bluuebunny/crossref_metadata_2025_split huggingface dataset:
3D genomic analysis reveals novel enhancer-hijacking caused by complex structural alterations that drive oncogene overexpression
Authors: Mortenson Katelyn L. , Dawes Courtney , Wilson Emily R. , Patchen Nathan E. , Johnson Hailey E. , Gertz Jason , Bailey Swneke D. , Liu Yang , Varley Katherine E. , Zhang Xiaoyang 
Published: July 2024

AbstractCancer genomes are composed of many complex structural alterations on chromosomes and extrachromosomal DNA (ecDNA), making it difficult to identify non-coding enhancer regions that are hijacked to activate oncogene expression. Here, we describe a 3D genomics-based analysis called HAPI (Highly Active Promoter Interactions) to characterize enhancer hijacking. HAPI analysis of HiChIP data from 34 cancer cell lines identified enhancer hijacking events that activate both known and potentially novel oncogenes such as MYC, CCND1, ETV1, CRKL, and ID4. Furthermore, we found enhancer hijacking among multiple oncogenes from different chromosomes, often including MYC, on the same complex amplicons such as ecDNA. We characterized a MYC-ERBB2 chimeric ecDNA, in which ERBB2 heavily hijacks MYC’s enhancers. Notably, CRISPRi of the MYC promoter led to increased interaction of ERBB2 with MYC enhancers and elevated ERBB2 expression. Our HAPI analysis tool provides a robust strategy to detect enhancer hijacking and reveals novel insights into oncogene activation.
Facile access to bicyclo[2.1.1]hexanes by Lewis acid-catalyzed formal cycloaddition between silyl enol ethers and bicyclo[1.1.0]butanes
Authors: Hu Sai , Pan Yuming , Ni Dongshun , Deng Li 
Published: July 2024

AbstractSaturated three-dimensional carbocycles have gained increasing prominence in synthetic and medicinal chemistry. In particular, bicyclo[2.1.1]hexanes (BCHs) have been identified as the molecular replacement for benzenes. Here, we present facile access to a variety of BCHs via a stepwise two-electron formal (3 + 2) cycloaddition between silyl enol ethers and bicyclo[1.1.0]butanes (BCBs) under Lewis acid catalysis. The reaction features wide functional group tolerance for silyl enol ethers, allowing the efficient construction of two vicinal quaternary carbon centers and a silyl-protected tertiary alcohol unit in a streamlined fashion. Interestingly, the reaction with conjugated silyl dienol ethers can provide access to bicyclo[4.1.1]octanes (BCOs) equipped with silyl enol ethers that facilitate further transformation. The utilities of this methodology are demonstrated by the late-stage modification of natural products, transformations of tertiary alcohol units on bicyclo[2.1.1]hexane frameworks, and derivatization of silyl enol ethers on bicyclo[4.1.1]octanes, delivering functionalized bicycles that are traditionally inaccessible.
Extremely large magnetoresistance in twisted intertwined graphene spirals
Authors: Zhang Yiwen , Xie Bo , Yang Yue , Wu Yueshen , Lu Xin , Hu Yuxiong , Ding Yifan , He Jiadian , Dong Peng , Wang Jinghui , Zhou Xiang , Liu Jianpeng , Wang Zhu-Jun , Li Jun 
Published: July 2024

AbstractExtremely large magnetoresistance (XMR) is highly applicable in spintronic devices such as magnetic sensors, magnetic memory, and hard drives. Typically, XMR is found in Weyl semimetals characterized by perfect electron–hole symmetry or exceptionally high electric conductivity and mobility. Our study explores this phenomenon in a recently developed graphene moiré system, which demonstrates XMR owing to its topological structure and high-quality crystal formation. We investigate the electronic properties of three-dimensional intertwined twisted graphene spirals (TGS), manipulating the screw dislocation axis to achieve a rotation angle of 7.3°. Notably, at 14 T and 2 K, the magnetoresistance of these structures reaches 1.7 × 107%, accompanied by a metal–insulator transition as the temperature increases. This transition becomes noticeable when the magnetic field exceeds a minimal threshold of approximately 0.1 T. These observations suggest the possible existence of complex, correlated states within the partially filled three-dimensional Landau levels of the 3D TGS system. Our findings open up possibilities for achieving XMR by engineering the topological structure of 2D layered moiré systems.
Ca2+ transients on the T cell surface trigger rapid integrin activation in a timescale of seconds
Authors: Li Yue , Wang ShiHui , Zhang YouHua , Liu ZhaoYuan , Zheng YunZhe , Zhang Kun , Chen ShiYang , Lv XiaoYing , Huang MengWen , Pan XingChao , Zheng YaJuan , Yuan MengYa , Ge GaoXiang , Zeng Yi Arial , Lin ChangDong , Chen JianFeng 
Published: July 2024

