bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recent advances in CRISPR-based functional genomics for the study of disease-associated genetic variants
Authors: Kim Heon Seok , Kweon Jiyeon , Kim Yongsub 
Published: April 2024

AbstractAdvances in sequencing technology have greatly increased our ability to gather genomic data, yet understanding the impact of genetic mutations, particularly variants of uncertain significance (VUSs), remains a challenge in precision medicine. The CRISPR‒Cas system has emerged as a pivotal tool for genome engineering, enabling the precise incorporation of specific genetic variations, including VUSs, into DNA to facilitate their functional characterization. Additionally, the integration of CRISPR‒Cas technology with sequencing tools allows the high-throughput evaluation of mutations, transforming uncertain genetic data into actionable insights. This allows researchers to comprehensively study the functional consequences of point mutations, paving the way for enhanced understanding and increasing application to precision medicine. This review summarizes the current genome editing tools utilizing CRISPR‒Cas systems and their combination with sequencing tools for functional genomics, with a focus on point mutations.
Advances in Engineered Macrophages: A New Frontier in Cancer Immunotherapy
Authors: Yang Shuaixi , Wang Yuhang , Jia Jiachi , Fang Yingshuai , Yang Yabing , Yuan Weitang , Hu Junhong 
Published: April 2024

AbstractMacrophages, as pivotal cells within the tumour microenvironment, significantly influence the impact of and reactions to treatments for solid tumours. The rapid evolution of bioengineering technology has revealed the vast potential of engineered macrophages in immunotherapy, disease diagnosis, and tissue engineering. Given this landscape, the goal of harnessing and innovating macrophages as a novel strategy for solid tumour immunotherapy cannot be overstated. The diverse strategies for engineered macrophages in the realm of cancer immunotherapy, encompassing macrophage drug delivery systems, chimeric antigen receptor macrophage therapy, and synergistic treatment approaches involving bacterial outer membrane vesicles and macrophages, are meticulously examined in this review. These methodologies are designed to enhance the therapeutic efficacy of macrophages against solid tumours, particularly those that are drug-resistant and metastatic. Collectively, these immunotherapies are poised to supplement and refine current solid tumour treatment paradigms, thus heralding a new frontier in the fight against malignant tumours.
Targeting RCC1 to block the human soft-tissue sarcoma by disrupting nucleo-cytoplasmic trafficking of Skp2
Authors: Zhuang Mingzhi , Li Fengyue , Liang Hong , Su Yongfu , Cheng Lei , Lin Bingkai , Zhou Jun , Deng Runzhi , Chen Linying , Lyu Peng , Lu Zhonglei 
Published: April 2024

AbstractSoft-tissue sarcomas (STS) emerges as formidable challenges in clinics due to the complex genetic heterogeneity, high rates of local recurrence and metastasis. Exploring specific targets and biomarkers would benefit the prognosis and treatment of STS. Here, we identified RCC1, a guanine-nucleotide exchange factor for Ran, as an oncogene and a potential intervention target in STS. Bioinformatics analysis indicated that RCC1 is highly expressed and correlated with poor prognosis in STS. Functional studies showed that RCC1 knockdown significantly inhibited the cell cycle transition, proliferation and migration of STS cells in vitro, and the growth of STS xenografts in mice. Mechanistically, we identified Skp2 as a downstream target of RCC1 in STS. Loss of RCC1 substantially diminished Skp2 abundance by compromising its protein stability, resulting in the upregulation of p27Kip1 and G1/S transition arrest. Specifically, RCC1 might facilitate the nucleo-cytoplasmic trafficking of Skp2 via direct interaction. As a result, the cytoplasmic retention of Skp2 would further protect it from ubiquitination and degradation. Notably, recovery of Skp2 expression largely reversed the phenotypes induced by RCC1 knockdown in STS cells. Collectively, this study unveils a novel RCC1-Skp2-p27Kip1 axis in STS oncogenesis, which holds promise for improving prognosis and treatment of this formidable malignancy.
Data-driven identification of predictive risk biomarkers for subgroups of osteoarthritis using interpretable machine learning
Authors: Nielsen Rikke Linnemann , Monfeuga Thomas , Kitchen Robert R. , Egerod Line , Leal Luis G. , Schreyer August Thomas Hjortshøj , Gade Frederik Steensgaard , Sun Carol , Helenius Marianne , Simonsen Lotte , Willert Marianne , Tahrani Abd A. , McVey Zahra , Gupta Ramneek 
Published: April 2024

