bluuebunny/crossref_metadata_2025_split huggingface dataset:
Leveraging Crosslinker Diffusion to Template Stiffness Gradients in Alginate Hydrogels
Authors: Ostrowski Zoe , Price Tyler , Zhang Juntao , Foroozandehfar Azarnoosh , Namanda Fred R. , Kaufmann Tim , Judka Natalia , Gardner Tyler , Thatcher Mary , Miller Emmaline , Mesyk Lily , Koep Abigail , Melvin Adam T. , Ren Juan , Schneider Ian C. 
Published: June 2024

AbstractMechanobiology drives many important cell biological behaviors such as stem cell differentiation, cancer drug resistance and cell migration up stiffness gradients, a process called durotaxis. The development of 3D hydrogel systems with tunable 2D mechanical gradient patterns affords the ability to study these mechanosensitive cell behaviors to understand cancer invasion or enhance wound healing through directed migration. In this paper, we developed an approach to spatially imprint within alginate hydrogels, gradients in mechanical properties that can be used to probe mechanobiology. Stencils were easily designed and fabricated using a common craft cutter to control the presentation of a calcium crosslinking solution to alginate gels. Different stencil shapes result in different gradients in opacity that can be imprinted into both thick and thin alginate gels of arbitrary 2D shape. The steepness of the opacity gradient as well as the maximum opacity can be controlled based on reproducible crosslinking kinetics regulated through calcium concentration and gradient developing time. Calcium crosslinking results in both opacity changes as well as increases in elastic modulus in the bulk hydrogel. Opacity correlates with elastic modulus, allowing it to be used as a proxy for local elastic modulus. Functionalized alginate gels with collagen and imprinting stiffness gradients within them resulted in cell invasion that was spatially dependent, where stiffer regions facilitated deeper invasion of breast cancer cells. Consequently, this stenciling approach represents a facile way to control stiffness gradients in alginate gels in order to study mechanosensitive cellular behavior.Graphical Abstract
Deciphering BRCAness Phenotype in Cancer: A Graph Convolutional Neural Network Approach with Layer-wise Relevance Propagation Analysis
Authors: Yang Jingyu , Chereda Hryhorii , Dönitz Jürgen , Bleckmann Annalen , Beißbarth Tim 
Published: June 2024

AbstractBackgroundCancer variability among patients underscores the need for personalized therapy based on genomic understanding. BRCAness, characterized by vulnerabilities similar to BRCA mutations, particularly in homologous recombination repair, shows potential sensitivity to DNA-damaging agents like PARP inhibitors, highlighting it’s clinical significance.MethodsWe employed Graph Convolutional Neural Networks (GCNNs) with Layer-wise Relevance Propagation (LRP) to analyze gene expression data from the TCGA Pan-Cancer dataset. The study compared the efficacy of GCNNs against traditional machine learning models and differential gene expression analysis, focusing on their ability to elucidate complex genomic interactions defining BRCAness.ResultsDifferential Gene Expression (DGE) analysis proved limited in capturing the nuances of BRCAness. In contrast, GLRP significantly identified genes related to transcription regulation and cancer processes, emphasizing the phenotype’s complexity. Gene Set Enrichment Analysis (GSEA) highlighted crucial pathways like Nuclear Receptors signaling, Cellular Senescence, and ESR-mediated signaling, underscoring their roles in BRCAness and therapeutic potential.ConclusionGLRP outperformed traditional approaches in analyzing BRCAness, providing deep insights into transcriptional and oncogenic processes critical to the BRCAness phenotype. Our findings suggest new directions for developing targeted and personalized cancer treatments, leveraging intricate molecular interactions associated with BRCAness.
Detection of pharmaceutical contamination in amphipods of Lake Baikal by the HPLC-MS method
Authors: Telnova Tamara Yu. , Morgunova Maria M. , Shashkina Sophie S. , Vlasova Anfisa A. , Dmitrieva Maria E. , Shelkovnikova Victoria N. , Malygina Ekaterina V. , Imidoeva Natalia A. , Belyshenko Alexander Yu. , Konovalov Alexander S. , Misharina Evgenia A. , Axenov-Gribanov Denis V. 
Published: June 2024

