bluuebunny/crossref_metadata_2025_split huggingface dataset:
The NERP-4–SNAT2 axis regulates pancreatic β-cell maintenance and function
Authors: Zhang Weidong , Miura Ayako , Abu Saleh Md Moin , Shimizu Koichiro , Mita Yuichiro , Tanida Ryota , Hirako Satoshi , Shioda Seiji , Gmyr Valery , Kerr-Conte Julie , Pattou Francois , Jin Chunhuan , Kanai Yoshikatsu , Sasaki Kazuki , Minamino Naoto , Sakoda Hideyuki , Nakazato Masamitsu 
Published: December 2023

AbstractInsulin secretion from pancreatic β cells is regulated by multiple stimuli, including nutrients, hormones, neuronal inputs, and local signalling. Amino acids modulate insulin secretion via amino acid transporters expressed on β cells. The granin protein VGF has dual roles in β cells: regulating secretory granule formation and functioning as a multiple peptide precursor. A VGF-derived peptide, neuroendocrine regulatory peptide-4 (NERP-4), increases Ca2+ influx in the pancreata of transgenic mice expressing apoaequorin, a Ca2+-induced bioluminescent protein complex. NERP-4 enhances glucose-stimulated insulin secretion from isolated human and mouse islets and β-cell–derived MIN6-K8 cells. NERP-4 administration reverses the impairment of β-cell maintenance and function in db/db mice by enhancing mitochondrial function and reducing metabolic stress. NERP-4 acts on sodium-coupled neutral amino acid transporter 2 (SNAT2), thereby increasing glutamine, alanine, and proline uptake into β cells and stimulating insulin secretion. SNAT2 deletion and inhibition abolish the protective effects of NERP-4 on β-cell maintenance. These findings demonstrate a novel autocrine mechanism of β-cell maintenance and function that is mediated by the peptide–amino acid transporter axis.
Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustion
Authors: Gu Xuemei , Wei Haoran , Suo Caixia , Shen Shengqi , Zhu Chuxu , Chen Liang , Yan Kai , Li Zhikun , Bian Zhenhua , Zhang Pinggen , Yuan Mengqiu , Yu Yingxuan , Du Jinzhi , Zhang Huafeng , Sun Linchong , Gao Ping 
Published: December 2023

AbstractItaconate is a well-known immunomodulatory metabolite; however, its role in hepatocellular carcinoma (HCC) remains unclear. Here, we find that macrophage-derived itaconate promotes HCC by epigenetic induction of Eomesodermin (EOMES)-mediated CD8+ T-cell exhaustion. Our results show that the knockout of immune-responsive gene 1 (IRG1), responsible for itaconate production, suppresses HCC progression. Irg1 knockout leads to a decreased proportion of PD-1+ and TIM-3+ CD8+ T cells. Deletion or adoptive transfer of CD8+ T cells shows that IRG1-promoted tumorigenesis depends on CD8+ T-cell exhaustion. Mechanistically, itaconate upregulates PD-1 and TIM-3 expression levels by promoting succinate-dependent H3K4me3 of the Eomes promoter. Finally, ibuprofen is found to inhibit HCC progression by targeting IRG1/itaconate-dependent tumor immunoevasion, and high IRG1 expression in macrophages predicts poor prognosis in HCC patients. Taken together, our results uncover an epigenetic link between itaconate and HCC and suggest that targeting IRG1 or itaconate might be a promising strategy for HCC treatment.
Amplified fluorogenic immunoassay for early diagnosis and monitoring of Alzheimer’s disease from tear fluid
Authors: Lee Sojeong , Kim Eunjung , Moon Chae-Eun , Park Chaewon , Lim Jong-Woo , Baek Minseok , Shin Moo-Kwang , Ki Jisun , Cho Hanna , Ji Yong Woo , Haam Seungjoo 
Published: December 2023