AbstractOsteoarthritis (OA) is increasing in prevalence and has a severe impact on patients’ lives. However, our understanding of biomarkers driving OA risk remains limited. We developed a model predicting the five-year risk of OA diagnosis, integrating retrospective clinical, lifestyle and biomarker data from the UK Biobank (19,120 patients with OA, ROC-AUC: 0.72, 95%CI (0.71–0.73)). Higher age, BMI and prescription of non-steroidal anti-inflammatory drugs contributed most to increased OA risk prediction ahead of diagnosis. We identified 14 subgroups of OA risk profiles. These subgroups were validated in an independent set of patients evaluating the 11-year OA risk, with 88% of patients being uniquely assigned to one of the 14 subgroups. Individual OA risk profiles were characterised by personalised biomarkers. Omics integration demonstrated the predictive importance of key OA genes and pathways (e.g., GDF5 and TGF-β signalling) and OA-specific biomarkers (e.g., CRTAC1 and COL9A1). In summary, this work identifies opportunities for personalised OA prevention and insights into its underlying pathogenesis.
CD276-dependent efferocytosis by tumor-associated macrophages promotes immune evasion in bladder cancer
Authors: Cheng Maosheng , Chen Shuang , Li Kang , Wang Ganping , Xiong Gan , Ling Rongsong , Zhang Caihua , Zhang Zhihui , Han Hui , Chen Zhi , Wang Xiaochen , Liang Yu , Tian Guoli , Zhou Ruoxing , Zhu Yan , Ma Jieyi , Liu Jiahong , Lin Shuibin , Xu Hao , Chen Demeng , Li Yang , Peng Liang 
Published: April 2024

AbstractInterplay between innate and adaptive immune cells is important for the antitumor immune response. However, the tumor microenvironment may turn immune suppressive, and tumor associated macrophages are playing a role in this transition. Here, we show that CD276, expressed on tumor-associated macrophages (TAM), play a role in diminishing the immune response against tumors. Using a model of tumors induced by N-butyl-N-(4-hydroxybutyl) nitrosamine in BLCA male mice we show that genetic ablation of CD276 in TAMs blocks efferocytosis and enhances the expression of the major histocompatibility complex class II (MHCII) of TAMs. This in turn increases CD4 + and cytotoxic CD8 + T cell infiltration of the tumor. Combined single cell RNA sequencing and functional experiments reveal that CD276 activates the lysosomal signaling pathway and the transcription factor JUN to regulate the expression of AXL and MerTK, resulting in enhanced efferocytosis in TAMs. Proving the principle, we show that simultaneous blockade of CD276 and PD-1 restrain tumor growth better than any of the components as a single intervention. Taken together, our study supports a role for CD276 in efferocytosis by TAMs, which is potentially targetable for combination immune therapy.
Systematic analysis of RNA-binding proteins identifies targetable therapeutic vulnerabilities in osteosarcoma
Authors: Zhou Yang , Ray Partho Sarothi , Zhu Jianguo , Stein Frank , Rettel Mandy , Sekaran Thileepan , Sahadevan Sudeep , Perez-Perri Joel I. , Roth Eva K. , Myklebost Ola , Meza-Zepeda Leonardo A. , von Deimling Andreas , Fu Chuli , Brosig Annika N. , Boye Kjetil , Nathrath Michaela , Blattmann Claudia , Lehner Burkhard , Hentze Matthias W. , Kulozik Andreas E. 
Published: April 2024

AbstractOsteosarcoma is the most common primary malignant bone tumor with a strong tendency to metastasize, limiting the prognosis of affected patients. Genomic, epigenomic and transcriptomic analyses have demonstrated the exquisite molecular complexity of this tumor, but have not sufficiently defined the underlying mechanisms or identified promising therapeutic targets. To systematically explore RNA-protein interactions relevant to OS, we define the RNA interactomes together with the full proteome and the transcriptome of cells from five malignant bone tumors (four osteosarcomata and one malignant giant cell tumor of the bone) and from normal mesenchymal stem cells and osteoblasts. These analyses uncover both systematic changes of the RNA-binding activities of defined RNA-binding proteins common to all osteosarcomata and individual alterations that are observed in only a subset of tumors. Functional analyses reveal a particular vulnerability of these tumors to translation inhibition and a positive feedback loop involving the RBP IGF2BP3 and the transcription factor Myc which affects cellular translation and OS cell viability. Our results thus provide insight into potentially clinically relevant RNA-binding protein-dependent mechanisms of osteosarcoma.
Deciphering the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer
Authors: Croizer Hugo , Mhaidly Rana , Kieffer Yann , Gentric Geraldine , Djerroudi Lounes , Leclere Renaud , Pelon Floriane , Robley Catherine , Bohec Mylene , Meng Arnaud , Meseure Didier , Romano Emanuela , Baulande Sylvain , Peltier Agathe , Vincent-Salomon Anne , Mechta-Grigoriou Fatima 
Published: April 2024

