised global concern once again. While several studies have provided valuable insights into the differences among MPXV clades, research on Clade Ib remains limited. In this study, we have conducted a comprehensive comparative genome sequence analysis and identified unique features across MPXV clade sequences. We report a ~1141 bp long novel deletion resulting in loss of the complement control protein (CCP) in Clade Ib sequences, a deletion earlier exclusively reported in Clade II sequences. Additionally, B22R, a crucial host receptor-binding protein involved in viral entry and known for its high immunogenicity, shows clade-specific amino acid changes across three MPXV clades. Moreover, multiple extragenic mutations were identified in the 5' UTR of several genes, which may impact gene transcription. Other frequently mutated proteins are linked to immune evasion, translation, and viral entry and exit. The above results and APOBEC signatures associated with sustained human-to-human transmission highlight the virus's potential for rapid adaptation, underscoring the need for vigilance against reverse zoonosis and the risk of spillover to new hosts.
Tumor microenvironment distinctions between esophageal cancer subtypes explain varied immunotherapy responses
Authors: Baek Seungbyn , Cha Junha , Hong Min-Hee , Kim Gamin , Koh Yoon Woo , Kim Dahee , Hemberg Martin , Park Seong Yong , Kim Hye Ryun , Lee Insuk
Published: September 2024

Esophageal cancer comprises two main subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Previous studies have revealed distinct genomic characteristics between these subtypes, with ESCC sharing similarities with head and neck squamous cell carcinoma (HNSCC), and EAC aligning with gastric adenocarcinoma (GAC). Additionally, recent immunotherapy clinical trials have shown a higher response rate in ESCC and HNSCC compared to EAC and GAC. However, how the tumor microenvironment contributes to these varied immunotherapy responses remains unclear. In this study, through a comparative analysis of single-cell tumor transcriptomes from 35 patients with ESCC, EAC, HNSCC, or GAC, we identified two groups with tumor microenvironment distinctions: ESCC and HNSCC versus EAC and GAC, consistent with their genomic classifications. Malignant epithelial cells displayed distinct separations based on histological origin. In the tumor immune microenvironment, we observed an enrichment of CXCL13+CD8+T cells and CXCL9+CXCL10+tumor-associated macrophages (TAMs) in ESCC and HNSCC, which activate cellular immunity through interferon-γ. In contrast, EAC and GAC exhibited a high presence of heat-shock protein-expressing CD8+T cells and MARCO+TAMs. These immune signatures help explain the varied immunotherapy responses among these cancer subtypes and successfully predict immunotherapy outcomes across diverse cancer types, underscoring their clinical significance.
ADrosophilaholidic diet optimised for growth and development
Authors: Sorge Sebastian , Girard Victor , Lampe Lena , Tixier Vanessa , Weaver Alexandra , Higgins Theresa , Gould Alex P.
Published: September 2024

Diets composed of chemically pure components (holidic diets) are useful for determining the metabolic roles of individual nutrients. For the model organismDrosophila melanogaster,existing holidic diets are unable to support rapid growth characteristic of the larval stage. Here, we use a nutrient co-optimisation strategy across more than 50 diet variants to design HoldFast, a holidic medium tailored to fast larval growth and development. We identify dietary amino acid ratios optimal for developmental speed but show that they compromise survival unless vitamins and sterols are co-optimised. Rapid development on HoldFast is not improved by adding fatty acids but it is dependent upon theirde novosynthesis in the fat body viafatty acid synthase(FASN). HoldFast outperforms other holidic diets, supporting rates of growth and development close to those of yeast-based diets and, under germ-free conditions, identical. HoldFast provides new opportunities for studying growth and metabolism duringDrosophiladevelopment.
Structural and Functional Glycosylation of the Abdala COVID-19 Vaccine
Authors: Burnap Sean A. , Calvaresi Valeria , Cabrera Gleysin , Pousa Satomy , Limonta Miladys , Ramos Yassel , González Luis Javier , Harvey David J. , Struwe Weston B.
Published: September 2024