AbstractOne question in lymphocyte homing is how integrins are rapidly activated to enable immediate arrest of fast rolling lymphocytes upon encountering chemokines at target vascular beds given the slow chemokine-induced integrin inside-out activation. Herein we demonstrate that chemokine CCL25-triggered Ca2+ influx induces T cell membrane-proximal external Ca2+ concentration ([Ca2+]ex) drop in 6 s from physiological concentration 1.2 mM to 0.3 mM, a critical extracellular Ca2+ threshold for inducing αLβ2 activation, triggering rapid αLβ2 activation and T cell arrest before occurrence of αLβ2 inside-out activation. Talin knockdown inhibits the slow inside-out activation of αLβ2 but not [Ca2+]ex drop-triggered αLβ2 quick activation. Blocking Ca2+ influx significantly suppresses T cell rolling-to-arrest transition and homing to skin lesions in a mouse psoriasis model, thus alleviating skin inflammation. [Ca2+]ex decrease-triggered rapid integrin activation bridges the gap between initial chemokine stimulation and slow integrin inside-out activation, ensuring immediate lymphocyte arrest and subsequent diapedesis on the right location.
LGR signaling mediates muscle-adipose tissue crosstalk and protects against diet-induced insulin resistance
Authors: Kubrak Olga , Jørgensen Anne F. , Koyama Takashi , Lassen Mette , Nagy Stanislav , Hald Jacob , Mazzoni Gianluca , Madsen Dennis , Hansen Jacob B. , Larsen Martin Røssel , Texada Michael J. , Hansen Jakob L. , Halberg Kenneth V. , Rewitz Kim 
Published: July 2024

AbstractObesity impairs tissue insulin sensitivity and signaling, promoting type-2 diabetes. Although improving insulin signaling is key to reversing diabetes, the multi-organ mechanisms regulating this process are poorly defined. Here, we screen the secretome and receptome in Drosophila to identify the hormonal crosstalk affecting diet-induced insulin resistance and obesity. We discover a complex interplay between muscle, neuronal, and adipose tissues, mediated by Bone Morphogenetic Protein (BMP) signaling and the hormone Bursicon, that enhances insulin signaling and sugar tolerance. Muscle-derived BMP signaling, induced by sugar, governs neuronal Bursicon signaling. Bursicon, through its receptor Rickets, a Leucine-rich-repeat-containing G-protein coupled receptor (LGR), improves insulin secretion and insulin sensitivity in adipose tissue, mitigating hyperglycemia. In mouse adipocytes, loss of the Rickets ortholog LGR4 blunts insulin responses, showing an essential role of LGR4 in adipocyte insulin sensitivity. Our findings reveal a muscle-neuronal-fat-tissue axis driving metabolic adaptation to high-sugar conditions, identifying LGR4 as a critical mediator in this regulatory network.
Tumor detection by analysis of both symmetric- and hemi-methylation of plasma cell-free DNA
Authors: Hua Xu , Zhou Hui , Wu Hui-Chen , Furnari Julia , Kotidis Corina P. , Rabadan Raul , Genkinger Jeanine M. , Bruce Jeffrey N. , Canoll Peter , Santella Regina M. , Zhang Zhiguo 
Published: July 2024

AbstractAberrant DNA methylation patterns have been used for cancer detection. However, DNA hemi-methylation, present at about 10% CpG dinucleotides, has been less well studied. Here we show that a majority of differentially hemi-methylated regions (DHMRs) in liver tumor DNA or plasma cells free (cf) DNA do not overlap with differentially methylated regions (DMRs) of the same samples, indicating that DHMRs could serve as independent biomarkers. Furthermore, we analyzed the cfDNA methylomes of 215 samples from individuals with liver or brain cancer and individuals without cancer (controls), and trained machine learning models using DMRs, DHMRs or both. The models incorporated with both DMRs and DHMRs show a superior performance compared to models trained with DMRs or DHMRs, with AUROC being 0.978, 0.990, and 0.983 in distinguishing control, liver and brain cancer, respectively, in a validation cohort. This study supports the potential of utilizing both DMRs and DHMRs for multi-cancer detection.
Two-dimensional and high-order directional information modulations for secure communications based on programmable metasurface
Authors: Xu Hui , Wu Jun Wei , Wang Zheng Xing , Shao Rui Wen , Yang Han Qing , Cui Tie Jun 
Published: July 2024