AbstractAlthough heterogeneity of FAP+ Cancer-Associated Fibroblasts (CAF) has been described in breast cancer, their plasticity and spatial distribution remain poorly understood. Here, we analyze trajectory inference, deconvolute spatial transcriptomics at single-cell level and perform functional assays to generate a high-resolution integrated map of breast cancer (BC), with a focus on inflammatory and myofibroblastic (iCAF/myCAF) FAP+ CAF clusters. We identify 10 spatially-organized FAP+ CAF-related cellular niches, called EcoCellTypes, which are differentially localized within tumors. Consistent with their spatial organization, cancer cells drive the transition of detoxification-associated iCAF (Detox-iCAF) towards immunosuppressive extracellular matrix (ECM)-producing myCAF (ECM-myCAF) via a DPP4- and YAP-dependent mechanism. In turn, ECM-myCAF polarize TREM2+ macrophages, regulatory NK and T cells to induce immunosuppressive EcoCellTypes, while Detox-iCAF are associated with FOLR2+ macrophages in an immuno-protective EcoCellType. FAP+ CAF subpopulations accumulate differently according to the invasive BC status and predict invasive recurrence of ductal carcinoma in situ (DCIS), which could help in identifying low-risk DCIS patients eligible for therapeutic de-escalation.
Bacteria contribute exopolysaccharides to an algal-bacterial joint extracellular matrix
Authors: Lipsman Valeria , Shlakhter Olesia , Rocha Jorge , Segev Einat 
Published: April 2024

AbstractMarine ecosystems are influenced by phytoplankton aggregation, which affects processes like marine snow formation and harmful events such as marine mucilage outbreaks. Phytoplankton secrete exopolymers, creating an extracellular matrix (ECM) that promotes particle aggregation. This ECM attracts heterotrophic bacteria, providing a nutrient-rich and protective environment. In terrestrial environments, bacterial colonization near primary producers relies on attachment and the formation of multidimensional structures like biofilms. Bacteria were observed attaching and aggregating within algal-derived exopolymers, but it is unclear if bacteria produce an ECM that contributes to this colonization. This study, using Emiliania huxleyi algae and Phaeobacter inhibens bacteria in an environmentally relevant model system, reveals a shared algal-bacterial ECM scaffold that promotes algal-bacterial aggregation. Algal exudates play a pivotal role in promoting bacterial colonization, stimulating bacterial exopolysaccharide (EPS) production, and facilitating a joint ECM formation. A bacterial biosynthetic pathway responsible for producing a specific EPS contributing to bacterial ECM formation is identified. Genes from this pathway show increased expression in algal-rich environments. These findings highlight the underestimated role of bacteria in aggregate-mediated processes in marine environments, offering insights into algal-bacterial interactions and ECM formation, with implications for understanding and managing natural and perturbed aggregation events.
Magnetically tunable supercurrent in dilute magnetic topological insulator-based Josephson junctions
Authors: Mandal Pankaj , Mondal Soumi , Stehno Martin P. , Ilić Stefan , Bergeret F. Sebastian , Klapwijk Teun M. , Gould Charles , Molenkamp Laurens W. 
Published: April 2024

AbstractA superconductor, when exposed to a spin-exchange field, can exhibit spatial modulation of its order parameter, commonly referred to as the Fulde–Ferrell–Larkin–Ovchinnikov state. Such a state can be induced by controlling the spin-splitting field in Josephson junction devices, allowing access to a wide range of the phase diagram. Here we demonstrate that a Fulde–Ferrell–Larkin–Ovchinnikov state can be induced in Josephson junctions based on the two-dimensional dilute magnetic topological insulator (Hg,Mn)Te. We do this by observing the dependence of the critical current on the magnetic field and temperature. The substitution of Mn dopants induces an enhanced Zeeman effect, which can be controlled with high precision by using a small external magnetic field. We observe multiple re-entrant behaviours of the critical current as a response to an in-plane magnetic field, which we assign to transitions between ground states with a phase shifted by π. This will enable the study of the Fulde–Ferrell–Larkin–Ovchinnikov state in much more accessible experimental conditions.
Complexity of avian evolution revealed by family-level genomes
Authors: Stiller Josefin , Feng Shaohong , Chowdhury Al-Aabid , Rivas-González Iker , Duchêne David A. , Fang Qi , Deng Yuan , Kozlov Alexey , Stamatakis Alexandros , Claramunt Santiago , Nguyen Jacqueline M. T. , Ho Simon Y. W. , Faircloth Brant C. , Haag Julia , Houde Peter , Cracraft Joel , Balaban Metin , Mai Uyen , Chen Guangji , Gao Rongsheng , Zhou Chengran , Xie Yulong , Huang Zijian , Cao Zhen , Yan Zhi , Ogilvie Huw A. , Nakhleh Luay , Lindow Bent , Morel Benoit , Fjeldså Jon , Hosner Peter A. , da Fonseca Rute R. , Petersen Bent , Tobias Joseph A. , Székely Tamás , Kennedy Jonathan David , Reeve Andrew Hart , Liker Andras , Stervander Martin , Antunes Agostinho , Tietze Dieter Thomas , Bertelsen Mads F. , Lei Fumin , Rahbek Carsten , Graves Gary R. , Schierup Mikkel H. , Warnow Tandy , Braun Edward L. , Gilbert M. Thomas P. , Jarvis Erich D. , Mirarab Siavash , Zhang Guojie 
Published: April 2024

