bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic streamlining of seagrass-associatedColletotrichumsp. may be related to its adaptation to a marine monocot host
Authors: Ettinger Cassandra L. , Eisen Jonathan A. , Stajich Jason E.
Published: December 2024

Colletotrichumspp. have a complicated history of association with land plants. Perhaps most well-known as plant pathogens for the devastating effect they can have on agricultural crops, someColletotrichumspp. have been reported as beneficial plant endophytes. However, there have been only a handful of reports ofColletotrichumspp. isolated from aquatic plant hosts and their ecological role in the marine ecosystem is underexplored. To address this, we present the draft genome and annotation ofColletotrichumsp. CLE4, previously isolated from rhizome tissue from the seagrassZostera marina. This genome (48.03 Mbp in length) is highly complete (BUSCO ascomycota: 98.8%) and encodes 12,015 genes, of which 5.7% are carbohydrate-active enzymes (CAZymes) and 12.6% are predicted secreted proteins. Phylogenetic placement putsColletotrichumsp. CLE4 within theC. acutatumcomplex, closely related toC. godetiae. We found a 8.69% smaller genome size, 21.90% smaller gene count, and the absence of 591 conserved gene families inColletotrichumsp. CLE4 relative to other members of theC. acutatumcomplex, suggesting a streamlined genome possibly linked to its specialized ecological niche in the marine ecosystem. Machine learning analyses using CATAStrophy on CAZyme domains predict this isolate to be a hemibiotroph, such that it has a biotrophic phase where the plant is kept alive during optimal environmental conditions followed by a necrotrophic phase where the fungi actively serves a pathogen. While future work is still needed to definitively tease apart the lifestyle strategy ofColletotrichumsp. CLE4, this study provides foundational insight and a high-quality genomic resource for starting to understand the evolutionary trajectory and ecological adaptations of marine-plant associated fungi.
Mathematical Models of Retinal Drug Delivery
Authors: Roberts Paul A. , Thomas Chloe N. , Plaice Gabriel Bellamy , Roberts James A. , Jones Marie-Christine , Andrews James W. , Hill Lisa J.
Published: December 2024

Purpose

Wet age-related macular degeneration (AMD) causes vision loss when vascular endothelial growth factor (VEGF) stimulates blood vessel growth into the light-sensitive retina. Anti-VEGF treatments such as ranibizumab are currently administered to treat wet AMD via intravitreal injections, which are unpleasant, expensive and risk complications. We explored the efficacy of topically administered ranibizumab, with cell penetrating peptides (CPPs).

Methods

Ex vivopig eyes were divided into 3 groups and treated with 1. topical or 2. intravitreal ranibizumab and CPP, or 3. intravitreal ranibizumab. ELISAs measured ranibizumab and VEGF concentrations in the aqueous and vitreous at 20 min, 40 min, 1 hr and 3.5 hr (n= 3, per group). An ordinary differential equation model was formulated to describe the evolving concentrations of ranibizumab, VEGF and their compounds in the tear, aqueous and vitreal compartments.

Results

Experimental — Topical: aqueous ranibizumab levels increased significantly, coincident with a significant drop in aqueous VEGF. Vitreal ranibizumab increased significantly, while vitreal VEGF remained constant. Intravitreal (with and without CPP): vitreal ranibizumab reached high concentrations, coincident with a significant drop in vitreal VEGF. Mathematical — topical treatment may provide sustained, moderate suppression of vitreal VEGF levels, while intravitreal treatment provides strong suppression which lessens between treatments.

Conclusions

CPP allows topical ranibizumab to penetrate the cornea but reduces ranibizumab availability and efficacy in neutralising VEGF for intravitreal treatment. Combined intravitreal/topical treatment presents a promising approach. Treatment efficacy would be enhanced if ranibizumab’s rate of binding to VEGF or tear residence time could be increased.
Low retention on PrEP and barriers to PrEP use among key populations in Kinshasa, DRC: a mixed method study
Authors: Zotova Natalia , Shongo Alisho , Lelo Patricia , Mbonze Nana , Kaba Didine , Ntangu Paul , Shi Qiuhu , Adedimeji Adebola , Anastos Kathryn , Yotebieng Marcel , Patel Viraj , Ross Jonathan
Published: December 2024

Female sex workers (FSW) and men who have sex with men (MSM) are disproportionately affected by HIV. Oral pre-exposure prophylaxis (PrEP) has become increasingly available in African countries including the Democratic Republic of Congo (DRC). However, limited data exist on PrEP uptake and retention or on factors that affect PrEP use among FSW and MSM. This mixed-method study, conducted at KP-friendly centers in Kinshasa, DRC, aimed to identify patterns of PrEP retention and to understand underlying factors of PrEP engagement. Collected data included programmatic data, extraction of routine clinical records, and qualitative interviews with FSW and MSM. Logistic regression was used to identify factors associated with PrEP retention. Qualitative data were analyzed thematically. Findings were then synthesized. Low rates of PrEP initiation and retention were of concern. Only 25% of eligible FSW and MSM initiated PrEP in 2019-2022. Among FSW, 79% returned to the clinic for PrEP refills at 1 month, with only 15% returning for a 3-month visit. Similarly, 74% of MSM were retained at 1 month, with 10% retained at 3 months. Previous experience using PrEP was significantly associated with retention at 3 months. Qualitative analyses identified stigma, side effects, dislike of daily medication regimen, and a shortage of KP-friendly facilities as major barriers to PrEP engagement. This warrants the need for interventions to strengthen messaging about PrEP and side effects wading over time. Raising awareness among the Congolese general population may help to avoid stigmatization of PrEP users and improve PrEP acceptance among key populations at risk.
Type II inflammatory comorbidities in patients with psoriasis: A nationwide study based on Chinese registration
Authors: Zhang Jiaying , Li Yanjun , Li Dengli , Yan Hongxia , Fu Hong jun , Li Tianhang , Li Ruoyu , Cui Ping , Shi Dongmei
Published: December 2024

Purpose

This study aims to investigate the prevalence and patterns of type II inflammatory disease among adult patients with psoriasis in China, including the associated comorbidities and coexisting conditions.

