bluuebunny/crossref_metadata_2025_split huggingface dataset:
Delta-5 elongase knockout reduces DHA and TAG synthesis coupled with an increase of heat sensitivity in a marine diatom
Authors: Zhu Junkai , Li Shuangqing , Chen Weizhong , Xu Xinde , Wang Xiaoping , Wang Xinwei , Han Jichang , Jouhet Juliette , Amato Alberto , Maréchal Eric , Hu Hanhua , Allen Andrew E. , Gong Yangmin , Jiang Haibo 
Published: April 2024

AbstractRecent global marine lipidomic analysis reveals a strong relationship in the ocean between temperature and phytoplanktonic abundance of omega-3 long-chain polyunsaturated fatty acids (LC-PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are essential for human nutrition and primarily from phytoplankton in marine food webs. In phytoplanktonic organisms, EPA may play a major role in regulating the phase transition temperature of membranes, while the function of DHA remains to be explored. In the oleaginous diatomPhaeodactylum tricornutum, DHA is distributed mainly on extraplastidial phospholipids, which is very different from the EPA enriched in thylakoid lipids. Here, CRISPR/Cas9-mediated knockout ofptELO5a, which encodes a delta-5 elongase catalyzing the elongation of EPA to synthesize DHA, led to a substantial interruption of DHA synthesis inP. tricornutum. TheptELO5amutants show significant alterations in transcriptome and glycerolipidomes including membrane lipids and triacylglycerols under normal temperature (22°C), and are more sensitive to elevated temperature (28°C) than wild type. We conclude that the PtELO5a-mediated synthesis of small amounts of DHA has indispensable functions in regulating the membrane lipid, and indirectly contributing storage lipid accumulation and maintaining thermomorphogenesis inP. tricornutum. This study also highlights the significance of DHA synthesis and lipid composition for environmental adaptation ofP. tricornutum.
Unveiling the Mechanisms to Bypass KRAS Inhibition:In VitroInsights into the Influence of Fibroblast-Secretome
Authors: Oliveira Susana Mendonça , Carvalho Patrícia Dias , Roma André , Oliveira Patrícia , Ribeiro Andreia , Carvalho Joana , Martins Flávia , Machado Ana Luísa , Oliveira Maria José , Velho Sérgia 
Published: April 2024

AbstractNovel KRAS-targeted therapies unlocked new treatment options for previously untreatable patients. However, in colorectal cancer (CRC), resistance to KRAS-targeted therapy develops rapidly, making it imperative to understand its underlying mechanisms.Cancer-associated fibroblasts (CAFs) induce therapy resistance by generating and maintaining cancer stem cells (CSCs). Additionally, CAFs secretome can modulate KRAS mutant CRC cells proteomic profile, independently of mutant KRAS. Hence, we investigated whether CAF-derived factors could induce resistance to KRAS inhibition by promoting a KRAS-independent stem-like phenotype.Evaluation of KRAS-mutant CRC cell lines (HCT15, HCT116, and SW480) revealed unique basal stem cell marker expression levels. Silencing KRAS lead to up-regulation of CD24, down- regulation of CD49f and CD104, and reduced stemness. However, CAF-secreted factors attenuated these effects, restoring stem cell markers expression and increasing stemness. RNA sequencing showed that CAF-secreted factors upregulate pro-tumorigenic pathways in KRAS-silenced cells, including cell cycle control, epithelial-mesenchymal transition (EMT), NOTCH, and immune regulation, leading to increased cell cycling and exit from quiescence.Overall, we provide mechanistic insights illuminating the role of fibroblasts in counteracting KRAS silencing-induced growth inhibition and enhancing stemness. Our results show that the limited success of KRAS-targeted therapies is not only derived from cell-intrinsic factors but also dependent on external factors derived from the tumor microenvironment, thus opening avenues to improve therapy responses in CRC.
A tale of two lakes: divergent evolutionary trajectories of twoDaphniapopulations experiencing distinct environments
Authors: Wersebe Matthew J. , Günther Torsten , Morton Philip K. , Weider Lawrence J. , Frisch Dagmar 
Published: April 2024