AbstractAccurate diagnosis of Alzheimer’s disease (AD) in its earliest stage can prevent the disease and delay the symptoms. Therefore, more sensitive, non-invasive, and simple screening tools are required for the early diagnosis and monitoring of AD. Here, we design a self-assembled nanoparticle-mediated amplified fluorogenic immunoassay (SNAFIA) consisting of magnetic and fluorophore-loaded polymeric nanoparticles. Using a discovery cohort of 21 subjects, proteomic analysis identifies adenylyl cyclase-associated protein 1 (CAP1) as a potential tear biomarker. The SNAFIA demonstrates a low detection limit (236 aM), good reliability (R2 = 0.991), and a wide analytical range (0.320–1000 fM) for CAP1 in tear fluid. Crucially, in the verification phase with 39 subjects, SNAFIA discriminates AD patients from healthy controls with 90% sensitivity and 100% specificity in under an hour. Utilizing tear fluid as a liquid biopsy, SNAFIA could potentially aid in long-term care planning, improve clinical trial efficiency, and accelerate therapeutic development for AD.
Unravelling the mechanism of neurotensin recognition by neurotensin receptor 1
Authors: Asadollahi Kazem , Rajput Sunnia , de Zhang Lazarus Andrew , Ang Ching-Seng , Nie Shuai , Williamson Nicholas A. , Griffin Michael D. W. , Bathgate Ross A. D. , Scott Daniel J. , Weikl Thomas R. , Jameson Guy N. L. , Gooley Paul R. 
Published: December 2023

AbstractThe conformational ensembles of G protein-coupled receptors (GPCRs) include inactive and active states. Spectroscopy techniques, including NMR, show that agonists, antagonists and other ligands shift the ensemble toward specific states depending on the pharmacological efficacy of the ligand. How receptors recognize ligands and the kinetic mechanism underlying this population shift is poorly understood. Here, we investigate the kinetic mechanism of neurotensin recognition by neurotensin receptor 1 (NTS1) using 19F-NMR, hydrogen-deuterium exchange mass spectrometry and stopped-flow fluorescence spectroscopy. Our results indicate slow-exchanging conformational heterogeneity on the extracellular surface of ligand-bound NTS1. Numerical analysis of the kinetic data of neurotensin binding to NTS1 shows that ligand recognition follows an induced-fit mechanism, in which conformational changes occur after neurotensin binding. This approach is applicable to other GPCRs to provide insight into the kinetic regulation of ligand recognition by GPCRs.
Senescence-associated 13-HODE production promotes age-related liver steatosis by directly inhibiting catalase activity
Authors: Duan Jinjie , Dong Wenhui , Wang Guangyan , Xiu Wenjing , Pu Guangyin , Xu Jingwen , Ye Chenji , Zhang Xu , Zhu Yi , Wang Chunjiong 
Published: December 2023

AbstractAging is a major risk factor for metabolic disorders. Polyunsaturated fatty acid-derived bioactive lipids play critical roles as signaling molecules in metabolic processes. Nonetheless, their effects on age-related liver steatosis remain unknown. Here we show that senescent liver cells induce liver steatosis in a paracrine manner. Linoleic acid-derived 9-hydroxy-octadecadienoic acid (9-HODE) and 13-HODE increase in middle-aged (12-month-old) and aged (20-month-old) male mouse livers and conditioned medium from senescent hepatocytes and macrophages. Arachidonate 15-lipoxygenase, an enzyme for 13-HODE and 9-HODE production, is upregulated in senescent cells. A 9-HODE and 13-HODE mixture induces liver steatosis and activates SREBP1. Furthermore, catalase (CAT) is a direct target of 13-HODE, and its activity is decreased by 13-HODE. CAT overexpression reduces 13-HODE-induced liver steatosis and protects male mice against age-related liver steatosis. Therefore, 13-HODE produced by senescent hepatocytes and macrophages activates SREBP1 by directly inhibiting CAT activity and promotes liver steatosis.
Harnessing PROTAC technology to combat stress hormone receptor activation
Authors: Gazorpak Mahshid , Hugentobler Karina M. , Paul Dominique , Germain Pierre-Luc , Kretschmer Miriam , Ivanova Iryna , Frei Selina , Mathis Kei , Rudolf Remo , Mompart Barrenechea Sergio , Fischer Vincent , Xue Xiaohan , Ptaszek Aleksandra L. , Holzinger Julian , Privitera Mattia , Hierlemann Andreas , Meijer Onno C. , Konrat Robert , Carreira Erick M. , Bohacek Johannes , Gapp Katharina 
Published: December 2023