AbstractDespite tremendous efforts in the past decades, relationships among main avian lineages remain heavily debated without a clear resolution. Discrepancies have been attributed to diversity of species sampled, phylogenetic method and the choice of genomic regions1–3. Here we address these issues by analysing the genomes of 363 bird species4 (218 taxonomic families, 92% of total). Using intergenic regions and coalescent methods, we present a well-supported tree but also a marked degree of discordance. The tree confirms that Neoaves experienced rapid radiation at or near the Cretaceous–Palaeogene boundary. Sufficient loci rather than extensive taxon sampling were more effective in resolving difficult nodes. Remaining recalcitrant nodes involve species that are a challenge to model due to either extreme DNA composition, variable substitution rates, incomplete lineage sorting or complex evolutionary events such as ancient hybridization. Assessment of the effects of different genomic partitions showed high heterogeneity across the genome. We discovered sharp increases in effective population size, substitution rates and relative brain size following the Cretaceous–Palaeogene extinction event, supporting the hypothesis that emerging ecological opportunities catalysed the diversification of modern birds. The resulting phylogenetic estimate offers fresh insights into the rapid radiation of modern birds and provides a taxon-rich backbone tree for future comparative studies.
Unconventional human CD61 pairing with CD103 promotes TCR signaling and antigen-specific T cell cytotoxicity
Authors: Hamid Megat H. B. A. , Cespedes Pablo F. , Jin Chen , Chen Ji-Li , Gileadi Uzi , Antoun Elie , Liang Zhu , Gao Fei , Teague Renuka , Manoharan Nikita , Maldonado-Perez David , Khalid-Alham Nasullah , Cerundolo Lucia , Ciaoca Raul , Hester Svenja S. , Pinto-Fernández Adán , Draganov Simeon D. , Vendrell Iolanda , Liu Guihai , Yao Xuan , Kvalvaag Audun , Dominey-Foy Delaney C. C. , Nanayakkara Charunya , Kanellakis Nikolaos , Chen Yi-Ling , Waugh Craig , Clark Sally-Ann , Clark Kevin , Sopp Paul , Rahman Najib M. , Verrill Clare , Kessler Benedikt M. , Ogg Graham , Fernandes Ricardo A. , Fisher Roman , Peng Yanchun , Dustin Michael L. , Dong Tao 
Published: April 2024

AbstractCancer remains one of the leading causes of mortality worldwide, leading to increased interest in utilizing immunotherapy strategies for better cancer treatments. In the past decade, CD103+ T cells have been associated with better clinical prognosis in patients with cancer. However, the specific immune mechanisms contributing toward CD103-mediated protective immunity remain unclear. Here, we show an unexpected and transient CD61 expression, which is paired with CD103 at the synaptic microclusters of T cells. CD61 colocalization with the T cell antigen receptor further modulates downstream T cell antigen receptor signaling, improving antitumor cytotoxicity and promoting physiological control of tumor growth. Clinically, the presence of CD61+ tumor-infiltrating T lymphocytes is associated with improved clinical outcomes, mediated through enhanced effector functions and phenotype with limited evidence of cellular exhaustion. In conclusion, this study identified an unconventional and transient CD61 expression and pairing with CD103 on human immune cells, which potentiates a new target for immune-based cellular therapies.
Non-encapsulated, encapsulated, and lyophilized probiotic Limosilactobacillus reuteri SW23 influenced the growth and gut health in calves
Authors: Yadav Manish , Kumar Sachin , Parsana Yash , Chauhan Nutan , Tyagi Nitin , Mondal Goutam , Samanta Ashis Kumar 
Published: April 2024