AbstractPollution by active ingredients is one of the most significant and widespread forms of pollution on Earth. Medicines can have a negative impact on ecosystems, and contamination can have unpredictable consequences. An urgent and unexplored task is to study the Lake Baikal ecosystem and its organisms for the presence of trace concentrations of active pharmaceutical ingredients. Our study aimed to conduct a qualitative analysis of active pharmaceutical ingredients, and quantitative analysis of ibuprofen in endemic amphipods of Lake Baikal, using methods of high-performance liquid chromatography and mass spectrometry (HPLC-MS). Acetylsalicylic acid (aspirin), ibuprofen, acetaminophen, azithromycin, dimetridazole, metronidazole, amikacin, spiramycin, and some tetracycline antibiotics were detected in the studied littoral amphipods. We also detected different annual loads of active pharmaceutical ingredients on amphipods. Using the multiple reaction monitoring (MRM) mode mentioned in GOST International Technical Standards, we detected molecules, fragmented as amikacin, chlortetracycline, doxycycline, oxytetracycline, dimetridazole, metronidazole and spiramycin. Thus, we first revealed that invertebrates of Lake Baikal can encounter pharmaceutical contaminants in the environment.
MICAL2 Is a Super Enhancer Associated Gene that Promotes Pancreatic Cancer Growth and Metastasis
Authors: Garg Bharti , Khan Sohini , Babu Deepa Sheikh , Mose Evangeline , Gulay Kevin , Sharma Shweta , Sood Divya , Wenzel Alexander T. , Martsinkovskiy Alexei , Patel Jay , Jaquish Dawn , Lambies Guillem , D’Ippolito Anthony , Austgen Kathryn , Johnston Brian , Orlando David , Jang Gung Ho , Gallinger Steven , Goodfellow Elliot , Brodt Pnina , Commisso Cosimo , Tamayo Pablo , Mesirov Jill P. , Tiriac Herve , Lowy Andrew M. 
Published: June 2024

ABSTRACTPancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid cancers and thus identifying more effective therapies is a major unmet need. In this study we characterized the super enhancer (SE) landscape of human PDAC to identify novel, potentially targetable, drivers of the disease. Our analysis revealed thatMICAL2is a super enhancer-associated gene in human PDAC. MICAL2 is a flavin monooxygenase that induces actin depolymerization and indirectly promotes SRF transcription by modulating the availability of serum response factor coactivators myocardin related transcription factors (MRTF-A and MRTF-B). We found that MICAL2 is overexpressed in PDAC and correlates with poor patient prognosis. Transcriptional analysis revealed that MICAL2 upregulates KRAS and EMT signaling pathways, contributing to tumor growth and metastasis. In loss and gain of function experiments in human and mouse PDAC cells, we observed that MICAL2 promotes both ERK1/2 and AKT activation. Consistent with its role in actin depolymerization and KRAS signaling, loss of MICAL2 expression also inhibited macropinocytosis. Throughin vitrophenotypic analyses, we show that MICAL2, MRTF-A and MRTF-B influence PDAC cell proliferation, migration and promote cell cycle progression. Importantly, we demonstrate that MICAL2 is essential forin vivotumor growth and metastasis. Interestingly, we find that MRTF-B, but not MRTF-A, phenocopies MICAL2-driven phenotypesin vivo. This study highlights the multiple ways in which MICAL2 impacts PDAC biology and suggests that its inhibition may impede PDAC progression. Our results provide a foundation for future investigations into the role of MICAL2 in PDAC and its potential as a target for therapeutic intervention.
Rbm24 maintains survival of cochlear outer hair cells by repressing Insm1
Authors: Li Chao , Wang Luyue , Li Shuting , Li Jie , Lu Ying , Liu Zhiyong 
Published: June 2024