Patients and methods

Data were collected from the register of China National Clinical Center for Skin and Immune Diseases between June 2020 and May 2023. Univariate and a multivariable logistic regression models were used to analyze the factors associated with type II inflammatory disease in patients with psoriasis.

Results

A total of 15172 adults with psoriasis were included in this study, and the mean age was 42.46 years and 35.21% were females. Among them, 725 were identified to have type II inflammatory disease, resulting in an overall prevalence of 4.78%. Multivariate logistic regression analysis suggested that the odds ratio (95% confidence interval) for type II inflammatory disease in patients with psoriasis was 1.12 (1.06-1.18) for older age (per 10-year increase), 1.05 (0.89-1.23) for female sex, 1.03 (0.81-1.32) for obesity (BMI≥28kg/m2), 1.32 (1.10-1.58) for smoking, 17.21 (10.46-28.30) for hypertension, 3.14 (2.47-3.99) for history of drug allergy, 1.56 (1.28-1.19) for family history of psoriasis, and 0.60 (0.49-0.73) for severity of the disease (severe vs mild psoriasis).

Conclusion

Our results indicate that type II inflammatory diseases in patients with psoriasis is associated with smoking, hypertension, history of drug allergy, and family history of psoriasis. Furthermore, we observed a correlation between the severity of psoriasis and a decreased likelihood of type II inflammatory diseases. This study contribute to valuable real-world data with regard to epidemiological features of type II inflammation among patients with psoriasis in China. It also offer insights into potential risk factors for targeted interventions and personalized treatment strategies in clinical setting.
Establishment of age-specific intervals based on the hematological and immunological parameters of commercial pigs in the Republic of Korea
Authors: Kim Won Gyeong , Chae Hansong , Song Doyoung
Published: December 2024

Health monitoring based on hematological and immunological parameters is crucial for optimizing performance in the swine industry. This study was conducted to address the lack of comprehensive reports on these parameters in commercial pigs in the Republic of Korea (ROK). To fill this gap, blood samples from 764 healthy pigs across 32 farms in the ROK were analyzed, with the pigs categorized into specific age groups, including weaners, growers, finishers, gilts, and sows. Complete blood counts (CBC) and immunoglobulin G (IgG) concentrations were measured, revealing significant differences across all age groups (p<0.0001). These findings allowed us to establish age-specific Reference Intervals (RIs) at a 95% confidence level and Confidence Intervals (CIs) at a 90% confidence level for each group. This study provides robust guidelines for evaluating the health status of commercial pigs at different stages of growth and development in the ROK. The established RIs and CIs offer valuable insights for future research and practical applications, ensuring reliable health assessments. Routine monitoring of these parameters represents a critical tool for early detection and improved health management in commercial pig populations.
Genomic Foundationless Models: Pretraining Does Not Promise Performance
Authors: Vishniakov Kirill , Viswanathan Karthik , Medvedev Aleksandr , Kanithi Praveen K , Pimentel Marco AF , Rajan Ronnie , Khan Shadab
Published: December 2024

Abstract

The success of Large Language Models has inspired the development of Genomic Foundation Models (GFMs) through similar pretraining techniques. However, the relationship between pretraining performance and effectiveness in downstream genomic tasks remains unclear. Additionally, the high computational cost of pre-training raises questions about its cost-efficiency. To assess the usefulness of pre-training in genomics, we evaluated seven different GFMs across various bench-marks, comparing them to their counterparts with randomly initialized weights. Surprisingly, we found that randomly initialized models can match or even surpass the performance of pretrained GFMs in finetuning and feature extraction tasks. We also discovered that pretrained GFMs fail to capture clinically relevant genetic mutations, which are crucial for understanding genetic disorders and phenotypic traits. Our results indicate that most of the current pretrained GFMs lack a “foundational” understanding of genomics and provide minimal utility, even for basic tasks such as sequence classification. These findings collectively highlight the need for critically rethinking the pretraining approaches for genomics. Our code is available athttps://github.com/m42-health/gfm-random-eval.
Climate drives long-term landscape and rapid short-term promoter evolution in the Western Canaries lizard,Gallotia galloti
Authors: Gilbert Edward , Megía-Palma Rodrigo , Žagar Anamarija , López-Darias Marta , Carretero Miguel A. , Serén Nina , Sellers Graham S. , Beltran-Alvarez Pedro , Wollenberg Valero Katharina C.
Published: December 2024

