bluuebunny/crossref_metadata_2025_split huggingface dataset:
TRAF6-mediated ubiquitination of AKT in the nucleus is a critical event underlying the desensitization of G protein-coupled receptors
Authors: Wu Chengyan , Hu Li , Liu Bing , Zeng Xingyue , Ma Haixiang , Cao Yongkai , Li Huijun , Zhang Xiaohan 
Published: April 2024

Abstract
Background
Desensitization of G protein–coupled receptors (GPCRs) refers to the attenuation of receptor responsiveness by prolonged or intermittent exposure to agonists. The binding of β-arrestin to the cytoplasmic cavity of the phosphorylated receptor, which competes with the G protein, has been widely accepted as an extensive model for explaining GPCRs desensitization. However, studies on various GPCRs, including dopamine D2-like receptors (D2R, D3R, D4R), have suggested the existence of other desensitization mechanisms. The present study employed D2R/D3R variants with different desensitization properties and utilized loss-of-function approaches to uncover the mechanisms underlying GPCRs homologous desensitization, focusing on the signaling cascade that regulates the ubiquitination of AKT.

Results
AKT undergoes K8/14 ubiquitination by TRAF6, which occurs in the nucleus and promotes its membrane recruitment, phosphorylation and activation under receptor desensitization conditions. The nuclear entry of TRAF6 relies on the presence of the importin complex. Src regulates the nuclear entry of TRAF6 by mediating the interaction between TRAF6 and importin β1. Ubiquitinated AKT translocates to the plasma membrane where it associates with Mdm2 to phosphorylate it at the S166 and S186 residues. Thereafter, phosphorylated Mdm2 is recruited to the nucleus, resulting in the deubiquitination of β-Arr2. The deubiquitinated β-Arr2 then forms a complex with Gβγ, which serves as a biomarker for GPCRs desensitization. Like in D3R, ubiquitination of AKT is also involved in the desensitization of β2 adrenoceptors.

Conclusion
Our study proposed that the property of a receptor that causes a change in the subcellular localization of TRAF6 from the cytoplasm to the nucleus to mediate AKT ubiquitination could initiate the desensitization of GPCRs.
EP300-ZNF384 transactivates IL3RA to promote the progression of B-cell acute lymphoblastic leukemia
Authors: Hou Zhijie , Ren Yifei , Zhang Xuehong , Huang Dan , Yan Fanzhi , Sun Wentao , Zhang Wenjuan , Zhang Qingqing , Fu Xihui , Lang Zhenghui , Chu Chenyang , Zou Boyang , Gao Beibei , Jin Bilian , Kang Zhijie , Liu Quentin , Yan Jinsong 
Published: April 2024

AbstractThe EP300-ZNF384 fusion gene is an oncogenic driver in B-cell acute lymphoblastic leukemia (B-ALL). In the present study, we demonstrated that EP300-ZNF384 substantially induces the transcription of IL3RA and the expression of IL3Rα (CD123) on B-ALL cell membranes. Interleukin 3 (IL-3) supplementation promotes the proliferation of EP300-ZNF348-positive B-ALL cells by activating STAT5. Conditional knockdown of IL3RA in EP300-ZF384-positive cells inhibited the proliferation in vitro, and induced a significant increase in overall survival of mice, which is attributed to impaired propagation ability of leukemia cells. Mechanistically, the EP300-ZNF384 fusion protein transactivates the promoter activity of IL3RA by binding to an A-rich sequence localized at -222/-234 of IL3RA. Furthermore, forced EP300-ZNF384 expression induces the expression of IL3Rα on cell membranes and the secretion of IL-3 in CD19-positive B precursor cells derived from healthy individuals. Doxorubicin displayed a selective killing of EP300-ZNF384-positive B-ALL cells in vitro and in vivo. Collectively, we identify IL3RA as a direct downstream target of EP300-ZNF384, suggesting CD123 is a potent biomarker for EP300-ZNF384-driven B-ALL. Targeting CD123 may be a novel therapeutic approach to EP300-ZNF384-positive patients, alternative or, more likely, complementary to standard chemotherapy regimen in clinical setting.
Inefficient antiviral response in reconstituted small-airway epithelium from chronic obstructive pulmonary disease patients following human parainfluenza virus type 3 infection
Authors: Bondeelle Louise , Salmona Maud , Houdouin Véronique , Diaz Elise , Dutrieux Jacques , Mercier-Delarue Séverine , Constant Samuel , Huang Song , Bergeron Anne , LeGoff Jérôme 
Published: April 2024