Abdala is a COVID-19 vaccine produced inPichia pastorisand is based on the receptor-binding domain (RBD) of the SARS-CoV-2 spike. Abdala is currently approved for use in multiple countries with clinical trials confirming its safety and efficacy in preventing severe illness and death. AlthoughP. pastorisis used as an expression system for protein-based vaccines, yeast glycosylation remains largely uncharacterised across immunogens. Here, we characterise N-glycan structures and their site of attachment on Abdala and show how yeast-specific glycosylation decreases binding to the ACE2 receptor and a receptor-binding motif (RBM) targeting antibody compared to the equivalent mammalian-derived RBD. Reduced receptor and antibody binding is attributed to changes in conformational dynamics resulting from N-glycosylation. These data highlight the critical importance of glycosylation in vaccine design and demonstrate how individual glycans can influence host interactions and immune recognition via protein structural dynamics.
Phonological decoding ability is associated with fiber density of the left arcuate fasciculus longitudinally across reading development
Authors: Perdue Meaghan V. , Geeraert Bryce L. , Manning Kathryn Y. , Dewey Deborah , Lebel Catherine
Published: September 2024

Numerous studies have linked reading ability to white matter microstructure using diffusion tensor imaging, but recent large studies have failed to show consistency. Fiber-specific diffusion-weighted magnetic resonance imaging (dMRI) models offer enhanced precision to measure specific features of white matter structure and may be more sensitive to individual differences in reading skills. However, fiber-specific models have not yet been applied to examine associations between reading ability and white matter microstructure over the course of reading acquisition. In this accelerated longitudinal study, we applied constrained spherical deconvolution (CSD) and fiber-specific modelling to characterize developmental changes in fiber density of key white matter tracts of the reading network bilaterally, and investigated associations between tract-wise fiber density and children’s phonological decoding abilities. Fiber density was measured from ages 2-13 years, and decoding ability (pseudoword reading) was assessed at ages 6 years and older. Higher decoding ability was associated with greater fiber density in the left arcuate fasciculus, and effects remained consistent over time. Follow-up analysis revealed that asymmetry changes in the arcuate fasciculus were moderated by decoding ability: good decoders showed leftward asymmetry from early childhood onward, while poorer decoders shifted toward leftward asymmetry over time. These results suggest that densely organized fibers in the left arcuate fasciculus serve as a foundation for the development of reading skills from the pre-reading stage through fluent reading. Ongoing developmental changes in fiber density and microstructural asymmetry throughout childhood may reflect a reciprocal relationship in which reading experience continues to refine and strengthen these pathways.
A multidisciplinary investigation into whether Andean caravans reached the southern lowlands of the Parana-Plata basin during pre-Columbian times
Authors: Loponte Daniel , Acosta Alejandro , Giovanardi Tommaso , Corriale Maria Jose , Higgings Owen , Carbonera Mirian , Buc Natacha , Scaggion Cinzia , Bortolini Eugenio , Marciani Giulia , Benazzi Stefano , Rombola Lucia , Westbury Michael Vincent
Published: September 2024

The expansion of llama caravans and the dispersal of domesticated camelids to extra-Andean regions is one of the key topics in South American archaeology, as it reflects the degree of connection between Andean societies and the surrounding lowland societies, as well as the extent of pre-Columbian pastoralism. One of the primary indicators of both processes is the presence of domesticated camelids in the archaeological record, particularly the llama (Lama glama). Based on somewhat ambiguous historical evidence, it has been suggested that llama caravanning may have reached the northern Pampean region and the southern Parana River valley from an unspecified time until historical times. While the archaeological sites in these two regions have abundant camelid remains that have thus far been identified as guanaco (Lama guanicoe), the possibility of misidentification due to the osteometric similarity between the domestic and wild camelids could mask the presence of llamas in the record, undermining evidence of this potential major expansion of llama caravans. To clarify this issue, we applied a multidisciplinary approach combining archaeological, isotopic, and paleogenomic analyses to determine the taxonomic status of camelids recovered from archaeological sites in both areas. Our findings demonstrate that all the individuals analyzed correspond to guanacos, whose survival extended into early historical times. There is no regional evidence to support the presence of llama caravanning or domesticated camelids in the northern Pampean region or the lower Parana River valley.