ABSTRACTThe inactivation of Rbm24, an RNA-binding protein, results in the degeneration of cochlear outer hair cells (OHCs) during the postnatal period. However, the specific molecular mechanisms underlying this OHC death remain elusive. To address this, we conducted a comprehensive analysis comparing the gene profiles of wild-type OHCs to those lacking Rbm24 (Rbm24-/-)at postnatal day 7 (P7). Our results revealed that the overall differentiation program of OHCs is delayed in the absence of Rbm24. Furthermore, the expression of Insm1, a crucial factor for OHC development that is normally switched off by P2, remains prolonged inRbm24-/-OHCs. Interestingly, when Insm1 is overexpressed, it also leads to OHC death. Significantly, the OHC degeneration is much less severe when bothRbm24andInsm1are simultaneously inactivated. These findings shed light on the important role of Rbm24 in repressing Insm1 and its impact on OHC differentiation and survival. Our study provides valuable insights into the complex genetic signaling pathways involved in OHC development.
Comparative study of gamma radiation tolerance between desiccation-sensitive and desiccation-tolerant tardigrades
Authors: Saigo Tokiko , Satoh Katsuya , Kunieda Takekazu 
Published: June 2024

ABSTRACTTardigrades are small metazoans renowned for their exceptional tolerance against various harsh environments in a dehydrated state. Some species exhibited an extraordinary tolerance against high-dose irradiation even in a hydrated state. Given that natural sources of high radiation are rare, the selective pressure to obtain such a high radiotolerance during evolution remains elusive. It has been postulated that high radiation tolerances could be derived from adaptation to dehydration, because both dehydration and radiation cause similar damage on biomolecules at least partly, e.g., DNA cleavage and oxidation of various biomolecules, and dehydration is a common environmental stress that terrestrial organisms should adapt to. Although tardigrades are known for high radiotolerance, the radiotolerance records have been reported only for desiccation-tolerant tardigrade species and nothing was known about the radio-tolerance in desiccation-sensitive tardigrade species. Hence, the relationship between desiccation-tolerance and radio-tolerance remained unexplored. To this end, we examined the radiotolerance of the desiccation-sensitive tardigrade,Grevenius myrops(formerly known asIsohypsibius myrops) in comparison to the well-characterized desiccation-tolerant tardigrade,Ramazzottius varieornatus. The median lethal dose (LD50) ofG. myropswas approximately 2,240 Gy. This was much lower than those reported for desiccation tolerant eutardigrades. The effects of irradiation on the lifespan and the ovipositions were more severe inG. myropscompared to those inR. varieornatus. The present study provides the precise records on the radiotolerance of a desiccation-sensitive tardigrade and the current data supported the certain correlation between desiccation tolerance and radiotolerance at least in eutardigrades.
Spatial-temporal dynamics of contact among free-ranging domestic dogsCanis familiarisin rural Africa
Authors: Wilson-Aggarwal Jared K. , Goodwin Cecily E.D. , Léchenne Monique , Swan George J.F. , Sidouin Metinou K. , Silk Matthew J. , Moundai Tchonfienet , Ozella Laura , Tizzoni Michele , Cattuto Ciro , McDonald Robbie A. 
Published: June 2024

Abstract1. Transmission of infection is affected by the spatial-temporal dynamics of host contacts. Domestic dogsCanis familiarisshare pathogens with humans and wildlife, and managing dog-mediated diseases is a priority for public health and conservation interests.2. We combined proximity sensors and GPS tracking to analyse spatial-temporal variation in contact among free-ranging dogs in six villages in rural Chad, during both the wet and dry seasons. We investigated dyadic interactions between dogs from different villages, the same village but different households and the same household. We assessed variation in (i) the probability of individuals having had contact, (ii) the hourly frequency of contact and (iii) contact durations.3. Our results highlight clear seasonal and hourly patterns in contact behaviour. Contacts between dogs from different villages were rare, short in duration, primarily between male-female dyads and predominantly occurred within villages and during the dry season. Contact between dogs in the same village peaked at dawn and dusk. Sex differences were most pronounced in the wet season, where males from different households had the highest hourly contact probabilities, followed by male-female dyads. For all dogs, contact durations were longer in the dry season, but showed little hourly variation.4. Contact patterns were not equal in space, and the probability of individuals having had contact was less than 5% when dwellings were more than 500m apart. Spatially, the probability of contact was lowest outside the village, but this increased in the dry season and peaked in the morning hours. Contact durations were notably longer outside the village, where they increased in duration for between-household dyads in the dry season.5. At a coarse temporal scale, variation in dog contacts within and among households, and rarely between villages, may underpin seasonal variation in the incidence of dog-mediated diseases. Variation at finer temporal (hourly) and spatial scales (around households, within and outside villages) highlights the importance of routine behaviours and space use in determining patterns of contact between dogs. Practitioners should consider behavioural heterogeneities, such as those reported here, when using strategic models to support disease management decisions.
MetaLATTE: Metal Binding Prediction via Multi-Task Learning on Protein Language Model Latents
Authors: Zhang Yinuo , He Phil , Hsu Ashley , Chatterjee Pranam 
Published: June 2024