AbstractMost studies of local adaptation substitute the correlation between spatial distance and environmental heterogeneity for the temporal dynamics over which local adaptation evolves. The availability of detailed ecological and genomic information from lake sediments provides an opportunity to study local adaptation with unparalleled clarity from the temporal perspective. Inference can be further enhanced by including multiple lakes along ecological axes to further isolate the effects of ecological change in driving local adaptation. Lakes throughout the world face the impact of numerous anthropogenically induced environmental changes. Top among these is the eutrophication of freshwaters from agriculture, development and land-use change. Here we use the genetic information recorded in lake sediments of two lakes experiencing contrasting histories of land-use change to study the evolution of local adaptation in the lakes’Daphnia pulicariapopulations. Utilizing nextRAD derived Single Nucleotide Polymorphisms (SNPs), we studied the evolutionary trajectories ofDaphnia pulicariain both lakes. Using gene-environment correlations and Fsttests for selection we found SNPs that appear to be under selection in both lakes. Specifically, we found more outlier SNPs in the highly impacted lake using Fst-based tests for selection. Conversely, gene-environment tests revealed the reverse pattern. We discuss numerous facets of experimental design that must be considered when using resurrection ecology to study local adaptation and critically evaluate how they may have impacted the results of this investigation.Lay SummaryResurrection ecology, the resuscitation or hatching of decades or centuries old dormant eggs, seeds or cysts provides the opportunity to study evolution in action. Here, we use resurrection ecology paired with Single Nucleotide Polymorphism (SNP) genotyping to study the evolutionary responses of two populations ofDaphnia pulicariato contrasting changes in the nutrient dynamics of their respective lakes. In the lake with more drastic changes in nutrient pollution, we find a stronger shift in allele frequencies through time and at a larger number of affected genomic positions compared with the environmentally more stable lake. However, Bayesian gene-environment correlations were stronger in the more stable lake reflecting higher power to detect correlations among allele frequency change and paleo-environmental variables in this location. Our results suggest that numerous factors might impact the ability to use different methodologies to detect local adaptation over time using resurrection ecology.
SqueakOut: Autoencoder-based segmentation of mouse ultrasonic vocalizations
Authors: Santana Gustavo M. , Dietrich Marcelo O. 
Published: April 2024

AbstractMice emit ultrasonic vocalizations (USVs) that are important for social communication. Despite great advancements in tools to detect USVs from audio files in the recent years, highly accurate segmentation of USVs from spectrograms (i.e., removing noise) remains a significant challenge. Here, we present a new dataset of12,954annotated spectrograms explicitly labeled for mouse USV segmentation. Leveraging this dataset, we developedSqueakOut, a lightweight (4.6Mparameters) fully convolutional autoencoder that achieves high accuracy in supervised segmentation of USVs from spectrograms, with aDicescore of90.22.SqueakOutcombines a MobileNetV2 backbone with skip connections and transposed convolutions to precisely segment USVs. Using stochastic data augmentation techniques and a hybrid loss function,SqueakOutlearns robust segmentation across varying recording conditions. We evaluate SqueakOut’s performance, demonstrating substantial improvements over existing methods like VocalMat (63.82Dicescore). The accurate USV segmentations enabled bySqueakOutwill facilitate novel methods for vocalization classification and more accurate analysis of mouse communication. To promote further research, we release the annotated12,954spectrogram USV segmentation dataset and theSqueakOutimplementation publicly.
A Transcriptomic Hourglass In Brown Algae
Authors: Lotharukpong Jaruwatana S. , Zheng Min , Luthringer Remy , Drost Hajk-Georg , Coelho Susana M. 
Published: April 2024

AbstractComplex multicellularity has emerged independently across a few eukaryotic lineages and is often associated with the rise of elaborate, tightly coordinated developmental processes. How multicellularity and development are interconnected in evolution is a major question in biology. The hourglass model of embryonic evolution depicts how developmental processes are conserved during evolution, predicting morphological and molecular divergence in early and late embryo stages, bridged by a conserved mid-embryonic (phylotypic) period linked to the formation of the basic body plan. Initially found in animal embryos, molecular hourglass patterns have recently been proposed for land plants and fungi. However, whether the hourglass pattern is an intrinsic feature of all developmentally complex eukaryotic lineages remains elusive. Here, we tested the prevalence of a (molecular) hourglass in the brown algae, the third most developmentally complex lineage on earth that has evolved multicellularity independently from animals, fungi, and plants. By exploring the evolutionary transcriptome of brown algae with distinct morphological complexities, we uncovered an hourglass pattern during embryogenesis in developmentally complex species. Filamentous algae without a canonical embryogenesis display an evolutionary transcriptome that is most conserved in multicellular stages of the life cycle, whereas unicellular stages are more rapidly evolving. Our findings suggest that transcriptome conservation in brown algae is associated with cell differentiation stages, but not necessarily linked to embryogenesis. Together with previous work in animals, plants and fungi, we provide further evidence for the generality of a developmental hourglass pattern across complex multicellular eukaryotes.
Oxytocin reduces subjective fear in naturalistic social contexts via enhancing top-down middle cingulate-amygdala regulation and brain-wide connectivity
Authors: Fu Kun , Xu Shuyue , Zhang Zheng , Liu Dan , Xu Ting , Zhang Yuan , Zhou Feng , Zhang Xiaodong , Lan Chunmei , Wang Junjie , Wang Lan , He Jingxian , Kendrick Keith M , Biswal Bharat , Liang Zhen , Zhao Weihua , Becker Benjamin 
Published: April 2024