Climate adaptation is caused by multiple mechanisms, including evolution of regulatory promoter sequences under broad environmental pressures, however, little is known about these processes in response to climate pressures in animals. Here, we examined spatial and temporal evolution of climate-related gene promoters in an insular species, the Western-Canaries lizardGallotia galloti, across diverse environmental conditions over nine years. Outlier SNPs linked to elevation-sensitive environmental factors identified adaptively significant loci, including in aquaporin and Electron Transfer Flavoprotein Subunit Alpha (ETFA) gene promoters, demonstrating roles in local climate adaptation. Adaptive indexing mapped climate-driven genetic differentiation across the landscape, revealing local adaptation along an elevational gradient. Signatures of climate-related selection at the temporal scale showed specific promoters shaped by balancing selection supporting survival across environments, while others experienced positive selection, revealing a selective sweep of beneficial alleles. In addition, elevation-based ancestry groups of climate loci differed from the pattern observed in neutral loci, and temporal shifts in ancestry composition responded to preceding extreme weather events over the span of a single generation. Selection on specific promoter regions indicated adaptive evolution in transcription factor binding sites with the potential to enhance transcriptional flexibility, resulting in increased cellular stress tolerance. Our findings open new avenues into genomic mechanisms of resilience across spatially heterogeneous environments and how rapid evolution correlates with extreme weather events associated with climate change.
WNT7B drives a program for pancreatic cancer subtype switching and progression
Authors: Sprangers Joep , Bugter Jeroen Matthijs , Xanthakis Despina , Boekhout Michiel , Kok Rutger N.U. , Brosens Lodewijk A.A. , Dijk Frederike , Rodriguez Colman Maria J , van der Vaart Jelte Y , Maurice Madelon M.
Published: December 2024

Hyperactivation of WNT signaling is a well-established hallmark of cancer. Various epithelial cancers express high levels of WNT7B and WNT10A that are not commonly expressed during tissue homeostasis, but rather associate with tissue development and regeneration. Although increased WNT7B/10A expression correlates with aggressive disease and lower patient survival rates, the mechanism by which these WNTs influence cancer progression remains unknown. Here, we use patient-derived organoids to show that tumor-intrinsic expression of WNT7B/10A drives survival and growth of advanced pancreatic ductal adenocarcinoma (PDAC). Bulk and single-cell profiling reveal that WNT7B drives proliferation and promotes expression of a poor prognosis basal-like state by preventing expression of a more differentiated, classical PDAC signature. By generating WNT7B reporter organoids, we show that heterogeneously distributed WNT-high PDAC cells are shifted towards a more basal-like phenotype and stably co-exist with WNT-low/negative lineages. Furthermore, hybrid co-cultures of WNT7B-proficient and -knockout PDAC organoids demonstrate that WNT-sending cells drive survival and proliferation of neighboring WNT-negative cells within the cancer epithelium via short range, cell contact-dependent signaling. In summary, our work uncovers a prominent role of WNT7B/10A in driving PDAC subtype heterogeneity and argues that WNT inhibition may be applied to force a class switch to a more differentiated, less aggressive cancer subtype that correlates with improved therapeutical response.
Gene expression adaptation of metastases to their host tissue
Authors: Nagel Luise , Wenzel Marten , Hoppe Sascha , Plum Patrick S. , Karimpour Mohammad , Franitza Marek , Wahba Roger , Bludau Marc , Bruns Christiane J. , Quaas Alexander , Beyer Andreas , Hillmer Axel M.
Published: December 2024

The adaptation of metastatic cells to their host tissue critically determines the pathogenicity of a cancer and therefore patient survival. Yet, it remains elusive to what extent the host environment drives gene expression programs in metastatic cells. Here we identify adaptive mechanisms that enable metastases to establish themselves in a novel tissue context. We performed single-cell RNA-sequencing on malignant and benign tissue samples from untreated donors with colorectal adenocarcinoma and liver metastasis to deduce tissue adaptive expression patterns. A novel computational approach identified genes and pathways that consistently adapted to the host tissue at the transition from the primary tumor to the paired metastasis across donors. This analysis revealed that the majority of expression changes in the metastasis reflect an expression signature reminiscent of benign liver epithelial cells. Cellular processes adapting to the liver environment include basic cellular functions such as energy metabolism, as well as tissue-specific pathways such as the regulation of lipid metabolism by PPAR-α. These adaptations potentially increase the pathogenicity of the metastatic cells and may provide new therapeutic strategies.
Wnt/β-Catenin coordinates muscle spindle development by regulating capsule differentiation, intrafusal fiber nuclei aggregation and proprioceptive nerve endings
Authors: Guo Qingyuan , Gatterer Ava , Rosner Avital , Krief Sharon , Rotkopf Ron , Passini Fabian S. , Wigoda Noa , Bornstein Bavat , Zelzer Elazar
Published: December 2024

Proprioception is essential for regulating posture, coordinating movements, and maintaining musculoskeletal integrity. The muscle spindle, a mechanosensory organ composed of several types of tissues, detects stretch, forming proprioceptive awareness. Despite its significance, the molecular mechanisms underlying the coordinated development of the different tissues composing the spindle remain unclear.

