bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recent advances in extracellular vesicles for therapeutic cargo delivery
Authors: Kim Hyo In , Park Jinbong , Zhu Yin , Wang Xiaoyun , Han Yohan , Zhang Duo 
Published: April 2024

AbstractExosomes, which are nanosized vesicles secreted by cells, are attracting increasing interest in the field of biomedical research due to their unique properties, including biocompatibility, cargo loading capacity, and deep tissue penetration. They serve as natural signaling agents in intercellular communication, and their inherent ability to carry proteins, lipids, and nucleic acids endows them with remarkable therapeutic potential. Thus, exosomes can be exploited for diverse therapeutic applications, including chemotherapy, gene therapy, and photothermal therapy. Moreover, their capacity for homotypic targeting and self-recognition provides opportunities for personalized medicine. Despite their advantages as novel therapeutic agents, there are several challenges in optimizing cargo loading efficiency and structural stability and in defining exosome origins. Future research should include the development of large-scale, quality-controllable production methods, the refinement of drug loading strategies, and extensive in vivo studies and clinical trials. Despite the unresolved difficulties, the use of exosomes as efficient, stable, and safe therapeutic delivery systems is an interesting area in biomedical research. Therefore, this review describes exosomes and summarizes cutting-edge studies published in high-impact journals that have introduced novel or enhanced therapeutic effects using exosomes as a drug delivery system in the past 2 years. We provide an informative overview of the current state of exosome research, highlighting the unique properties and therapeutic applications of exosomes. We also emphasize challenges and future directions, underscoring the importance of addressing key issues in the field. With this review, we encourage researchers to further develop exosome-based drugs for clinical application, as such drugs may be among the most promising next-generation therapeutics.
Experimental capture of miRNA targetomes: disease-specific 3′UTR library-based miRNA targetomics for Parkinson’s disease
Authors: Hart Martin , Kern Fabian , Fecher-Trost Claudia , Krammes Lena , Aparicio Ernesto , Engel Annika , Hirsch Pascal , Wagner Viktoria , Keller Verena , Schmartz Georges Pierre , Rheinheimer Stefanie , Diener Caroline , Fischer Ulrike , Mayer Jens , Meyer Markus R. , Flockerzi Veit , Keller Andreas , Meese Eckart 
Published: April 2024

AbstractThe identification of targetomes remains a challenge given the pleiotropic effect of miRNAs, the limited effects of miRNAs on individual targets, and the sheer number of estimated miRNA–target gene interactions (MTIs), which is around 44,571,700. Currently, targetome identification for single miRNAs relies on computational evidence and functional studies covering smaller numbers of targets. To ensure that the targetome analysis could be experimentally verified by functional assays, we employed a systematic approach and explored the targetomes of four miRNAs (miR-129-5p, miR-129-1-3p, miR-133b, and miR-873-5p) by analyzing 410 predicted target genes, both of which were previously associated with Parkinson’s disease (PD). After performing 13,536 transfections, we validated 442 of the 705 putative MTIs (62,7%) through dual luciferase reporter assays. These analyses increased the number of validated MTIs by at least 2.1-fold for miR-133b and by a maximum of 24.3-fold for miR-873-5p. Our study contributes to the experimental capture of miRNA targetomes by addressing i) the ratio of experimentally verified MTIs to predicted MTIs, ii) the sizes of disease-related miRNA targetomes, and iii) the density of MTI networks. A web service to support the analyses on the MTI level is available online (https://ccb-web.cs.uni-saarland.de/utr-seremato), and all the data have been added to the miRATBase database (https://ccb-web.cs.uni-saarland.de/miratbase).
Transmembrane proteins with unknown function (TMEMs) as ion channels: electrophysiological properties, structure, and pathophysiological roles
Authors: Kang Hyunji , Lee C. Justin 
Published: April 2024