AbstractChronic obstructive pulmonary disease (COPD) affects over 250 million individuals globally and stands as the third leading cause of mortality. Respiratory viral infections serve as the primary drivers of acute exacerbations, hastening the decline in lung function and worsening the prognosis. Notably, Human Parainfluenza Virus type 3 (HPIV-3) is responsible for COPD exacerbations with a frequency comparable to that of Respiratory Syncytial Virus and Influenza viruses. However, the impact of HPIV-3 on respiratory epithelium within the context of COPD remains uncharacterized.In this study, we employed in vitro reconstitution of lower airway epithelia from lung tissues sourced from healthy donors (n = 4) and COPD patients (n = 5), maintained under air–liquid interface conditions. Through a next-generation sequencing-based transcriptome analysis, we compared the cellular response to HPIV-3 infection.Prior to infection, COPD respiratory epithelia exhibited a pro-inflammatory profile, notably enriched in canonical pathways linked to antiviral response, B cell signaling, IL-17 signaling, and epithelial-mesenchymal transition, in contrast to non-COPD epithelia. Intriguingly, post HPIV-3 infection, only non-COPD epithelia exhibited significant enrichment in interferon signaling, pattern recognition receptors of viruses and bacteria, and other pathways involved in antiviral responses. This deficiency could potentially hinder immune cell recruitment essential for controlling viral infections, thus fostering prolonged viral presence and persistent inflammation.
[1-11C]-Butanol Positron Emission Tomography reveals an impaired brain to nasal turbinates pathway in aging amyloid positive subjects
Authors: Mehta Neel H. , Wang Xiuyuan , Keil Samantha A. , Xi Ke , Zhou Liangdong , Lee Kevin , Tan Wanbin , Spector Edward , Goldan Amirhossein , Kelly James , Karakatsanis Nicolas A. , Mozley P. David , Nehmeh Sadek , Chazen J. Levi , Morin Simon , Babich John , Ivanidze Jana , Pahlajani Silky , Tanzi Emily B. , Saint-Louis Leslie , Butler Tracy , Chen Kewei , Rusinek Henry , Carare Roxana O. , Li Yi , Chiang Gloria C. , de Leon Mony J. 
Published: April 2024

Abstract
Background
Reduced clearance of cerebrospinal fluid (CSF) has been suggested as a pathological feature of Alzheimer’s disease (AD). With extensive documentation in non-human mammals and contradictory human neuroimaging data it remains unknown whether the nasal mucosa is a CSF drainage site in humans. Here, we used dynamic PET with [1-11C]-Butanol, a highly permeable radiotracer with no appreciable brain binding, to test the hypothesis that tracer drainage from the nasal pathway reflects CSF drainage from brain. As a test of the hypothesis, we examined whether brain and nasal fluid drainage times were correlated and affected by brain amyloid.

Methods
24 cognitively normal subjects (≥ 65 years) were dynamically PET imaged for 60 min. using [1-11C]-Butanol. Imaging with either [11C]-PiB or [18F]-FBB identified 8 amyloid PET positive (Aβ+) and 16 Aβ- subjects. MRI-determined regions of interest (ROI) included: the carotid artery, the lateral orbitofrontal (LOF) brain, the cribriform plate, and an All-turbinate region comprised of the superior, middle, and inferior turbinates. The bilateral temporalis muscle and jugular veins served as control regions. Regional time-activity were used to model tracer influx, egress, and AUC.

Results
LOF and All-turbinate 60 min AUC were positively associated, thus suggesting a connection between the brain and the nose. Further, the Aβ+ subgroup demonstrated impaired tracer kinetics, marked by reduced tracer influx and slower egress.

Conclusion
The data show that tracer kinetics for brain and nasal turbinates are related to each other and both reflect the amyloid status of the brain. As such, these data add to evidence that the nasal pathway is a potential CSF drainage site in humans. These data warrant further investigation of brain and nasal contributions to protein clearance in neurodegenerative disease.
Clinical efficacy of intraoral ultrasonography versus transgingival probing for measurement of gingival thickness in different gingival biotypes: a clinical trial
Authors: Alizad-Rahvar Maryam , Safi Yaser , Kadkhodazadeh Mahdi , Ghomashi Mohammad Parham 
Published: April 2024

Abstract
Background
Transgingival probing is conventionally used for gingival thickness (GT) measurement. However, invasiveness is a major drawback of transgingival probing. Thus, researchers have been in search of alternative methods for measurement of GT. This study compared the clinical efficacy of intraoral ultrasonography and transgingival probing for measurement of GT in different biotypes.