Here we show that Wnt ligands and their Fzd receptors are expressed in the developing spindle. Similarly, β-catenin is active in both the spindle capsule and intrafusal fibers throughout their development. Embryonic deletion of β-catenin from these tissues impaired capsule cell differentiation, intrafusal fiber nuclei organization, and proprioceptive nerve ending morphology. Postnatal deletion of β-catenin solely in intrafusal fibers results in abnormal proprioceptive nerve endings, suggesting both cell-autonomous and cell-non-autonomous roles of β-catenin in muscle spindle development. Our subsequent RNA transcriptome analysis of the β-catenin mutant spindle not only provides a molecular mechanism underlying the role of β-catenin in spindle development, but also expands the repertoire of molecules involved in spindle biology. By exposing a vast repertoire of new molecules involving all spindle tissues, our transcriptome could serve as a resource and benchmark for future discoveries in spindle biology.

Collectively, our findings position the Wnt/β-catenin pathway as a central regulator with cell- autonomous and cell-non-autonomous roles, coordinating the diverse tissues of the spindle into a functional organ. Our transcriptome data further provide insight into spindle biology through a set of newly discovered molecules.
Neuronal fatty acid oxidation fuels memory after intensive learning
Authors: Pavlowsky Alice , Silva Bryon , Danglot Lydia , Plaçais Pierre-Yves , Preat Thomas
Published: December 2024

Metabolic flexibility allows cells to adapt to different fuel sources, which is particularly important for cells with high metabolic demands. In contrast, neurons, which are major energy consumers, are considered to rely almost solely on glucose and its derivatives to support their metabolism1–3. Here, usingDrosophila melanogaster, we show memory formed after intensive massed training is dependent on mitochondrial fatty acid (FA) β-oxidation to produce ATP in neurons of the mushroom bodies (MB), a major integrative center in insects’ brain. We identify neuronal lipid droplets as the main source of FAs for this type of memory. Furthermore, we demonstrate that this intensive massed training is associated with mitochondria network remodeling in the soma of MB neurons, resulting in increased mitochondrial size. Artificially increasing mitochondria size in adult MB neurons increases ATP production in their soma and, at the behavioral level, strikingly results in improved memory performance after massed training. These findings challenge the prevailing view that neurons are unable to use FAs for energy production, and importantly revealing on the contrary thatin vivoneuronal FA oxidation has an essential role in cognitive function, including memory formation.
Predicting Future Development of Stress-Induced Anhedonia From Cortical Dynamics and Facial Expression
Authors: Coley Austin A. , Batra Kanha , Delahanty Jeremy M. , Keyes Laurel R. , Pamintuan Rachelle , Ramot Assaf , Hagemann Jim , Lee Christopher R. , Liu Vivian , Adivikolanu Harini , Cressy Jianna , Jia Caroline , Massa Francesca , LeDuke Deryn , Gabir Moumen , Durubeh Bra’a , Linderhof Lexe , Patel Reesha , Wichmann Romy , Li Hao , Fischer Kyle B. , Pereira Talmo , Tye Kay M.
Published: December 2024

The current state of mental health treatment for individuals diagnosed with major depressive disorder leaves billions of individuals with first-line therapies that are ineffective or burdened with undesirable side effects. One major obstacle is that distinct pathologies may currently be diagnosed as the same disease and prescribed the same treatments. The key to developing antidepressants with ubiquitous efficacy is to first identify a strategy to differentiate between heterogeneous conditions. Major depression is characterized by hallmark features such as anhedonia and a loss of motivation1,2, and it has been recognized that even among inbred mice raised under identical housing conditions, we observe heterogeneity in their susceptibility and resilience to stress3. Anhedonia, a condition identified in multiple neuropsychiatric disorders, is described as the inability to experience pleasure and is linked to anomalous medial prefrontal cortex (mPFC) activity4. The mPFC is responsible for higher order functions5–8, such as valence encoding; however, it remains unknown how mPFC valence-specific neuronal population activity is affected during anhedonic conditions. To test this, we implemented the unpredictable chronic mild stress (CMS) protocol9–11in mice and examined hedonic behaviors following stress and ketamine treatment. We used unsupervised clustering to delineate individual variability in hedonic behavior in response to stress. We then performedin vivo2-photon calcium imaging to longitudinally track mPFC valence-specific neuronal population dynamics during a Pavlovian discrimination task. Chronic mild stress mice exhibited a blunted effect in the ratio of mPFC neural population responses to rewards relative to punishments after stress that rebounds following ketamine treatment. Also, a linear classifier revealed that we can decode susceptibility to chronic mild stress based on mPFC valence-encoding properties prior to stress-exposure and behavioral expression of susceptibility. Lastly, we utilized markerless pose tracking computer vision tools to predict whether a mouse would become resilient or susceptible based on facial expressions during a Pavlovian discrimination task. These results indicate that mPFC valence encoding properties and behavior are predictive of anhedonic states. Altogether, these experiments point to the need for increased granularity in the measurement of both behavior and neural activity, as these factors can predict the predisposition to stress-induced anhedonia.
Direct cryo-ET detection of native SNARE and Munc13 protein bridges using AI classification and preprocessing
Authors: Orozco-Borunda Daniel H. , Papantoniou Christos , Brose Nils , Lučić Vladan
Published: December 2024