AbstractThe bioremediation of environments contaminated with heavy metals is an important challenge in environmental biotechnology, which may benefit from the identification of proteins that bind and neutralize these metals. Here, we introduce a novel predictive algorithm that conductsMetalbinding prediction viaLAnguage model laTenT Embeddings using a multi-task learning approach to accurately classify the metal-binding properties of input protein sequences. OurMetaLATTEmodel utilizes the state-of-the-art ESM-2 protein language model (pLM) embeddings and a position-sensitive attention mechanism to predict the likelihood of binding to specific metals, such as zinc, lead, and mercury. Importantly, our approach addresses the challenges posed by proteins from understudied organisms, which are often absent in traditional metal-binding databases, without the requirement of an input structure. By providing a probability distribution over potential binding metals, our classifier elucidates specific interactions of proteins with diverse metal ions. We envision that MetaLATTE will serve as a powerful tool for rapidly screening and identifying new metal-binding proteins, from metagenomic discovery orde novodesign efforts, which can later be employed in targeted bioremediation campaigns.
The Respiratory-Pupillary Phase Effect: Pupils size is smallest around inhalation onset and largest during exhalation
Authors: Schaefer Martin , Mathôt Sebastiaan , Lundqvist Mikael , Lundström Johan N. , Arshamian Artin 
Published: June 2024

AbstractThe prevailing view in the study of animal and human pupillary function has been that pupils dilate and are largest during inhalation and constrict and are smallest during exhalation. However, this notion has recently been challenged. Here, we systematically address this question by conducting a study encompassing three experiments (two resting tasks and one visual perception task), with the latter two being pre-registered. Collectively, across nasal and oral breathing, resting, and task conditions, our experiments consistently and robustly demonstrate that pupil size is smallest around inhalation onset and largest around peak exhalation. This phenomenon, which we term the Respiratory-Pupillary Phase Effect (RPPE), directly contradicts the long-held notion that pupils are largest during inhalation and smallest during exhalation. Notably, the dilation and constriction processes overlap with both phases. The observed consistency and significance of the RPPE across various conditions underscore the need for further investigation into its underlying mechanisms and potential impact on human behavior.
Macrophages facilitate interclonal cooperation-induced tumor heterogeneity and malignancy by activating the innate immune signaling
Authors: Zhao Sihua , Guo Yifan , Kuang Xiaoyu , Li Xiaoqin , Wu Chenxi , Lin Peng , Xie Qi , Kong Du , Ma Xianjue 
Published: June 2024

AbstractTumor heterogeneity is a common hallmark of cancer and is considered a major cause of treatment failure and relapse, yet it remains poorly understood how various types of cells communicate within the tumor microenvironment (TME) to regulate tumor progressionin vivo. Here we establish a tumor heterogeneity model inDrosophilaeye epithelium by mutating the tricellular junction proteinM6in cells surroundingRasV12benign tumors and dissect thein vivomechanisms underlying interclonal cooperation-induced malignancy by utilizing sophisticated genetic techniques in conjunction with single-cell RNA sequencing (scRNA-seq). Our findings reveal that loss ofM6facilitates the malignant transformation of neighboringRasV12tumors by activating the Toll signaling, the innate immune response pathway. Notably, inhibiting Toll signaling impedes tumor progression, whereas its activation synergistically promotesRasV12tumor malignancy by inactivating the Hippo pathway. Mechanistically,RasV12tumors surrounded byM6mutant clones lead to increased recruitment of hemocytes, which are the equivalent of macrophages inDrosophila, in a JNK pathway-dependent manner. Consequently, these tumor-associated macrophages secrete the Spatzle (Spz) ligand, which subsequently activates the Toll receptor within theRasV12tumors, thereby triggering tumorigenesis. In summary, our study elucidates the complexin vivointeractions between genetically distinct oncogenic cells and between tumors and macrophages, shedding light on how macrophages exploit the innate immune signaling within tumors to regulate tumor heterogeneity and promote tumor progression.Significance statementIntratumoral heterogeneity profoundly affects cancer development and treatment in human tumors. The intricate nature of tumor cells and the presence of diverse cell types pose challenges to uncoveringin vivomechanisms responsible for heterogeneity. OurDrosophilatumor heterogeneity model reveals that fruit fly macrophages promotes both tumor heterogeneity and malignancy. Following recruitment by tumor cells, these macrophages secrete the ligand Spz to activate the Toll signaling pathway within tumor cells, which subsequently inactivates the Hippo pathway to drive tumorigenesis. Our study highlights the crucial role of hemocytes as intermediaries in coordinating tumor heterogeneity and facilitating intercellular communication between different cells within the TME.
Human-specific paralogs of SRGAP2 induce neotenic features of microglia structural and functional maturation
Authors: Diaz-Salazar Carlos , Krzisch Marine , Yoo Juyoun , Nano Patricia R. , Bhaduri Aparna , Jaenisch Rudolf , Polleux Franck 
Published: June 2024