Materials and methods
This clinical trial was conducted on 34 patients requiring crown lengthening surgery. GT was measured at 40 points with 2- and 4-mm distances from the free gingival margin (FGM) of anterior and premolar teeth of both jaws in each patient by an intraoral ultrasound probe. For measurement of GT by the transgingival probing method, infiltration anesthesia was induced, and a #25 finger spreader (25 mm) was vertically inserted into the soft tissue until contacting bone. The inserted length was measured by a digital caliper with 0.01 mm accuracy. All measurements were made by an operator with high reliability under the supervision of a radiologist. Data were analyzed by t-test, Power and Effect Size formula, and intraclass correlation coefficient (ICC).

Results
The two methods were significantly different in measurement of GT in both thick and thin biotypes at 2- and 4-mm distances (P < 0.001). The two methods had a significant difference in both the mandible (P < 0.001) and maxilla (P < 0.001) and in both the anterior (P < 0.003) and premolar (P < 0.003) regions. Although the difference was statistically significant in t-tests, the power and effect formula proved it to be clinically insignificant. Also, the ICC of the two methods revealed excellent agreement.

Conclusion
The results showed optimal agreement of ultrasound and transgingival probing for measurement of GT.

Trial registration
The study was approved by the ethics committee of Shahid Beheshti University of Medical Sciences on 2021-12-28 (IR.SBMU.DRC.REC.1400.138) and registered in the Iranian Registry of Clinical Trials on 2022-03-14 (IRCT20211229053566N1).
Synaptopodin is required for long-term depression at Schaffer collateral-CA1 synapses
Authors: Inglebert Yanis , Wu Pei You , Tourbina-Kolomiets Julia , Dang Cong Loc , McKinney R. Anne 
Published: April 2024

AbstractSynaptopodin (SP), an actin-associated protein found in telencephalic neurons, affects activity-dependant synaptic plasticity and dynamic changes of dendritic spines. While being required for long-term depression (LTD) mediated by metabotropic glutamate receptor (mGluR-LTD), little is known about its role in other forms of LTD induced by low frequency stimulation (LFS-LTD) or spike-timing dependent plasticity (STDP). Using electrophysiology in ex vivo hippocampal slices from SP-deficient mice (SPKO), we show that absence of SP is associated with a deficit of LTD at Sc-CA1 synapses induced by LFS-LTD and STDP. As LTD is known to require AMPA- receptors internalization and IP3-receptors calcium signaling, we tested by western blotting and immunochemistry if there were changes in their expression which we found to be reduced. While we were not able to induce LTD, long-term potentiation (LTP), albeit diminished in SPKO, can be recovered by using a stronger stimulation protocol. In SPKO we found no differences in NMDAR, which are the primary site of calcium signalling to induce LTP. Our study shows, for the first time, the key role of the requirement of SP to allow induction of activity-dependant LTD at Sc-CA1 synapses.
Nanoparticles in tumor microenvironment remodeling and cancer immunotherapy
Authors: Lu Qiang , Kou Dongquan , Lou Shenghan , Ashrafizadeh Milad , Aref Amir Reza , Canadas Israel , Tian Yu , Niu Xiaojia , Wang Yuzhuo , Torabian Pedram , Wang Lingzhi , Sethi Gautam , Tergaonkar Vinay , Tay Franklin , Yuan Zhennan , Han Peng 
Published: April 2024