AbstractCounteracting the overactivation of glucocorticoid receptors (GR) is an important therapeutic goal in stress-related psychiatry and beyond. The only clinically approved GR antagonist lacks selectivity and induces unwanted side effects. To complement existing tools of small-molecule-based inhibitors, we present a highly potent, catalytically-driven GR degrader, KH-103, based on proteolysis-targeting chimera technology. This selective degrader enables immediate and reversible GR depletion that is independent of genetic manipulation and circumvents transcriptional adaptations to inhibition. KH-103 achieves passive inhibition, preventing agonistic induction of gene expression, and significantly averts the GR’s genomic effects compared to two currently available inhibitors. Application in primary-neuron cultures revealed the dependency of a glucocorticoid-induced increase in spontaneous calcium activity on GR. Finally, we present a proof of concept for application in vivo. KH-103 opens opportunities for a more lucid interpretation of GR functions with translational potential.
Structural and functional analysis of the minimal orthomyxovirus-like polymerase of Tilapia Lake Virus from the highly diverged Amnoonviridae family
Authors: Arragain Benoit , Pelosse Martin , Thompson Albert , Cusack Stephen 
Published: December 2023

AbstractTilapia Lake Virus (TiLV), a recently discovered pathogen of tilapia fish, belongs to the Amnoonviridae family from the Articulavirales order. Its ten genome segments have characteristic conserved ends and encode proteins with no known homologues, apart from the segment 1, which encodes an orthomyxo-like RNA-dependent-RNA polymerase core subunit. Here we show that segments 1–3 encode respectively the PB1, PB2 and PA-like subunits of an active heterotrimeric polymerase that maintains all domains found in the distantly related influenza polymerase, despite an unprecedented overall size reduction of 40%. Multiple high-resolution cryo-EM structures of TiLV polymerase in pre-initiation, initiation and active elongation states, show how it binds the vRNA and cRNA promoters and performs RNA synthesis, with both transcriptase and replicase configurations being characterised. However, the highly truncated endonuclease-like domain appears inactive and the putative cap-binding domain is autoinhibited, emphasising that many functional aspects of TiLV polymerase remain to be elucidated.
Structural insights into photosystem II supercomplex and trimeric FCP antennae of a centric diatom Cyclotella meneghiniana
Authors: Zhao Songhao , Shen Lili , Li Xiaoyi , Tao Qiushuang , Li Zhenhua , Xu Caizhe , Zhou Cuicui , Yang Yanyan , Sang Min , Han Guangye , Yu Long-Jiang , Kuang Tingyun , Shen Jian-Ren , Wang Wenda 
Published: December 2023

AbstractDiatoms are dominant marine algae and contribute around a quarter of global primary productivity, the success of which is largely attributed to their photosynthetic capacity aided by specific fucoxanthin chlorophyll-binding proteins (FCPs) to enhance the blue-green light absorption under water. We purified a photosystem II (PSII)-FCPII supercomplex and a trimeric FCP from Cyclotella meneghiniana (Cm) and solved their structures by cryo-electron microscopy (cryo-EM). The structures reveal detailed organizations of monomeric, dimeric and trimeric FCP antennae, as well as distinct assemblies of Lhcx6_1 and dimeric FCPII-H in PSII core. Each Cm-PSII-FCPII monomer contains an Lhcx6_1, an FCP heterodimer and other three FCP monomers, which form an efficient pigment network for harvesting energy. More diadinoxanthins and diatoxanthins are found in FCPs, which may function to quench excess energy. The trimeric FCP contains more chlorophylls c and fucoxanthins. These diversified FCPs and PSII-FCPII provide a structural basis for efficient light energy harvesting, transfer, and dissipation in C. meneghiniana.
Total wash elimination for solid phase peptide synthesis
Authors: Collins Jonathan M. , Singh Sandeep K. , White Travis A. , Cesta Drew J. , Simpson Colin L. , Tubb Levi J. , Houser Christopher L. 
Published: December 2023

AbstractWe present a process for solid phase peptide synthesis (SPPS) that completely eliminates all solvent intensive washing steps during each amino acid addition cycle. A key breakthrough is the removal of a volatile Fmoc deprotection base through bulk evaporation at elevated temperature while preventing condensation on the vessel surfaces with a directed headspace gas flushing. This process was demonstrated at both research and production scales without any impact on product quality and when applied to a variety of challenging sequences (up to 89 amino acids in length). The overall result is an extremely fast, high purity, scalable process with a massive waste reduction (up to 95%) while only requiring 10–15% of the standard amount of base used. This transformation of SPPS represents a step-change in peptide manufacturing process efficiency, and should encourage expanded access to peptide-based therapeutics.
Genotoxic stress stimulates eDNA release via explosive cell lysis and thereby promotes streamer formation of Burkholderia cenocepacia H111 cultured in a microfluidic device
Authors: Heredia-Ponce Zaira , Secchi Eleonora , Toyofuku Masanori , Marinova Gabriela , Savorana Giovanni , Eberl Leo 
Published: December 2023