AbstractAccumulating evidence from animal and human studies suggests a fear-regulating potential of the neuropeptide oxytocin (OT), yet the clinical translation into novel interventions for pathological fear requires a behavioral and neurofunctional characterization under close-to-real life conditions. Here, we combined a naturalistic fMRI-design inducing high and immersive fear experience in social and non-social contexts with a preregistered between-subjects randomized double-blind placebo-controlled intranasal OT trial (24 IU, n = 67 healthy men). OT reduced subjective fear in non-social and social contexts with small or moderate effect sizes, respectively. In the social fear contexts, OT enhanced left middle cingulate cortex (lMCC) activation and its functional connectivity with the contralateral amygdala, with both neural indices significantly and inversely associated with subjective fear following OT. On the network level, OT enhanced communication between the dorsal attention network (DAN) with the fronto-parietal (FPN) and the default-mode network (DMN) as well as on the more fine-grained level brain-wide communication. These findings indicate a fear-reducing potential of OT under naturalistic conditions with pronounced effects in social contexts, suggesting a high treatment value in disorders with social context-related excessive fear.
Ultra-sensitivity metaproteomics redefines the gut “dark metaproteome”, uncovering host-microbiome interactions and drug targets in intestinal inflammatory diseases
Authors: Xian Feng , Brenek Malena , Krisp Christoph , Aguanno Doriane , Urbauer Elisabeth , Srikumar Tharan , Ravi Kumar Ranjith Kumar , Liu Qixin , Barry Allison M , Ma Bin , Krieger Jonathan , Haller Dirk , Schmidt Manuela , Gómez-Varela David 
Published: April 2024

ABSTRACTThe gut microbiome is a complex ecosystem with significant inter-individual variability determined by hundreds of low-abundant species as revealed by genomic methods. Functional redundancy demands direct quantification of microbial biological functions to understand their influence on host physiology. This functional landscape remains unexplored due to limited sensitivity in metaproteomics methods. We present uMetaP, an ultra-sensitive metaproteomic solution combining advanced LC-MS technologies with a novel FDR- controlled de novo strategy. uMetaP improves the taxonomic detection limit of the gut "dark metaproteome" by 5,000-fold with exceptional quantification precision and accuracy. In a mouse model of colonic injury, uMetaP extended metagenomics findings and identified host functions and microbial metabolic networks linked to disease. We obtained orthogonal validation using transcriptomic data from biopsies of 204 Crohn’s patients and presented the concept of a "druggable metaproteome". Among the drug-protein interactions discovered are treatments for intestinal inflammatory diseases, showcasing uMetaP’s potential for disease diagnostics and data-driven drug repurposing strategies.
Microbiota from young mice counteracts susceptibility to age-related gout through modulating butyric acid levels in aged mice
Authors: Song Ning , Gao Hang , Li Jianhao , Liu Yi , Wang Mingze , Ma Zhiming , Zhang Naisheng , Zhang Wenlong 
Published: April 2024