Synaptic transmission requires Munc13 and SNARE proteins for synaptic vesicle priming and fusion, and cryo-electron tomography detected multiple types of Munc13-or SNARE-dependent dependent molecular bridges that tether synaptic vesicles to the presynaptic active zone plasma membrane. To integrate the molecular scenario with structural observations, we obtained de novo, in situ cryo-electron tomography averages of native, mammalian SNARE-dependent and Munc13-dependent synaptic vesicle tethers. These provide direct evidence that both Munc13 and a complex comprising SNARE proteins link synaptic vesicles to the active zone plasma membrane. Furthermore, we determined the plausibility of different molecular compositions of tethers, placed constraints on their conformations and positioning, and propose the ex-istence of a complex downstream of Munc13 and upstream of SNARE complex formation. Because the detection and subtomogram averaging of membrane-bridging complexes is complicated by the presence of two lipid membranes and multiple protein species and conformations, we developed novel preprocessing methods and feature-based AI classifiers that outperformed the standard methods.
Profiling the Regulatory Landscape of Sialylation through miRNA Targeting of CMP- Sialic Acid Synthetase
Authors: Jame-Chenarboo Faezeh , Reyes Joseph N. , Arachchige Thusini Uggalla , Mahal Lara K.
Published: December 2024

Cell surface sialic acid is an important glycan modification that contributes to both normal and pathological physiology. The enzyme cytidine monophosphate N-acetylneuraminic acid synthetase (CMAS) biosynthesizes the activated sugar donor cytidine monophosphate (CMP) sialic acid, which is required for all sialylation. CMAS levels impact sialylation with corresponding biological effects. The mechanisms that regulate CMAS are relatively uncharacterized. Herein, we use a high throughput genetically encoded fluorescence assay (miRFluR) to comprehensively profile the posttranscriptional regulation of CMAS by miRNA. These small non-coding RNAs have been found to impact glycosylation. Mapping the interactions of the human miRNAome with the 3’-untranslated region of CMAS, we identified miRNA whose impact on CMAS expression was either downregulatory or upregulatory. This follows previous work from our laboratory and others showing that miRNA regulation is bidirectional. Validation of the high-throughput results confirmed our findings. We also identified the direct binding sites for 2 upregulatory and 2 downregulatory miRNAs. Functional enrichment analysis for miRNAs upregulating CMAS revealed associations with pancreatic cancer, where sialic acid metabolism and the α-2,6-sialyltransferase ST6GAL1 have been found to be important. We found that miRNA associated with the enriched signature enhanced pancreatic cell-surface α-2,6-sialylation via CMAS expression in the absence of effects on ST6GAL1. We also find overlap between the miRNA regulation of CMAS and that of previously analyzed sialyltransferases. Overall, our work points to the importance of miRNA in regulating sialylation levels in disease and add further evidence to the bidirectional nature of miRNA regulation.
A personalized multi-platform assessment of somatic mosaicism in the human frontal cortex
Authors: Zhou Weichen , Mumm Camille , Gan Yanming , Switzenberg Jessica A. , Wang Jinhao , De Oliveira Paulo , Kathuria Kunal , Losh Steven J. , McDonald Torrin L. , Bessell Brandt , Van Deynze Kinsey , McConnell Michael J. , Boyle Alan P. , Mills Ryan E.
Published: December 2024

Somatic mutations in individual cells lead to genomic mosaicism, contributing to the intricate regulatory landscape of genetic disorders and cancers. To evaluate and refine the detection of somatic mosaicism across different technologies with personalized donor-specific assembly (DSA), we obtained tissue from the dorsolateral prefrontal cortex (DLPFC) of a post-mortem neurotypical 31-year-old individual.

We sequenced bulk DLPFC tissue using Oxford Nanopore Technologies (∼60X), NovaSeq (∼30X), and linked-read sequencing (∼28X). Additionally, we applied Cas9 capture methodology coupled with long-read sequencing (TEnCATS), targeting active transposable elements. We also isolated and amplified DNA from flow-sorted single DLPFC neurons using MALBAC, sequencing 115 of these MALBAC libraries on Nanopore and 94 on NovaSeq.

We constructed a haplotype-resolved assembly with a total length of 5.77 Gb and a phase block length of 2.67 Mb (N50) to facilitate cross-platform analysis of somatic genetic variations. We observed an increase in the phasing rate from 11.6% to 38.0% between short-read and long-read technologies. By generating a catalog of phased germline SNVs, CNVs, and TEs from the assembled genome, we applied standard approaches to recall these variants across sequencing technologies. We achieved aggregated recall rates from 97.3% to 99.4% based on long-read bulk tissue data, setting an upper bound for detection limits.

Moreover, utilizing haplotype-based analysis from DSA, we achieved a remarkable reduction in false positive somatic calls in bulk tissue, ranging from 14.9% to 72.4%. We developed pipelines leveraging DSA information to enhance somatic large genetic variant calling in long-read single cells. By examining somatic variation using long-reads in 115 individual neurons, we identified 468 candidate somatic heterozygous large deletions (1.5Mb - 20Mb), 137 of which intersected with short-read single-cell data. Additionally, we identified 61 putative somatic TEs (60Alus, one LINE-1) in the single-cell data.