SUMMARYMicroglia play key roles in shaping synaptic connectivity during neural circuits development. Whether microglia display human-specific features of structural and functional maturation is currently unknown. We show that the ancestral geneSRGAP2Aand its human-specific (HS) paralogsSRGAP2B/Care not only expressed in cortical neurons but are the only HS gene duplications expressed in human microglia. Here, using combination of xenotransplantation of human induced pluripotent stem cell (hiPSC)-derived microglia and mouse genetic models, we demonstrate that (1) HS SRGAP2B/C are necessary and sufficient to induce neotenic features of microglia structural and functional maturation in a cell-autonomous manner, and (2) induction of SRGAP2-dependent neotenic features of microglia maturation non-cell autonomously impacts synaptic development in cortical pyramidal neurons. Our results reveal that, during human brain evolution, human-specific genes SRGAP2B/C coordinated the emergence of neotenic features of synaptic development by acting as genetic modifiers of both neurons and microglia.
Directed evolution of bacteriophages: impacts of prolific prophage
Authors: Peters Tracey Lee , Schow Jacob , Spencer Emma , Van Leuven JT , Wichman Holly , Miller Craig 
Published: June 2024

ABSTRACTVarious directed evolution methods exist that seek to procure bacteriophages with expanded host ranges, typically targeting phage-resistant or non-permissive bacterial hosts. The general premise of these methods is to propagate phage on multiple bacterial hosts, pool the lysate, and repeat the propagation process until phage(s) can form plaques on the target host(s). In theory, this propagation process produces a phage lysate that contains input phages and their evolved phage progeny. However, in practice, this phage lysate can also include prophages originating from bacterial hosts. Here we describe our experience implementing one directed evolution method, the Appelmans protocol, to study phage evolution in thePseudomonas aeruginosaphage-host system, in which we observed rapid host-range expansion of the phage cocktail. Further experimentation and sequencing analysis revealed that this observed host-range expansion was due to aCasadabanvirusprophage that originated from one of the Appelmans hosts. Host-range analysis of the prophage showed that it could infect five of eight bacterial hosts initially used, allowing it to proliferate and persist through the end of the experiment. This prophage was represented in half of the sequenced phage samples isolated from the Appelmans experiment. This work highlights the impact of prophages in directed evolution experiments and the importance of incorporating sequencing data in analyses to verify output phages, particularly for those attempting to procure phages intended for phage therapy applications. This study also notes the usefulness of intraspecies antagonism assays between bacterial host strains to establish a baseline for inhibitory activity and determine presence of prophage.IMPORTANCEDirected evolution is a common strategy for evolving phages to expand host range, often targeting pathogenic strains of bacteria. In this study we investigated phage host-range expansion using directed evolution in thePseudomonas aeruginosasystem. We show that prophage are active players in directed evolution and can contribute to observation of host-range expansion. Since prophage are prevalent in bacterial hosts, particularly pathogenic strains of bacteria, and all directed evolution approaches involve iteratively propagating phage on one or more bacterial hosts, the presence of prophage in phage preparations is a factor that needs to be considered in experimental design and interpretation of results. These results highlight the importance of screening for prophages either genetically or through intraspecies antagonism assays during selection of bacterial strains and will contribute to improving experimental design of future directed evolution studies.