AbstractA transmembrane (TMEM) protein with an unknown function is a type of membrane-spanning protein expressed in the plasma membrane or the membranes of intracellular organelles. Recently, several TMEM proteins have been identified as functional ion channels. The structures and functions of these proteins have been extensively studied over the last two decades, starting with TMEM16A (ANO1). In this review, we provide a summary of the electrophysiological properties of known TMEM proteins that function as ion channels, such as TMEM175 (KEL), TMEM206 (PAC), TMEM38 (TRIC), TMEM87A (GolpHCat), TMEM120A (TACAN), TMEM63 (OSCA), TMEM150C (Tentonin3), and TMEM43 (Gapjinc). Additionally, we examine the unique structural features of these channels compared to those of other well-known ion channels. Furthermore, we discuss the diverse physiological roles of these proteins in lysosomal/endosomal/Golgi pH regulation, intracellular Ca2+ regulation, spatial memory, cell migration, adipocyte differentiation, and mechanical pain, as well as their pathophysiological roles in Parkinson’s disease, cancer, osteogenesis imperfecta, infantile hypomyelination, cardiomyopathy, and auditory neuropathy spectrum disorder. This review highlights the potential for the discovery of novel ion channels within the TMEM protein family and the development of new therapeutic targets for related channelopathies.
The pathogenic mechanism of syndactyly type V identified in a Hoxd13Q50R knock-in mice
Authors: Wang Han , Chen Xiumin , Meng Xiaolu , Cao Yixuan , Han Shirui , Liu Keqiang , Zhao Ximeng , Zhao Xiuli , Zhang Xue 
Published: April 2024

AbstractSyndactyly type V (SDTY5) is an autosomal dominant extremity malformation characterized by fusion of the fourth and fifth metacarpals. In the previous publication, we first identified a heterozygous missense mutation Q50R in homeobox domain (HD) of HOXD13 in a large Chinese family with SDTY5. In order to substantiate the pathogenicity of the variant and elucidate the underlying pathogenic mechanism causing limb malformation, transcription-activator-like effector nucleases (TALEN) was employed to generate a Hoxd13Q50R mutant mouse. The mutant mice exhibited obvious limb malformations including slight brachydactyly and partial syndactyly between digits 2–4 in the heterozygotes, and severe syndactyly, brachydactyly and polydactyly in homozygotes. Focusing on BMP2 and SHH/GREM1/AER-FGF epithelial mesenchymal (e-m) feedback, a crucial signal pathway for limb development, we found the ectopically expressed Shh, Grem1 and Fgf8 and down-regulated Bmp2 in the embryonic limb bud at E10.5 to E12.5. A transcriptome sequencing analysis was conducted on limb buds (LBs) at E11.5, revealing 31 genes that exhibited notable disparities in mRNA level between the Hoxd13Q50R homozygotes and the wild-type. These genes are known to be involved in various processes such as limb development, cell proliferation, migration, and apoptosis. Our findings indicate that the ectopic expression of Shh and Fgf8, in conjunction with the down-regulation of Bmp2, results in a failure of patterning along both the anterior-posterior and proximal-distal axes, as well as a decrease in interdigital programmed cell death (PCD). This cascade ultimately leads to the development of syndactyly and brachydactyly in heterozygous mice, and severe limb malformations in homozygous mice. These findings suggest that abnormal expression of SHH, FGF8, and BMP2 induced by HOXD13Q50R may be responsible for the manifestation of human SDTY5.
FOXP3 promote the progression of glioblastoma via inhibiting ferroptosis mediated by linc00857/miR-1290/GPX4 axis
Authors: Cao Wenpeng , He Ya , Lan Jinzhi , Luo Shipeng , Sun Baofei , Xiao Chaolun , Yu Wenfeng , Zeng Zhirui , Lei Shan 
Published: April 2024

AbstractThe oncogenic properties of members belonging to the forkhead box (FOX) family have been extensively documented in different types of cancers. In this study, our objective was to investigate the impact of FOXP3 on glioblastoma multiforme (GBM) cells. By conducting a screen using a small hairpin RNA (shRNA) library, we discovered a significant association between FOXP3 and ferroptosis in GBM cells. Furthermore, we observed elevated levels of FOXP3 in both GBM tissues and cell lines, which correlated with a poorer prognosis. FOXP3 was found to promote the proliferation of GBM cells by inhibiting cell ferroptosis in vitro and in vivo. Mechanistically, FOXP3 not only directly upregulated the transcription of GPX4, but also attenuated the degradation of GPX4 mRNA through the linc00857/miR-1290 axis, thereby suppressing ferroptosis and promoting proliferation. Additionally, the FOXP3 inhibitor epirubicin exhibited the ability to impede proliferation and induce ferroptosis in GBM cells both in vitro and in vivo. In summary, our study provided evidences that FOXP3 facilitates the progression of glioblastoma by inhibiting ferroptosis via the linc00857/miR-1290/GPX4 axis, highlighting FOXP3 as a potential therapeutic target for GBM.
A novel long non-coding RNA SLNCR1 promotes proliferation, migration, and invasion of melanoma via transcriptionally regulating SOX5
Authors: Cong Lele , Zhao Qing , Sun Hongyan , Zhou Zilong , Hu Yue , Li Chunyi , Hao Miao , Cong Xianling 
Published: April 2024