Collectively, our analysis spans personalized assembly to single-cell somatic variant calling, providing a comprehensiveab initio ad finemapproach and resource in real human tissue.
Transfusion Probability as a Novel Measure for Lab-Guided Medical Decision-Making
Authors: Risk Malcolm , Callum Jeannie , Trentino Kevin , Murray Kevin , Zhao Lili , Shi Xu , Verma Amol , Razak Fahad , Raza Sheharyar
Published: December 2024

The clinical decision to transfuse is strongly influenced by laboratory results. Analysis of transfusion decision-making based on pre-transfusion laboratory results (e.g. pre-transfusion hemoglobin) is a common yet misleading approach to study lab-guided transfusion practice. We introduce “Transfusion Probability” as a novel method which overcomes many limitations of pre-transfusion lab result analyses. Under this approach, we estimate the probability of transfusion after results at a specific value (e.g. hemoglobin 7.4 g/dL) or in a range of values (e.g. 7.0-7.9 g/dL) using the proportion of tests followed by transfusion. We provide statistical methodology for causal inference on the effect of patient conditions and apply our method to a large multi-center dataset. Analyses using pre-transfusion and transfusion probability were compared using data from a large longitudinal cohort of hospitalized patients (N=525,032 patients). We found red blood cell transfusion probabilities of 76.2% in the 6.0-6.9 g/dL, 18.9% in the 7.0-7.9 g/dL, and 4.5% in the 8.0-8.9 g/dL hemoglobin range. After confounder adjustment, patients with gastrointestinal bleeding patients were more likely to be transfused across all ranges, with risk differences ranging from 6.6% in the 8.0-8.9 g/dL range to 13.8% in the 6.0-6.9 g/dL range. Pre-transfusion hemoglobin results showed minimal differences between gastrointestinal bleeding patients and other patients in unadjusted (0.00 g/dL) and adjusted analyses (-0.20 g/dL). In contrast to pre-transfusion result analysis, transfusion probability offers a nuanced account of transfusion practice and allows for natural comparisons between patient groups. Wider adoption of transfusion probability analysis may provide direct and actionable insights for clinical decision-making.

KEY POINTS

Pre-transfusion lab results are a widely used method for studying lab-guided transfusion but subject to many limitations

Transfusion probability analysis is a novel and superior approach
Secondary analysis of the Game of Stones trial of text messages with financial incentives for men with obesity
Authors: Dombrowski Stephan U , Hoddinott Pat , Macaulay Lisa , O’Dolan Catriona , Swingler James , Cotton Seonaidh , Avenell Alison , Getaneh Abraham M , Gray Cindy , Hunt Kate , Kee Frank , MacLean Alice , McKinley Michelle C , Torrens Claire , Turner Katrina , Marjon van der Pol , MacLennan Graeme
Published: December 2024

Objective

To explore whether socio-economic, health and behavioural characteristics moderate effectiveness of a text message intervention with or without financial incentives versus a control group, and to examine differences in exploratory outcomes.

Methods

Three-group randomized trial including 585 men with obesity comparing daily automated behavioural text messages for 12-months alongside financial incentives; text messages alone; or a waiting list control. Moderator analyses examined percent weight change after 12 months for 9 socio-economic and 11 health factors. Exploratory outcomes included: self-reported physical activity, sedentary behaviour, smoking and alcohol behaviours, engagement in 15 weight management strategies, and weight-management related confidence.

Results

No moderator effects were found by any factors for either comparison versus control. There were no differences between groups for health behaviours. The texts with incentives group had higher levels of engagement in six strategies including weight goals, food changes and self-weighing, and higher levels of confidence compared to the control group.

Conclusion

No evidence of differential intervention effectiveness was found across socio-economic, health or wellbeing status. The texts and financial incentives group showed greater engagement in weight management and favourable changes in weight management confidence compared to the control group.
Social Determinants of Sepsis Mortality in the United States: A Retrospective, Epidemiologic Analysis
Authors: Ardabili Ahad Khaleghi , Sadr Alireza Vafaei , Abedi Vida , Bonavia Anthony S
Published: December 2024

Objective

To determine whether neighborhood-level social determinants of health (SDoH) influence mortality following sepsis in the United States.

Study Setting and Design

Retrospective analysis of data from 4.4 million hospitalized patients diagnosed with sepsis, identified using International Classification of Diseases-10 codes, across the United States.

Data Sources and Analytic Sample

De-identified, aggregated data were sourced from the TriNetX Diamond Network. SDoH variables included income, housing cost burden, broadband access, park proximity, racial/ethnic diversity, and the Area Deprivation Index (ADI). The primary outcome was mortality, assessed using univariate and multivariate binomial generalized linear models. Predictors with high multicollinearity (Variance Inflation Factor > 5) were excluded to enhance model stability.

Principal Findings

Lower median income, higher ADI scores, limited park access, and lack of broadband connectivity were strongly associated with increased sepsis mortality. Unexpectedly, greater racial/ethnic diversity was negatively associated with mortality, possibly reflecting regional disparities in healthcare access and socioeconomic conditions. Multivariate analyses revealed that the inclusion of SDoH variables attenuated some effects observed in univariate models, highlighting their complex interplay. Random Forest analysis identified park access as the most important predictor of sepsis mortality, emphasizing its role as a potential proxy for broader neighborhood resources.

Conclusions

Neighborhood-level SDoH are critical for risk stratification in sepsis prognostic models and should be systematically integrated into predictive frameworks. These findings highlight the need for targeted public health interventions to address social vulnerabilities, enhance access to green spaces, and reduce disparities in sepsis outcomes across diverse populations.

Callout Box

What is known on this topic

Social determinants of health (SDoH) influence a variety of health outcomes although their impact on sepsis mortality has been under-explored.

Sepsis is a leading cause of mortality in the United States, with over 350,000 deaths annually.