AbstractConventional wireless communication schemes indiscriminately transmit information into the whole space and pose inherent security risks. Recently, directional information modulation (DIM) has attracted enormous attention as a promising technology. DIM generates correct constellation symbols in the desired directions and distorts them in undesired directions, thus ensuring the security of the transmitted information. Although several DIM schemes have been reported, they suffer from defects of bulkiness, energy consumption, high cost, and inability to support two-dimensional (2D) and high-order modulations. Here, we propose a DIM scheme based on a 2-bit programmable metasurface (PM) that overcomes these defects. A fast and efficient discrete optimization algorithm is developed to optimize the digital coding sequences, and the correct constellation symbols can be generated and transmitted in multi-directional beams. As a proof-of-concept, three sets of constellation diagrams (8 phase shift keying (PSK), 16 quadrature amplitude modulation (QAM), and 64QAM) are realized in the multi-channel modes. This work provides an important route of employing DIM for ensuring physical-layer security and serves as a stepping stone toward endogenous secure communications.
Temporal pattern recognition in retinal ganglion cells is mediated by dynamical inhibitory synapses
Authors: Ebert Simone , Buffet Thomas , Sermet B.Semihcan , Marre Olivier , Cessac Bruno 
Published: July 2024

AbstractA fundamental task for the brain is to generate predictions of future sensory inputs, and signal errors in these predictions. Many neurons have been shown to signal omitted stimuli during periodic stimulation, even in the retina. However, the mechanisms of this error signaling are unclear. Here we show that depressing inhibitory synapses shape the timing of the response to an omitted stimulus in the retina. While ganglion cells, the retinal output, responded to an omitted flash with a constant latency over many frequencies of the flash sequence, we found that this was not the case once inhibition was blocked. We built a simple circuit model and showed that depressing inhibitory synapses were a necessary component to reproduce our experimental findings. A new prediction of our model is that the accuracy of the constant latency requires a sufficient amount of flashes in the stimulus, which we could confirm experimentally. Depressing inhibitory synapses could thus be a key component to generate the predictive responses observed in the retina, and potentially in many brain areas.
Towards enhanced functionality of vagus neuroprostheses through in silico optimized stimulation
Authors: Ciotti Federico , John Robert , Katic Secerovic Natalija , Gozzi Noemi , Cimolato Andrea , Jayaprakash Naveen , Song Weiguo , Toth Viktor , Zanos Theodoros , Zanos Stavros , Raspopovic Stanisa 
Published: July 2024

AbstractBioelectronic therapies modulating the vagus nerve are promising for cardiovascular, inflammatory, and mental disorders. Clinical applications are however limited by side-effects such as breathing obstruction and headache caused by non-specific stimulation. To design selective and functional stimulation, we engineered VaStim, a realistic and efficient in-silico model. We developed a protocol to personalize VaStim in-vivo using simple muscle responses, successfully reproducing experimental observations, by combining models with trials conducted on five pigs. Through optimized algorithms, VaStim simulated the complete fiber population in minutes, including often omitted unmyelinated fibers which constitute 80% of the nerve. The model suggested that all Aα-fibers across the nerve affect laryngeal muscle, while heart rate changes were caused by B-efferents in specific fascicles. It predicted that tripolar paradigms could reduce laryngeal activity by 70% compared to typically used protocols. VaStim may serve as a model for developing neuromodulation therapies by maximizing efficacy and specificity, reducing animal experimentation.
Malleable, printable, bondable, and highly conductive MXene/liquid metal plasticine with improved wettability
Authors: Jiang Haojie , Yuan Bin , Guo Hongtao , Pan Fei , Meng Fanmao , Wu Yongpeng , Wang Xiao , Ruan Lingyang , Zheng Shuhuai , Yang Yang , Xiu Zheng , Li Lixin , Wu Changsheng , Gong Yongqing , Yang Menghao , Lu Wei 
Published: July 2024