AbstractSteroid receptor RNA activator (SRA)-like non-coding RNA (SLNCR1) has been implicated in various tumorigenic processes, but the precise regulatory role in melanoma progression remains uncertain. We performed a comprehensive analysis to investigate the prognostic value of SLNCR1 expression in patients with melanoma by TCGA database and melanoma tissue samples via the Kaplan–Meier method. Subsequently, we conducted qRT-PCR and Fluorescence in Situ Hybridization (FISH) assays to identify SLNCR1 expression levels and localization in tissues and cells, respectively. Loss-of-function assays utilizing shRNAs vectors were used to investigate the potential impact of SLNCR1. Our data showed that SLNCR1 is significantly up-regulated in human malignant melanoma tissues and cell lines and functions as an oncogene. Silencing of SLNCR1 suppressed melanoma cell proliferation, migration, invasion, and inhibited tumorigenesis in a mouse xenograft model. Additionally, we employed bioinformatic predictive analysis, combined with dual-luciferase reporter analysis and functional rescue assays, to elucidate the mechanistic target of the SLNCR1/SOX5 axis in melanoma. Mechanistically, we discovered that SLNCR1 promotes EMT of human melanoma by targeting SOX5, as downregulation of SLNCR1 expression leads to a decrease in SOX5 protein levels and inhibits melanoma tumorigenesis. Our research offers promising insights for more precise diagnosis and treatment of human melanoma.
p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response
Authors: Serra François , Nieto-Aliseda Andrea , Fanlo-Escudero Lucía , Rovirosa Llorenç , Cabrera-Pasadas Mónica , Lazarenkov Aleksey , Urmeneta Blanca , Alcalde-Merino Alvaro , Nola Emanuele M. , Okorokov Andrei L. , Fraser Peter , Graupera Mariona , Castillo Sandra D. , Sardina Jose L. , Valencia Alfonso , Javierre Biola M. 
Published: April 2024

AbstractActivation of the p53 tumor suppressor triggers a transcriptional program to control cellular response to stress. However, the molecular mechanisms by which p53 controls gene transcription are not completely understood. Here, we uncover the critical role of spatio-temporal genome architecture in this process. We demonstrate that p53 drives direct and indirect changes in genome compartments, topologically associating domains, and DNA loops prior to one hour of its activation, which escort the p53 transcriptional program. Focusing on p53-bound enhancers, we report 340 genes directly regulated by p53 over a median distance of 116 kb, with 74% of these genes not previously identified. Finally, we showcase that p53 controls transcription of distal genes through newly formed and pre-existing enhancer-promoter loops in a cohesin dependent manner. Collectively, our findings demonstrate a previously unappreciated architectural role of p53 as regulator at distinct topological layers and provide a reliable set of new p53 direct target genes that may help designs of cancer therapies.
The PTM profiling of CTCF reveals the regulation of 3D chromatin structure by O-GlcNAcylation
Authors: Tang Xiuxiao , Zeng Pengguihang , Liu Kezhi , Qing Li , Sun Yifei , Liu Xinyi , Lu Lizi , Wei Chao , Wang Jia , Jiang Shaoshuai , Sun Jun , Chang Wakam , Yu Haopeng , Chen Hebing , Zhou Jiaguo , Xu Chengfang , Fan Lili , Miao Yi-Liang , Ding Junjun 
Published: April 2024

AbstractCCCTC-binding factor (CTCF), a ubiquitously expressed and highly conserved protein, is known to play a critical role in chromatin structure. Post-translational modifications (PTMs) diversify the functions of protein to regulate numerous cellular processes. However, the effects of PTMs on the genome-wide binding of CTCF and the organization of three-dimensional (3D) chromatin structure have not been fully understood. In this study, we uncovered the PTM profiling of CTCF and demonstrated that CTCF can be O-GlcNAcylated and arginine methylated. Functionally, we demonstrated that O-GlcNAcylation inhibits CTCF binding to chromatin. Meanwhile, deficiency of CTCF O-GlcNAcylation results in the disruption of loop domains and the alteration of chromatin loops associated with cellular development. Furthermore, the deficiency of CTCF O-GlcNAcylation increases the expression of developmental genes and negatively regulates maintenance and establishment of stem cell pluripotency. In conclusion, these results provide key insights into the role of PTMs for the 3D chromatin structure.
Comparison studies identify mesenchymal stromal cells with potent regenerative activity in osteoarthritis treatment
Authors: Chu Hongshang , Zhang Shaoyang , Zhang Zhenlin , Yue Hua , Liu Huijuan , Li Baojie , Yin Feng 
Published: April 2024