AbstractDNA is a component of biofilms, but the triggers of DNA release during biofilm formation and how DNA contributes to biofilm development are poorly investigated. One key mechanism involved in DNA release is explosive cell lysis, which is a consequence of prophage induction. In this article, the role of explosive cell lysis in biofilm formation was investigated in the opportunistic human pathogen Burkholderia cenocepacia H111 (H111). Biofilm streamers, flow-suspended biofilm filaments, were used as a biofilm model in this study, as DNA is an essential component of their matrix. H111 contains three prophages on chromosome 1 of its genome, and the involvement of each prophage in causing explosive cell lysis of the host and subsequent DNA and membrane vesicle (MV) release, as well as their contribution to streamer formation, were studied in the presence and absence of genotoxic stress. The results show that two of the three prophages of H111 encode functional lytic prophages that can be induced by genotoxic stress and their activation causes DNA and MVs release by explosive cell lysis. Furthermore, it is shown that the released DNA enables the strain to develop biofilm streamers, and streamer formation can be enhanced by genotoxic stress. Overall, this study demonstrates the involvement of prophages in streamer formation and uncovers an often-overlooked problem with the use of antibiotics that trigger the bacterial SOS response for the treatment of bacterial infections.
Space microgravity increases expression of genes associated with proliferation and differentiation in human cardiac spheres
Authors: Hwang Hyun , Rampoldi Antonio , Forghani Parvin , Li Dong , Fite Jordan , Boland Gene , Maher Kevin , Xu Chunhui 
Published: December 2023

AbstractEfficient generation of cardiomyocytes from human-induced pluripotent stem cells (hiPSCs) is important for their application in basic and translational studies. Space microgravity can significantly change cell activities and function. Previously, we reported upregulation of genes associated with cardiac proliferation in cardiac progenitors derived from hiPSCs that were exposed to space microgravity for 3 days. Here we investigated the effect of long-term exposure of hiPSC-cardiac progenitors to space microgravity on global gene expression. Cryopreserved 3D hiPSC-cardiac progenitors were sent to the International Space Station (ISS) and cultured for 3 weeks under ISS microgravity and ISS 1 G conditions. RNA-sequencing analyses revealed upregulation of genes associated with cardiac differentiation, proliferation, and cardiac structure/function and downregulation of genes associated with extracellular matrix regulation in the ISS microgravity cultures compared with the ISS 1 G cultures. Gene ontology analysis and Kyoto Encyclopedia of Genes and Genomes mapping identified the upregulation of biological processes, molecular function, cellular components, and pathways associated with cell cycle, cardiac differentiation, and cardiac function. Taking together, these results suggest that space microgravity has a beneficial effect on the differentiation and growth of cardiac progenitors.
Sentence completion in progressive supranuclear palsy following transcranial direct current stimulation
Authors: Scholtz Johanna , Weiss Sabine , Redecker Christoph , Müller Horst M. 
Published: December 2023

AbstractProgressive supranuclear palsy (PSP) is an atypical Parkinsonian disorder which results in deterioration of motor and cognitive skills, including language disorders such as impaired word retrieval. While there is evidence of successful use of tDCS to improve word fluency in PSP, little is known about the effectiveness of brain stimulation for word retrieval in sentence context. Therefore, we investigated whether tDCS reduces sentence completion time in PSP patients. In this sham-controlled, triple-blinded crossover study, anodal tDCS (atDCS) was applied over the left Broca’s area at 2 mA for 20 min (n = 23). In contrast to patients with multiple system atrophy (MSA), also an atypical Parkinsonian disorder, and healthy elderlies, sentence completion improved in PSP patients when tDCS was applied. The improvement in word fluency reported in previous studies using other electrode positions was not replicated. By using atDCS of the left Broca’s area, we were able to demonstrate a difference between the two movement disorders. The obtained insight could be helpful to improve language therapy of these disorders.
Pharmaco-EEG of antipsychotic treatment response: a systematic review
Authors: De Pieri Marco , Rochas Vincent , Sabe Michel , Michel Cristoph , Kaiser Stefan 
Published: December 2023