AbstractCancer immunotherapy and vaccine development have significantly improved the fight against cancers. Despite these advancements, challenges remain, particularly in the clinical delivery of immunomodulatory compounds. The tumor microenvironment (TME), comprising macrophages, fibroblasts, and immune cells, plays a crucial role in immune response modulation. Nanoparticles, engineered to reshape the TME, have shown promising results in enhancing immunotherapy by facilitating targeted delivery and immune modulation. These nanoparticles can suppress fibroblast activation, promote M1 macrophage polarization, aid dendritic cell maturation, and encourage T cell infiltration. Biomimetic nanoparticles further enhance immunotherapy by increasing the internalization of immunomodulatory agents in immune cells such as dendritic cells. Moreover, exosomes, whether naturally secreted by cells in the body or bioengineered, have been explored to regulate the TME and immune-related cells to affect cancer immunotherapy. Stimuli-responsive nanocarriers, activated by pH, redox, and light conditions, exhibit the potential to accelerate immunotherapy. The co-application of nanoparticles with immune checkpoint inhibitors is an emerging strategy to boost anti-tumor immunity. With their ability to induce long-term immunity, nanoarchitectures are promising structures in vaccine development. This review underscores the critical role of nanoparticles in overcoming current challenges and driving the advancement of cancer immunotherapy and TME modification.
LncRNA SNHG12 promotes cell proliferation and inhibits apoptosis of granulosa cells in polycystic ovarian syndrome by sponging miR-129 and miR-125b
Authors: Xuan Feilan , Jin Ruiying , Zhou Weimei , Ye Yongju , Ren Yuefang , Lu Jiali , Chen Aixue 
Published: April 2024

Abstract
Background
Polycystic ovarian syndrome (PCOS) is the most common endocrine disease in women of childbearing age which is often associated with abnormal proliferation or apoptosis of granulosa cells (GCs). Studies proved that long non-coding RNA SNHG12 (lncRNA SNHG12) is significantly increased in ovarian cancer and cervical cancer patients and cells. The inhibition of lncRNA SNHG12 restrains the proliferation, migration, and invasion in tumor cells.

Objective
This study explores the role of lncRNA SNHG12 in the apoptosis of GCs in PCOS and the underlying regulated mechanism.

Methods
In this study, the injection of dehydroepiandrosterone (DHEA) successfully induced the PCOS model in SD rats. The human granulosa-like tumor cell line KGN was incubated with insulin to assess the effects of lncRNA SNHG12 on GC proliferation and apoptosis.

Results
Overexpression of lncRNA SNHG12 influenced the body weight, ovary weight, gonadal hormone, and pathological changes, restrained the expressions of microRNA (miR)-129 and miR-125b, while downregulation of lncRNA SNHG12 exerted the opposite effects in PCOS rats. After silencing lncRNA SNHG12 in cells, the cell viability and proliferation were lessened whereas apoptosis of cells was increased. A loss-of-functions test was implemented by co-transfecting miR-129 and miR-125b inhibitors into lncRNA SNHG12-knocking down cells to analyze the effects on cell viability and apoptosis. Next, the existence of binding sites of SNHG12 and miR-129/miR-125b was proved based on the pull-down assay.

Conclusion
lncRNA SNHG12 might be a potential regulatory factor for the development of PCOS by sponging miR-129 and miR-125b in GCs.
Non-technical skills needed by medical disaster responders– a scoping review
Authors: Westman Anja , Kurland Lisa , Hugelius Karin 
Published: April 2024

Background
There is no universal agreement on what competence in disaster medicine is, nor what competences and personal attributes add value for disaster responders. Some studies suggest that disaster responders need not only technical skills but also non-technical skills. Consensus of which non-technical skills are needed and how training for these can be provided is lacking, and little is known about how to apply knowledge of non-technical skills in the recruitment of disaster responders. Therefore, this scoping review aimed to identify the non-technical skills required for the disaster medicine response.

Method
A scooping review using the Arksey & O´Malley framework was performed. Structured searches in the databases PuBMed, CINAHL Full Plus, Web of Science, PsycInfo and Scopus was conducted. Thereafter, data were structured and analyzed.

Results
From an initial search result of 6447 articles, 34 articles were included in the study. These covered both quantitative and qualitative studies and different contexts, including real events and training. The most often studied real event were responses following earthquakes. Four non-technical skills stood out as most frequently mentioned: communication skills; situational awareness; knowledge of human resources and organization and coordination skills; decision-making, critical-thinking and problem-solving skills. The review also showed a significant lack of uniform use of terms like skills or competence in the reviewed articles.