AbstractOsteoarthritis affects 15% of people over 65 years of age. It is characterized by articular cartilage degradation and inflammation, leading to joint pain and disability. Osteoarthritis is incurable and the patients may eventually need joint replacement. An emerging treatment is mesenchymal stromal cells (MSCs), with over two hundred clinical trials being registered. However, the outcomes of these trials have fallen short of the expectation, due to heterogeneity of MSCs and uncertain mechanisms of action. It is generally believed that MSCs exert their function mainly by secreting immunomodulatory and trophic factors. Here we used knee osteoarthritis mouse model to assess the therapeutic effects of MSCs isolated from the white adipose or dermal adipose tissue of Prrx1-Cre; R26tdTomato mice and Dermo1-Cre; R26tdTomato mice. We found that the Prrx1-lineage MSCs from the white adipose tissues showed the greatest in vitro differentiation potentials among the four MSC groups and single cell profiling showed that the Prrx1-lineage MSCs contained more stem cells than the Dermo1 counterpart. Only the Prrx1-lineage cells isolated from white adipose tissues showed long-term therapeutic effectiveness on early-stage osteoarthritis models. Mechanistically, Prrx1-lineage MSCs differentiated into Col2+ chondrocytes and replaced the damage cartilage, activated Col1 expressing in resident chondrocytes, and inhibited synovial inflammation. Transcriptome analysis showed that the articular chondrocytes derived from injected MSCs expressed immunomodulatory cytokines, trophic factors, and chondrocyte-specific genes. Our study identified a MSC population genetically marked by Prrx1 that has great multipotentiality and can differentiate into chondrocytes to replace the damaged cartilage.
Tailored alumina nanocomposite membranes featuring MIL-125-NH2 metal-organic frameworks for oily wastewater treatment
Authors: Baig Umair , Waheed Abdul , Yogarathinam Lukka Thuyavan , Aljundi Isam H. 
Published: April 2024

AbstractCeramic membranes offer significant potential for addressing challenging and harsh wastewater streams such as produced water (PW) and surfactant-stabilized oil/water (O/W) emulsions. This study focuses on developing a stable and a uniformly structured active layer solely composed of MIL-125-NH2 MOF on a ceramic Alumina support. A stable covalent bonding approach was employed using interfacial polymerization, with isophthaloyl chloride (IPC) acting as the organic crosslinker during interfacial polymerization reaction. Three distinct MIL-125-NH2 decorated membranes M50, M75, and M100 were prepared by using varying MOF concentrations. Surface wettability analysis of the membranes indicated that the MIL-125-NH2 MOF active layer displayed super-hydrophilic characteristics in the air (water contact angle = 0°) and super-oleophobic characteristics underwater (oil contact angle = 161.5°). In oil separation experiments, all the MIL-125-NH2 deposited membranes displayed >99% oil rejection. Among the fabricated membranes, M50 demonstrated the highest water flux of 2100 Lm−2 h−1 under a transmembrane pressure of 2 bar. The MIL-125-NH2 MOF deposited membranes also showed stable performance under longer-run filtration. This study would be a simple and effective method of decorating MOFs as an active layer on ceramic support for efficient O/W emulsion separation and desalination applications.
Glucose controls lipolysis through Golgi PtdIns4P-mediated regulation of ATGL
Authors: Ding Lianggong , Huwyler Florian , Long Fen , Yang Wu , Binz Jonas , Wernlé Kendra , Pfister Matthias , Klug Manuel , Balaz Miroslav , Ukropcova Barbara , Ukropec Jozef , Wu Chunyan , Wang Tongtong , Gao Min , Clavien Pierre-Alain , Dutkowski Philipp , Tibbitt Mark W. , Wolfrum Christian 
Published: April 2024