AbstractResponse to antipsychotic medications (AP) is subjected to a wide and unpredictable variability and efforts were directed to discover predictive biomarkers to personalize treatment. Electroencephalography abnormalities in subjects with schizophrenia are well established, as well as a pattern of EEG changes induced by APs. The aim of this review is to provide a synthesis of the EEG features that are related to AP efficacy, including both pre-treatment signatures and changes induced by APs during treatment. A systematic review of English articles using PubMed, PsychINFO and the Cochrane database of systematic reviews was undertaken until july 2023. Additional studies were added by hand search. Studies having as an endpoint the relationship between AP-related clinical improvement and electroencephalographic features were included. Heterogeneity prevented a quantitative synthesis. Out of 1232 records screened, 22 studies were included in a final qualitative synthesis. Included studies evaluated resting-state and task-related power spectra, functional connectivity, microstates and epileptic abnormalities. At pre-treatment resting-state EEG, the most relevant predictors of a poor response were a change in theta power compared to healthy control, a high alpha power and connectivity, and diminished beta power. Considering EEG during treatment, an increased theta power, a reduced beta-band activity, an increased alpha activity, a decreased coherence in theta, alpha and beta-band were related to a favorable outcome. EEG is promising as a method to create a predictive biomarker for response to APs; further investigations are warranted to harmonize and generalize the contradictory results of reviewed studies.
A Drosophila heart optical coherence microscopy dataset for automatic video segmentation
Authors: Fishman Matthew , Matt Abigail , Wang Fei , Gracheva Elena , Zhu Jiantao , Ouyang Xiangping , Komarov Andrey , Wang Yuxuan , Liang Hongwu , Zhou Chao 
Published: December 2023

AbstractThe heart of the fruit fly, Drosophila melanogaster, is a particularly suitable model for cardiac studies. Optical coherence microscopy (OCM) captures in vivo cross-sectional videos of the beating Drosophila heart for cardiac function quantification. To analyze those large-size multi-frame OCM recordings, human labelling has been employed, leading to low efficiency and poor reproducibility. Here, we introduce a robust and accurate automated Drosophila heart segmentation algorithm, called FlyNet 2.0+, which utilizes a long short-term memory (LSTM) convolutional neural network to leverage time series information in the videos, ensuring consistent, high-quality segmentation. We present a dataset of 213 Drosophila heart videos, equivalent to 604,000 cross-sectional images, containing all developmental stages and a wide range of beating patterns, including faster and slower than normal beating, arrhythmic beating, and periods of heart stop to capture these heart dynamics. Each video contains a corresponding ground truth mask. We expect this unique large dataset of the beating Drosophila heart in vivo will enable new deep learning approaches to efficiently characterize heart function to advance cardiac research.
An innovative optics lab design for residency training in ophthalmology
Authors: Alipour Fateme , Samavati Katayoon , Abdi Parisa , Shirazi Mandana , Tavassoly Mohammad Taghi 
Published: December 2023

AbstractProper understanding of the optical function of the eye is the foundation of clinical understanding of ophthalmologists. Although teaching principals of optics has always been a part of ophthalmology residency curriculum, it seems that successful strategies other than lecture—based methods are needed to engage students and facilitate the understanding of optical principals. A collaborative team of physicists (optics Ph.D.), ophthalmologists and medical education experts designed an optics lab for ophthalmology residents to help them practically simulate different optical phenomena. The educational course consisted of 4 sessions of 90 min to practice the optical tests using the lab instruments. Each class consisted of 6–9 residents, divided into 3 groups with a fully equipped unit, and two mentors (an optics Ph.D. professor and an ophthalmology professor). A quasi-experimental design with pre-post test was used to evaluate the effectiveness of the training workshop in changing the ophthalmology residents’ optical knowledge and attitude. Thirty-five residents participated in the study. The average score of residents' performance before the workshop was 5.21 (out of 100), which increased significantly to 66.1 after the workshop. Also, the average knowledge of residents, which was measured as self-reported, increased significantly from 28.85 to 71.09. The average score of students' attitudes and interest was increased from 40.49 to 74.81. It seems that training workshops and labs are effective to bring about change in knowledge and attitude of ophthalmology residents toward optics as a new teaching strategy that would be implemented in their curriculum.