AbstractIntegration of functional fillers into liquid metals (LM) induces rheology modification, enabling the free-form shaping of LM at the micrometer scale. However, integrating non-chemically modified low-dimensional materials with LM to form stable and uniform dispersions remain a great challenge. Herein, we propose a solvent-assisted dispersion (SAD) method that utilizes the fragmentation and reintegration of LM in volatile solvents to engulf and disperse fillers. This method successfully integrates MXene uniformly into LM, achieving better internal connectivity than the conventional dry powder mixing (DPM) method. Consequently, the MXene/LM (MLM) coating exhibits high electromagnetic interference (EMI) shielding performance (105 dB at 20 μm, which is 1.6 times that of coatings prepared by DPM). Moreover, the rheological characteristic of MLM render it malleable and facilitates direct printing and adaptation to diverse structures. This study offers a convenient method for assembling LM with low-dimensional materials, paving the way for the development of multifunctional soft devices.
Electrochromic windows with fast response and wide dynamic range for visible-light modulation without traditional electrodes
Authors: Jia Zhuofei , Sui Yiming , Qian Long , Ren Xi , Zhao Yunxiang , Yao Rui , Wang Lumeng , Chao Dongliang , Yang Cheng 
Published: July 2024

AbstractElectrochromic (EC) devices represent an emerging energy-saving technology, exhibiting the capability to dynamically modulate light and heat transmittance. Despite their promising potential, the commercialization of EC devices faces substantial impediments such as high cost, intricate fabrication process, and low optical contrast inherent in conventional EC materials relying on the ion insertion/extraction mechanism. In this study, we introduce an innovative “electrode-free” electrochromic (EC) device, termed the EECD, which lacks an EC-layer on the electrodes during device assembling and in the bleached state. This device features a simplified fabrication process and delivers superior optical modulation. It achieves a high optical contrast ranging from 68-85% across the visible spectrum and boasts a rapid response time, reaching 90% coloring in just 17 seconds. In addition, EECD exhibits stable cycling for over 10,000 cycles without noticeable degradation and maintains functionality across a broad temperature range (0 °C to 50 °C). Furthermore, the fabricated large-area devices (40 cm × 40 cm) demonstrate excellent tinting uniformity, suggesting excellent scalability of this approach. Our study establishes a paradigmatic breakthrough for EC smart windows.
Kupffer cells determine intrahepatic traffic of PEGylated liposomal doxorubicin
Authors: Jiang Kuan , Tian Kaisong , Yu Yifei , Wu Ercan , Yang Min , Pan Feng , Qian Jun , Zhan Changyou 
Published: July 2024

AbstractIntrahepatic accumulation dominates organ distribution for most nanomedicines. However, obscure intrahepatic fate largely hampers regulation on their in vivo performance. Herein, PEGylated liposomal doxorubicin is exploited to clarify the intrahepatic fate of both liposomes and the payload in male mice. Kupffer cells initiate and dominate intrahepatic capture of liposomal doxorubicin, following to deliver released doxorubicin to hepatocytes with zonated distribution along the lobule porto-central axis. Increasing Kupffer cells capture promotes doxorubicin accumulation in hepatocytes, revealing the Kupffer cells capture-payload release-hepatocytes accumulation scheme. In contrast, free doxorubicin is overlooked by Kupffer cells, instead quickly distributing into hepatocytes by directly crossing fenestrated liver sinusoid endothelium. Compared to free doxorubicin, liposomal doxorubicin exhibits sustained metabolism/excretion due to the extra capture-release process. This work unveils the pivotal role of Kupffer cells in intrahepatic traffic of PEGylated liposomal therapeutics, and quantitively describes the intrahepatic transport/distribution/elimination process, providing crucial information for guiding further development of nanomedicines.
The structural insight into the functional modulation of human anion exchanger 3
Authors: Jian Liyan , Zhang Qing , Yao Deqiang , Wang Qian , Chen Moxin , Xia Ying , Li Shaobai , Shen Yafeng , Cao Mi , Qin An , Li Lin , Cao Yu 
Published: July 2024