AbstractMetabolic crosstalk of the major nutrients glucose, amino acids and fatty acids (FAs) ensures systemic metabolic homeostasis. The coordination between the supply of glucose and FAs to meet various physiological demands is especially important as improper nutrient levels lead to metabolic disorders, such as diabetes and metabolic dysfunction-associated steatohepatitis (MASH). In response to the oscillations in blood glucose levels, lipolysis is thought to be mainly regulated hormonally to control FA liberation from lipid droplets by insulin, catecholamine and glucagon. However, whether general cell-intrinsic mechanisms exist to directly modulate lipolysis via glucose sensing remains largely unknown. Here we report the identification of such an intrinsic mechanism, which involves Golgi PtdIns4P-mediated regulation of adipose triglyceride lipase (ATGL)-driven lipolysis via intracellular glucose sensing. Mechanistically, depletion of intracellular glucose results in lower Golgi PtdIns4P levels, and thus reduced assembly of the E3 ligase complex CUL7FBXW8 in the Golgi apparatus. Decreased levels of the E3 ligase complex lead to reduced polyubiquitylation of ATGL in the Golgi and enhancement of ATGL-driven lipolysis. This cell-intrinsic mechanism regulates both the pool of intracellular FAs and their extracellular release to meet physiological demands during fasting and glucose deprivation. Moreover, genetic and pharmacological manipulation of the Golgi PtdIns4P–CUL7FBXW8–ATGL axis in mouse models of simple hepatic steatosis and MASH, as well as during ex vivo perfusion of a human steatotic liver graft leads to the amelioration of steatosis, suggesting that this pathway might be a promising target for metabolic dysfunction-associated steatotic liver disease and possibly MASH.
Weak anvil cloud area feedback suggested by physical and observational constraints
Authors: McKim Brett , Bony Sandrine , Dufresne Jean-Louis 
Published: April 2024

AbstractChanges in anvil clouds with warming remain a leading source of uncertainty in estimating Earth’s climate sensitivity. Here we develop a feedback analysis that decomposes changes in anvil clouds and creates testable hypotheses for refining their proposed uncertainty ranges with observations and theory. To carry out this storyline approach, we derive a simple but quantitative expression for the anvil area feedback, which is shown to depend on the present-day measurable cloud radiative effects and the fractional change in anvil area with warming. Satellite observations suggest an anvil cloud radiative effect of about ±1 W m−2, which requires the fractional change in anvil area to be about 50% K−1 in magnitude to produce a feedback equal to the current best estimate of its lower bound. We use quantitative theory and observations to show that the change in anvil area is closer to about −4% K−1. This constrains the area feedback and leads to our revised estimate of 0.02 ± 0.07 W m−2 K−1, which is many times weaker and more constrained than the overall anvil cloud feedback. In comparison, we show the anvil cloud albedo feedback to be much less constrained, both theoretically and observationally, which poses an obstacle for bounding Earth’s climate sensitivity.
Enhanced gorilla troops optimizer powered by marine predator algorithm: global optimization and engineering design
Authors: Hassan Mohamed H. , Kamel Salah , Mohamed Ali Wagdy 
Published: April 2024

AbstractThis study presents an advanced metaheuristic approach termed the Enhanced Gorilla Troops Optimizer (EGTO), which builds upon the Marine Predators Algorithm (MPA) to enhance the search capabilities of the Gorilla Troops Optimizer (GTO). Like numerous other metaheuristic algorithms, the GTO encounters difficulties in preserving convergence accuracy and stability, notably when tackling intricate and adaptable optimization problems, especially when compared to more advanced optimization techniques. Addressing these challenges and aiming for improved performance, this paper proposes the EGTO, integrating high and low-velocity ratios inspired by the MPA. The EGTO technique effectively balances exploration and exploitation phases, achieving impressive results by utilizing fewer parameters and operations. Evaluation on a diverse array of benchmark functions, comprising 23 established functions and ten complex ones from the CEC2019 benchmark, highlights its performance. Comparative analysis against established optimization techniques reveals EGTO's superiority, consistently outperforming its counterparts such as tuna swarm optimization, grey wolf optimizer, gradient based optimizer, artificial rabbits optimization algorithm, pelican optimization algorithm, Runge Kutta optimization algorithm (RUN), and original GTO algorithms across various test functions. Furthermore, EGTO's efficacy extends to addressing seven challenging engineering design problems, encompassing three-bar truss design, compression spring design, pressure vessel design, cantilever beam design, welded beam design, speed reducer design, and gear train design. The results showcase EGTO's robust convergence rate, its adeptness in locating local/global optima, and its supremacy over alternative methodologies explored.