AbstractGout is a prevalent form of inflammatory arthritis that occurs due to high levels of uric acid in the blood leading to the formation of urate crystals in and around the joints, particularly affecting the elderly. Recent research has provided evidence of distinct differences in the gut microbiota of patients with gout and hyperuricemia when compared to healthy individuals. However, the link between gut microbiota and age-related gout remained underexplored. Our study found that gut microbiota plays a crucial role in determining susceptibility to age-related gout. Specifically, we observed that age-related gut microbiota regulated the activation of the NLRP3 inflammasome pathway and modulated uric acid metabolism. More scrutiny highlighted the positive impact of "younger" microbiota on the gut microbiota structure of old or aged mice, enhancing butanoate metabolism and butyric acid content. Experimentation with butyrate supplementation indicated that butyric acid exerts a dual effect, inhibiting inflammation in acute gout and reducing serum uric acid levels. These insights emphasize the potential of gut microbiome rejuvenation in mitigating senile gout, unraveling the intricate dynamics between microbiota, aging, and gout. It potentially serves as a therapeutic target for senile gout-related conditions.
The role of endospore appendages in spore-spore contacts in pathogenic bacilli
Authors: Jonsmoen Unni Lise , Malyshev Dmitry , Sleutel Mike , Kristensen Elise Egeli , Zegeye Ephrem Debebe , Remaut Han , Andersson Magnus , Aspholm Marina Elisabeth 
Published: April 2024

AbstractSpecies within the spore-formingBacillus cereussensu lato group are recognized for their role in food spoilage and food poisoning.B. cereusspores are decorated with numerous pilus-like appendages, called S-ENAs and L-ENAs. These appendages are believed to play crucial roles in self-aggregation, adhesion, and biofilm formation. By using both bulk and single-cell approaches, we investigate the role of S-and L-ENAs as well as the impact of different environmental factors in spore-to-spore contacts and in the interaction between spores and vegetative cells. Our findings reveal that ENAs, and particularly their tip fibrilla, play an essential role in spore self-aggregation but not in the adhesion of spores to vegetative cells. The absence of L-BclA, which builds the L-ENA tip fibrillum, reduced both S-and L-ENA mediated spore aggregation, emphasizing the interconnected roles of S-and L-ENAs. Increased salt concentrations in the liquid environment significantly reduced spore aggregation, implying a charge dependency of spore-spore interactions. By elucidating these complex interactions, our study provides valuable insights into spore dynamics. This knowledge can guide future studies on spore behavior in environmental settings and aids in developing strategies to manage bacterial aggregation for beneficial purposes, like controlling biofilms in food production equipment.
Conservation of C4BP-binding Sequence Patterns inStreptococcus pyogenesM and Enn Proteins
Authors: Kolesiński Piotr , McGowan Matthew , Botteaux Anne , Smeesters Pierre R. , Ghosh Partho 
Published: April 2024

AbstractAntigenically sequence variable M proteins of the major bacterial pathogenStreptococcus pyogenes(Strep A) are responsible for recruiting human C4b-binding protein (C4BP) to the bacterial surface, which enables Strep A to evade destruction by the immune system. The most sequence divergent portion of M proteins, the hypervariable region (HVR), is responsible for binding C4BP. Structural evidence points to the conservation of two C4BP-binding sequence patterns (M2 and M22) in the HVR of numerous M proteins, with this conservation applicable to vaccine immunogen design. These two patterns, however, only partially explain C4BP-binding by Strep A. Here, we identified several M proteins that lack these patterns but still bind C4BP, and determined the structures of two, M68 and M87 HVRs, in complex with a C4BP fragment. Mutagenesis of these M proteins led to identification of amino acids that are crucial for C4BP-binding, enabling formulation of new C4BP-binding patterns. Mutagenesis was also carried out on M2 and M22 proteins to refine or generate experimentally grounded C4BP-binding patterns. The M22 pattern was the most populated among M proteins, followed by the M87 and M2 patterns, while the M68 pattern was rare. These patterns, except for M68, were also evident in numerous M-like Enn proteins. Binding of C4BP via these patterns to Enn proteins was verified. We conclude that C4BP-binding patterns occur frequently in Strep A strains of differing M types, being present in their M or Enn proteins, or frequently both, providing further impetus for their use as vaccine immunogens.
Structural basis for the inhibition of coronaviral main proteases by PF-00835231
Authors: Zhou Xuelan , Lu Xiaolu , Lin Cheng , Zou Xiaofang , Li Wenwen , Zeng Xiangyi , Wang Jie , Zeng Pei , Wang Weiwei , Zhang Jin , Jiang Haihai , Li Jian 
Published: April 2024