AbstractAnion exchanger 3 (AE3) is pivotal in regulating intracellular pH across excitable tissues, yet its structural intricacies and functional dynamics remain underexplored compared to other anion exchangers. This study unveils the structural insights into human AE3, including the cryo-electron microscopy structures for AE3 transmembrane domains (TMD) and a chimera combining AE3 N-terminal domain (NTD) with AE2 TMD (hAE3NTD2TMD). Our analyzes reveal a substrate binding site, an NTD-TMD interlock mechanism, and a preference for an outward-facing conformation. Unlike AE2, which has more robust acid-loading capabilities, AE3’s structure, including a less stable inward-facing conformation due to missing key NTD-TMD interactions, contributes to its moderated pH-modulating activity and increased sensitivity to the inhibitor DIDS. These structural differences underline AE3’s distinct functional roles in specific tissues and underscore the complex interplay between structural dynamics and functional specificity within the anion exchanger family, enhancing our understanding of the physiological and pathological roles of the anion exchanger family.
Electrochemical deoxygenative amination of stabilized alkyl radicals from activated alcohols
Authors: Xu Jia , Liu Yilin , Wang Qing , Tao Xiangzhang , Ni Shengyang , Zhang Weigang , Yu Lei , Pan Yi , Wang Yi 
Published: July 2024

AbstractAlkylamine structures represent one of the most functional and widely used in organic synthesis and drug design. However, the general methods for the functionalization of the shielded and deshielded alkyl radicals remain elusive. Here, we report a general deoxygenative amination protocol using alcohol-derived carbazates and nitrobenzene under electrochemical conditions. A range of primary, secondary, and tertiary alkylamines are obtained. This practical procedure can be scaled up through electrochemical continuous flow technique.
The role of cellular senescence in ovarian aging
Authors: Hense Jéssica D. , Isola José V. V. , Garcia Driele N. , Magalhães Larissa S. , Masternak Michal M. , Stout Michael B. , Schneider Augusto 
Published: July 2024

AbstractThis review explores the relationship between ovarian aging and senescent cell accumulation, as well as the efficacy of senolytics to improve reproductive longevity. Reproductive longevity is determined by the age-associated decline in ovarian reserve, resulting in reduced fertility and eventually menopause. Cellular senescence is a state of permanent cell cycle arrest and resistance to apoptosis. Senescent cells accumulate in several tissues with advancing age, thereby promoting chronic inflammation and age-related diseases. Ovaries also appear to accumulate senescent cells with age, which might contribute to aging of the reproductive system and whole organism through SASP production. Importantly, senolytic drugs can eliminate senescent cells and may present a potential intervention to mitigate ovarian aging. Herein, we review the current literature related to the efficacy of senolytic drugs for extending the reproductive window in mice.
Adult-onset deletion of ATP13A2 in mice induces progressive nigrostriatal pathway dopaminergic degeneration and lysosomal abnormalities
Authors: Erb Madalynn L. , Sipple Kayla , Levine Nathan , Chen Xi , Moore Darren J. 
Published: July 2024

AbstractAlthough most cases of Parkinson’s disease (PD) are sporadic, mutations in over 20 genes are known to cause heritable forms of the disease. Recessive loss-of-function mutations in ATP13A2, a lysosomal transmembrane P5B-type ATPase and polyamine exporter, can cause early-onset familial PD. Familial ATP13A2 mutations are also linked to related neurodegenerative diseases, including Kufor-Rakeb syndrome, hereditary spastic paraplegias, neuronal ceroid lipofuscinosis, and amyotrophic lateral sclerosis. Despite the severe effects of ATP13A2 mutations in humans, ATP13A2 knockout (KO) mice fail to exhibit neurodegeneration even at advanced ages, making it challenging to study the neuropathological effects of ATP13A2 loss in vivo. Germline deletion of ATP13A2 in rodents may trigger the upregulation of compensatory pathways during embryonic development that mask the full neurotoxic effects of ATP13A2 loss in the brain. To explore this idea, we selectively deleted ATP13A2 in the adult mouse brain by the unilateral delivery of an AAV-Cre vector into the substantia nigra of young adult mice carrying conditional loxP-flanked ATP13A2 KO alleles. We observe a progressive loss of striatal dopaminergic nerve terminals at 3 and 10 months after AAV-Cre delivery. Cre-injected mice also exhibit robust dopaminergic neuronal degeneration in the substantia nigra at 10 months. Adult-onset ATP13A2 KO also recreates many of the phenotypes observed in aged germline ATP13A2 KO mice, including lysosomal abnormalities, p62-positive inclusions, and neuroinflammation. Our study demonstrates that the adult-onset homozygous deletion of ATP13A2 in the nigrostriatal pathway produces robust and progressive dopaminergic neurodegeneration that serves as a useful in vivo model of ATP13A2-related neurodegenerative diseases.