What this study adds

Neighborhood-level, SDoH such as park access and Area Deprivation Index (ADI) are associated with mortality in sepsis.

Incorporation of these variables may assist in patient risk stratification, potentially improving public health initiatives or allowing them to be more targeted to at-risk populations.
Marsupial limb patterning redefines the necessity of lateral plate mesoderm subdivision for limb formation
Authors: Newton Axel H , Leggatt Alexandra , Farley Ella R , Sears Karen E , Couzens Aidan MC , Ord Sara , Pask Andrew J
Published: December 2024

The tetrapod limb has long served as a model for elucidating molecular and cellular mechanisms driving tissue patterning, development and evolution. While significant advances have been made in understanding the drivers of limb initiation, outgrowth, and patterning, the early morphogenetic processes that transform the lateral plate mesoderm (LPM) into limb fields remain less resolved. Marsupial mammals provide a unique opportunity to investigate these foundational processes due to their accelerated forelimb development, driven by the functional demands of altricial neonates to crawl into the pouch at birth. Heterochronic formation of the forelimbs occurs prior to development of other surrounding structures, offering unparalleled insights into the plasticity of limb field specification. Here, we reveal that marsupial limb initiation and outgrowth bypasses physical subdivision of the LPM, a process previously considered critical for tetrapod limb formation. Instead, limb development proceeds through early activation of LPM-associated genes and proliferation before coelom formation, demonstrating remarkable morphogenetic plasticity. This evolutionary adaptation enables heterochronic limb development, redefining conserved processes to meet extreme functional constraints. These findings challenge previous models of tetrapod limb specification, highlighting the evolutionary plasticity of limb patterning mechanisms and reshaping our understanding of how selective pressures influence foundational developmental events.
Recurrent cancer-associated ERBB4 mutations are transforming and confer resistance to targeted therapies
Authors: Ojala Veera K. , Ahonen Sini , Tuohisto-Kokko Aura , Esparta Olaya , Suominen Peppi , Jokilammi Anne , Farahani Iman , Chakroborty Deepankar , Dibus Nikol , Boettcher Steffen , Airenne Tomi T. , Johnson Mark S. , Eli Lisa D. , Elenius Klaus , Kurppa Kari J.
Published: December 2024

Receptor tyrosine kinase ERBB4 (HER4) is frequently mutated in human cancer, andERBB4mutations have been identified in patients relapsing on targeted therapy. Here, we addressed the functional consequences of recurrent cancer-associatedERBB4mutations that are located at regions important for dimer interactions and/or are paralogous to known oncogenic hotspot mutations in otherERBBgenes. Eleven out of 18 analyzed mutations were transforming in cell models, thus suggesting oncogenic potential for more than half of the recurrent ERBB4 mutations. More detailed analyses of the most potent mutations, S303F, E452K and L798R, showed that they are activating, can co-operate with other ERBB receptors and are targetable with clinically available second-generation pan-ERBB inhibitors neratinib, afatinib and dacomitinib. Furthermore, the S303F mutation, together with a previously identified activating ERBB4 mutation, E715K, promoted resistance to third-generation EGFR inhibitor osimertinib in EGFR-mutant lung cancer modelin vitroandin vivo. Together, these results are expected to facilitate clinical interpretation of the most recurrent cancer-associatedERBB4mutations. The findings provide rationale for testing the efficacy of clinically used pan-ERBB inhibitors in patients harboring driverERBB4mutations both in the treatment-naïve setting, and upon development of resistance to targeted agents.
Common and distinct neural correlates of social interaction perception and theory of mind
Authors: Miao Zizhuang , Jung Heejung , Kragel Philip A. , Sadil Patrick , Lindquist Martin A. , Wager Tor D.
Published: December 2024

Social cognition spans from perceiving agents and their interactions to making inferences based on theory of mind (ToM). Despite their frequent co-occurrence in real life, the commonality and distinction between social interaction perception and ToM at behavioral and neural levels remain unclear. Here, participants (N= 231) provided moment-by-moment ratings of four text and four audio narratives on social interactions and ToM engagement. Social interaction and ToM ratings were reliable (split-halfr= .98 and .92, respectively) but only modestly correlated across time (r= .32). In a second sample (N= 90), we analyzed co-variation between normative social interaction and ToM ratings and functional magnetic resonance (fMRI) activity during narrative reading (text) and listening (audio). Social interaction perception and ToM activity maps generalized across text and audio presentation (r= .83 and .57 between unthresholdedtmaps, respectively). When ToM was held constant, merely perceiving social interactions activated all regions canonically associated with ToM under both modalities (FDRq< .01), including temporoparietal junction, superior temporal sulcus, medial prefrontal cortex, and precuneus. ToM activated these regions as well, indicating a shared, modality-general system for social interaction perception and ToM. Furthermore, ToM uniquely engaged lateral occipitotemporal cortex, left anterior intraparietal sulcus, and right premotor cortex. These results imply that perceiving social interactions automatically engages regions implicated in mental state inferences. In addition, ToM is distinct from social interaction perception in its recruitment of regions associated with higher- level cognitive processes, including action understanding and executive functions.

