bluuebunny/crossref_metadata_2025_split huggingface dataset:
HIV-SEQ Reveals Global Host Gene Expression Differences Between HIV-Transcribing Cells from Viremic and Suppressed People with HIV
Authors: Frouard Julie , Telwatte Sushama , Luo Xiaoyu , Elphick Natalie , Thomas Reuben , Arneson Douglas , Roychoudhury Pavitra , Butte Atul J , Wong Joseph K , Hoh Rebecca , Deeks Steven G. , Lee Sulggi A. , Roan Nadia R. , Yukl Steven 
Published: December 2024

Abstract“Active” reservoir cells transcribing HIV can perpetuate chronic inflammation in virally suppressed people with HIV (PWH) and likely contribute to viral rebound after antiretroviral therapy (ART) interruption, so they represent an important target for new therapies. These cells, however, are difficult to study using single-cell RNA-seq (scRNA-seq) due to their low frequency and low levels of HIV transcripts, which are usually not polyadenylated. Here, we developed “HIV-seq” to enable more efficient capture of HIV transcripts – including non-polyadenylated ones – for scRNA-seq analysis of cells from PWH. By spiking in a set of custom-designed capture sequences targeting conserved regions of the HIV genome during scRNA-seq, we increased our ability to find HIV RNA+ cells from PWH by up to 44%. Implementing HIV-seq in conjunction with surface phenotyping by CITE-seq on paired blood specimens from PWH before vs. after ART suppression, we found that HIV RNA+ cells were enriched among T effector memory (Tem) cells during both viremia and ART suppression, but exhibited a cytotoxic signature during viremia only. By contrast, HIV RNA+ cells from the ART-suppressed timepoints exhibited a distinct anti-inflammatory signature involving elevated TGF-β and diminished IFN signaling. Overall, these findings demonstrate that active reservoir cells exhibit transcriptional features distinct from HIV RNA+ cells during viremia, and underscore HIV-seq as a useful tool to better understand the mechanisms by which HIV-transcribing cells can persist during ART.
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

AbstractColletotrichumspp. 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

AbstractPurposeWet 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).MethodsEx 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.ResultsExperimental — 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.ConclusionsCPP 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

ABSTRACTFemale 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

AbstractPurposeThis 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 methodsData 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.ResultsA 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).ConclusionOur 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

AbstractHealth 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

AbstractThe 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

AbstractClimate 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.
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

AbstractThe 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

AbstractProprioception 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

AbstractMetabolic 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.
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

AbstractSynaptic 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

AbstractCell 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.