AbstractThe main protease (Mpro) of coronaviruses plays a key role in viral replication, thus serving as a hot target for drug design. It has been proven that PF-00835231 is promising inhibitor of SARS-CoV-2 Mpro. Here, we report the inhibition potency of PF-00835231 against SARS-CoV-2 Mproand seven Mpromutants (G15S, M49I, Y54C, K90R, P132H, S46F, and V186F) from SARS-CoV-2 variants. The results confirm that PF-00835231 has broad-spectrum inhibition against various coronaviral Mpros. In addition, the crystal structures of SARS-CoV-2 Mpro, SARS-CoV Mpro, MERS-CoV Mpro, and seven SARS-CoV-2 Mpromutants (G15S, M49I, Y54C, K90R, P132H, S46F, and V186F) in complex with PF-00835231 are solved. A detailed analysis of these structures reveal key determinants essential for inhibition and elucidates the binding modes of different coronaviral Mpros. Given the importance of the main protease for the treatment of coronaviral infection, structural insights into the Mproinhibition by PF-00835231 can accelerate the design of novel antivirals with broad-spectrum efficacy against different human coronaviruses.
Massively parallel reporter assays and mouse transgenic assays provide complementary information about neuronal enhancer activity
Authors: Kosicki Michael , Cintrón Dianne Laboy , Page Nicholas F. , Georgakopoulos-Soares Ilias , Akiyama Jennifer A. , Plajzer-Frick Ingrid , Novak Catherine S. , Kato Momoe , Hunter Riana D. , von Maydell Kianna , Barton Sarah , Godfrey Patrick , Beckman Erik , Sanders Stephan J. , Pennacchio Len A. , Ahituv Nadav 
Published: April 2024

AbstractGenetic studies find hundreds of thousands of noncoding variants associated with psychiatric disorders. Massively parallel reporter assays (MPRAs) andin vivotransgenic mouse assays can be used to assay the impact of these variants. However, the relevance of MPRAs toin vivofunction is unknown and transgenic assays suffer from low throughput. Here, we studied the utility of combining the two assays to study the impact of non-coding variants. We carried out an MPRA on over 50,000 sequences derived from enhancers validated in transgenic mouse assays and from multiple fetal neuronal ATAC-seq datasets. We also tested over 20,000 variants, including synthetic mutations in highly active neuronal enhancers and 177 common variants associated with psychiatric disorders. Variants with a high impact on MPRA activity were further tested in mice. We found a strong and specific correlation between MPRA and mouse neuronal enhancer activity including changes in neuronal enhancer activity in mouse embryos for variants with strong MPRA effects. Mouse assays also revealed pleiotropic variant effects that could not be observed in MPRA. Our work provides a large catalog of functional neuronal enhancers and variant effects and highlights the effectiveness of combining MPRAs and mouse transgenic assays.
Crossing the digital divide: The workload of manual data entry for integration between mobile health applications and eHealth infrastructure
Authors: Feldacker Caryl , Usiri Joel , Kiruthu-Kamamia Christine , Waehrer Geetha , Weldemariam Hiwot , Huwa Jacqueline , Hau Jessie , Thawani Agness , Chapanda Mirriam , Tweya Hannock 
Published: April 2024

AbstractBackgroundMany digital health interventions (DHIs), including mobile health (mHealth) apps, aim to improve both client outcomes and efficiency like electronic medical record systems (EMRS). Although interoperability is the gold standard, it is also complex and costly, requiring technical expertise, stakeholder permissions, and sustained funding.Manual data linkageprocesses are commonly used to “integrate” across systems and allow for assessment of DHI impact, a best practice, before further investment. For mHealth, the manual data linkage workload, including related monitoring and evaluation (M&E) activities, remains poorly understood.MethodologyAs a baseline study for an open-source app to mirror EMRS and reduce healthcare worker (HCW) workload while improving care in the Nurse-led Community-based Antiretroviral therapy Program (NCAP) in Lilongwe, Malawi, we conducted a time-motion study observing HCWs completing data management activities, including routine M&E and manual data linkage of individual-level app data to EMRS. Data management tasks should reduce or end with successful app implementation and EMRS integration. Data was analysed in Excel.ResultsWe observed 69:53:00 of HCWs performing routine NCAP service delivery tasks: 39:52:00 (57%) was spent completing M&E data related tasks of which 15:57:00 (23%) was spent on manual data linkage workload, alone.ConclusionUnderstanding the workload to ensure quality M&E data, including to complete manual data linkage of mHealth apps to EMRS, provides stakeholders with inputs to drive DHI innovations and integration decision making. Quantifying potential mHealth benefits on more efficient, high-quality M&E data may trigger new innovations to reduce workloads and strengthen evidence to spur continuous improvement.