Author Note

Thanks to Bogdan Petre, Yaroslav O. Halchenko, David M. Gantz, Sydney L. Shohan, Xinming Xu, Maryam Amini, Bethany J. Hunt, and Eilis I. Murphy for data collection and management. This project was supported by grants NIBIB R01EB026549. Matlab code for analyses is available at:https://github.com/canlab, with documentation and examples athttps://canlab.github.io.
A non-canonical glucose metabolic rewiring enables resistance to cancer targeted therapy
Authors: Lei Huimin , Xia Ruixue , Tang Yabin , Lu Jun , Xiang Chan , Li Yujing , Liu Hongyu , Zou Peichen , Aihemaiti Ayinazhaer , Zhang Wei , Shen Ying , Han Baohui , Han Yuchen , Zhong Hua , Chen Hongzhuan , Zhu Liang
Published: December 2024

Targeting glucose metabolism for cancer therapy is a long-lasting pursuit but with disappointing translational success. Revelation of actionable distinctions between the malignancy traits to achieve selectivity is a prerequisite for fulfilling a therapeutic window. We discover a non-canonical glucose transporter GLUT6-facilitated, lactate-independent, glucose metabolic rewiring that selectively enables resistance to targeted therapy in lung cancer. Downstream, GLUT6 facilitated glucose influx and straying to methylglyoxal which dimerized KEAP1 and upregulated NRF2 pathway to confer resistance. Upstream, GLUT6 was transcriptionally upregulated by therapy-induced MAZ activation. Targeting GLUT6 prevented and overcame resistance to EGFR and KRAS inhibitors and the MAZ-GLUT6-NRF2 signaling correlated with clinical therapy response and relapse. Our findings uncover an unrecognized non-genetic, metabolic mechanism for drug resistance and a scenario specifically determined by a distinct glucose metabolic rewiring in cancer. The preferential dependance of the non-canonical, general-homeostasis-less-perturbing transporter GLUT6 implies a promise for resistance overcoming and for glucose metabolism-targeting strategy, two long and urgent quests.
The conserved global regulator H-NS has a strain-specific impact on biofilm formation inVibrio fischerisymbionts
Authors: Zarate Dani , Isenberg Ruth Y. , Pavelsky Morgan , Speare Lauren , Jackson Aundre , Mandel Mark J. , Septer Alecia N.
Published: December 2024

Strain-level variation among host-associated bacteria often determines host range and the extent to which colonization is beneficial, benign, or pathogenic.Vibrio fischeriis a beneficial symbiont of the light organs of fish and squid with known strain-specific differences that impact host specificity, colonization efficiency, and interbacterial competition. Here, we describe how the conserved global regulator, H-NS, has a strain-specific impact on a critical colonization behavior: biofilm formation. We isolated a mutant of the fish symbiontV. fischeriMJ11 with a transposon insertion in thehnsgene. This mutant formed sticky, moderately wrinkled colonies on LBS plates, a condition not known to induce biofilm in this species. A reconstructedhnsmutant displayed the same wrinkled colony, which became smooth whenhnswas complementedin trans, indicating thehnsdisruption is causal for biofilm formation in MJ11. Transcriptomes revealed differential expression for thesypbiofilm locus in thehnsmutant, relative to the parent, suggesting biofilm may in part involve SYP polysaccharide. However, enhanced biofilm in the MJ11hnsmutant was not sufficient to allow colonization of a non-native squid host. Finally, moving thehnsmutation into otherV. fischeristrains, including the squid symbionts ES114 and ES401, and seawater isolate PP3, revealed strain-specific biofilm phenotypes: ES114 and ES401hnsmutants displayed minimal biofilm phenotypes while PP3hnsmutant colonies were more wrinkled than the MJ11hnsmutant. These findings together define H-NS as a novel regulator ofV. fischerisymbiotic biofilm and demonstrate key strain specificity in that role.

Importance

This work, which shows how H-NS has strain-specific impacts on biofilm inVibrio fischeri, underscores the importance of studying multiple strains, even when examining highly conserved genes and functions. Our observation that knocking out a conserved regulator can result in a wide range of biofilm phenotypes, depending on the isolate, serves as a powerful reminder that strain-level variation is common and worthy of exploration. Indeed, uncovering the mechanisms of strain-specific phenotypic differences is essential to understand drivers of niche differentiation and bacterial evolution. Thus, it is important to carefully match the number and type of strains used in a study with the research question to accurately interpret and extrapolate the results beyond a single genotype. The additional work required for multi-strain studies is often worth the investment of time and resources, as it provides a broader view of the complexity of within-species diversity in microbial systems.
Coordination of Glucose and Glutamine Metabolism in Tendon is Lost in Aging
Authors: Mlawer Samuel J , Pinto Felicia R , Sikes Katie J , Connizzo Brianne K
Published: December 2024

Tendinopathy is an age-associated degenerative disease characterized by a loss in extracellular matrix (ECM). Since glucose and glutamine metabolism is critical to amino acid synthesis and known to be altered in aging, we sought to investigate if age-related changes in metabolism are linked to changes in ECM remodeling. We exposed young and aged tendon explants to various concentrations of glucose and glutamine to observe changes in metabolic processing (enzyme levels, gene expression, etc.) and matrix biosynthesis. Interestingly, we found that glutamine processing is affected by glucose levels, but this effect was lost with aging. ECM synthesis was altered in a protein-dependent manner by increased glucose and glutamine levels in young tendons. However, these changes were not conserved in aged tendons. Overall, our work suggests that glucose and glutamine metabolism is important for ECM homeostasis, and age-related changes in nutrient metabolism could be a key driver of tendon degeneration.