AbstractThe present study was conducted to assess the impact of non-encapsulated, air-dried microencapsulated, and lyophilized microencapsulated probiotics in indigenous cattle calves (Bos indicus). Twenty-four (5–7 days old) indigenous cattle calves were selected and assigned into four groups, with six calves in each as follows: control (CON), fed milk and basal diet alone, and treatment groups supplemented with non-encapsulated (NEC), air-dried microencapsulated (AEC) and lyophilized microencapsulated (LEC) probiotic L. reuteri SW23 at 108 CFU/head/day in skim milk as a carrier provided for 60 days. The animals were divided into four groups, adopting a complete randomized design, and the effects were considered significant at p ≤ 0.05. Probiotics supplementation increased (p < 0.05) body weight gain (kg), average daily gain, and structural growth measurements in calves of all treatment groups. Dry matter intake (g/d), feed conversion efficiency, and fecal counts of Lactobacilli and Bifidobacteria were also increased in the treatment groups compared to CON. The fecal consistency index was highest in CON (0.70 ± 0.03), followed by NEC (0.68 ± 0.01), AEC (0.66 ± 0.02), and LEC (0.65 ± 0.02). Fecal pH and ammonia levels were reduced (p < 0.05) in the probiotic-fed groups compared to CON, with a concomitant increase in fecal lactate, acetate, and propionate levels. In addition, cell-mediated and humoral immunity were significantly increased in supplemented groups as compared to CON. Thus, it can be concluded that supplementation of the probiotics in microencapsulated/non-encapsulated forms to neonatal calves had a variety of positive effects on their health, including better performance, improved gut health, and a lower fecal consistency index. Moreover, among all supplemented groups, the lyophilized microencapsulated group outperformed air-dried microencapsulated and non-microencapsulated groups in terms of ADG, DMI, and gut health.
Effect of super absorbent hydrogel on hydro-physical properties of soil under deficit irrigation
Authors: Abdelghafar Rasha , Abdelfattah Ahmed , Mostafa Harby 
Published: April 2024

AbstractDue to water scarcity challenges, efficient management of irrigation water is becoming crucial. Water use efficiency (WUE) involves increasing crop productivity without increasing water consumption. This study was carried out to study the effect of hydrogel, deficit irrigation and soil type on WUE, soil hydro-physical properties and lettuce productivity. For this purpose, four irrigation treatments (100%, 85%, 70% and 60% of full irrigation requirements), four hydrogel concentrations (0, 0.1, 0.2 and 0.3% w/w) and three soil textural classes (clay, loamy sand, and sandy-clay soil) were conducted in pot experiment at open field during two consecutive seasons. The results revealed that crop growth parameters and soil hydro-physical properties were significantly affected by hydrogel application rates. Hydrogel addition significantly enhanced head fresh and dry weights, chlorophyll content, number of leaves and WUE. Application of hydrogel at 0.3% and 85% of irrigation requirements achieved the highest WUE without significant yield reductions. Changes in the studied hydro-physical properties of soil were more dependent on soil texture and hydrogel application rate than on the amount of irrigation water. The significant decrease in soil saturated hydraulic conductivity and bulk density confirms that super absorbent hydrogels could be recommended to improve soil water retention and enhance water use efficiency under deficit irrigation conditions.
Proteomic analysis of fipronil-induced molecular defects in spermatozoa
Authors: Bae Jeong-Won , Kwon Woo-Sung 
Published: April 2024

AbstractThe phenylpyrazole insecticide fipronil has wide-ranging applications from agriculture to public health to control undesirable organisms. However, several studies have reported the residual environmental hazards of fipronil and demonstrated its harmful effects even in mammalian reproduction. Therefore, this study was conducted to demonstrate the mode of action of fipronil on mouse spermatozoa. We treated fipronil to spermatozoa and performed comprehensive function evaluations. Moreover, proteomic analyses were conducted to identify the alteration of protein expression levels in spermatozoa. Most of sperm motility and kinematic parameters and intracellular ATP levels were diminished, and the spontaneous acrosome reaction was promoted after treatment with fipronil. Proteomic analyses revealed altered expression levels of 14 proteins after treatment. These proteins have been reported to be associated with sperm-specific pathways, prominently the cytoskeleton of the sperm, “9 + 2” axoneme composition, metabolism, and fertility. Collectively, our results showed that fipronil alters sperm functional-related proteins and therefore influences male fertility. This study elucidates the possible reproductive toxic hazards associated with male infertility through aberrant suppression of sperm proteins.