Conclusion
Non-technical skills are skills that disaster responders need. Which non-technical skills are most needed, how to train and measure non-technical skills, and how to implement non-technical skills in disaster medicine need further studies.
Regulatory mechanisms of autophagy on DHA and carotenoid accumulation in Crypthecodinium sp. SUN
Authors: Li Yiming , Zhao Tiantian , Gao Weizheng , Miao Bowen , Fu Zhongxiang , Zhang Zhao , Li Qingyang , Sun Dongzhe 
Published: April 2024

Abstract
Background
Autophagy is a crucial process of cellular self-destruction and component reutilization that can affect the accumulation of total fatty acids (TFAs) and carotenoids in microalgae. The regulatory effects of autophagy process in a docosahexaenoic acid (DHA) and carotenoids simultaneously producing microalga, Crypthecodinium sp. SUN, has not been studied. Thus, the autophagy inhibitor (3-methyladenine (MA)) and activator (rapamycin) were used to regulate autophagy in Crypthecodinium sp. SUN.

Results
The inhibition of autophagy by 3-MA was verified by transmission electron microscopy, with fewer autophagy vacuoles observed. Besides, 3-MA reduced the glucose absorption and intracellular acetyl-CoA level, which resulting in the decrease of TFA and DHA levels by 15.83 and 26.73% respectively; Surprisingly, 3-MA increased intracellular reactive oxygen species level but decreased the carotenoids level. Comparative transcriptome analysis showed that the downregulation of the glycolysis, pentose phosphate pathway and tricarboxylic acid cycle may underlie the decrease of acetyl-CoA, NADPH and ATP supply for fatty acid biosynthesis; the downregulation of PSY and HMGCR may underlie the decreased carotenoids level. In addition, the class I PI3K-AKT signaling pathway may be crucial for the regulation of carbon and energy metabolism. At last, rapamycin was used to activate autophagy, which significantly enhanced the cell growth and TFA level and eventually resulted in 1.70-fold increase in DHA content.

Conclusions
Our findings indicate the mechanisms of autophagy in Crypthecodinium sp. SUN and highlight a way to manipulate cell metabolism by regulating autophagy. Overall, this study provides valuable insights to guide further research on autophagy-regulated TFA and carotenoids accumulation in Crypthecodinium sp. SUN.
Biosynthesis of fragrance 2-phenylethanol from sugars by Pseudomonas putida
Authors: Godoy Patricia , Udaondo Zulema , Duque Estrella , Ramos Juan L. 
Published: April 2024

Abstract
Background
Petrochemicals contribute to environmental issues, with concerns ranging from energy consumption and carbon emission to pollution. In contrast, microbial biorefineries offer eco-friendly alternatives. The solvent-tolerant Pseudomonasputida DOT-T1E serves as a suitable host for producing aromatic compounds, specifically l-phenylalanine and its derivative, 2-phenylethanol (2-PE), which find widespread applications in various industries.

Results
This study focuses on enhancing 2-PE production in two l-phenylalanine overproducing strains of DOT-T1E, namely CM12-5 and CM12-5Δgcd (xylABE), which grow with glucose and glucose-xylose, respectively. To synthesize 2-PE from l-phenylalanine, these strains were transformed with plasmid pPE-1, bearing the Ehrlich pathway genes, and it was found higher 2-PE production with glucose (about 50–60 ppm) than with xylose (< 3 ppm). To understand the limiting factors, we tested the addition of phenylalanine and intermediates from the Ehrlich and shikimate pathways. The results identified intracellular l-phenylalanine as a key limiting factor for 2-PE production. To overcame this limitation, a chorismate mutase/prephenate dehydratase variant—insentive to feedback inhibition by aromatic amino acids—was introduced in the producing strains. This led to increased l-phenylalanine production and subsequently produced more 2-PE (100 ppm). Random mutagenesis of the strains also produced strains with higher l-phenylalanine titers and increased 2-PE production (up to 120 ppm). The improvements resulted from preventing dead-end product accumulation from shikimate and limiting the catabolism of potential pathway intermediates in the Ehrlich pathway. The study explored agricultural waste substrates, such as corn stover, sugarcane straw and corn-syrup as potential C sources. The best results were obtained using 2G substrates at 3% (between 82 and 100 ppm 2-PE), with glucose being the preferred sugar for 2-PE production among the monomeric sugars in these substrates.

Conclusions
The findings of this study offer strategies to enhance phenylalanine production, a key substrate for the synthesis of aromatic compounds. The ability of P.putida DOT-T1E to thrive with various C-sources and its tolerance to substrates, products, and potential toxicants in industrial wastes, are highlighted. The study identified and overcome possible bottlenecks for 2-PE production. Ultimately, the strains have potential to become efficient microbial platforms for synthesizing 2-PE from agro-industrial waste materials.