bluuebunny/crossref_metadata_2025_split huggingface dataset:
B cell-derived IL-10 promotes the resolution of lipopolysaccharide-induced acute lung injury
Authors: Sun Zhun , Chen Anning , Fang Hongwei , Sun Donglin , Huang Meiying , Cheng Erdeng , Luo Mengyuan , Zhang Xiaoren , Fang Hao , Qian Guojun 
Published: July 2023

AbstractInflammation resolution is critical for acute lung injury (ALI) recovery. Interleukin (IL)-10 is a potent anti-inflammatory factor. However, its role in ALI resolution remains unclear. We investigated the effects of IL-10 during the ALI resolution process in a murine lipopolysaccharide (LPS)-induced ALI model. Blockade of IL-10 signaling aggravates LPS-induced lung injury, as manifested by elevated pro-inflammatory factors production and increased neutrophils recruitment to the lung. Thereafter, we used IL-10 GFP reporter mice to discern the source cell of IL-10 during ALI. We found that IL-10 is predominantly generated by B cells during the ALI recovery process. Furthermore, we used IL-10-specific loss in B-cell mice to elucidate the effect of B-cell-derived IL-10 on the ALI resolution process. IL-10-specific loss in B cells leads to increased pro-inflammatory cytokine expression, persistent leukocyte infiltration, and prolonged alveolar barrier damage. Mechanistically, B cell-derived IL-10 inhibits the activation and recruitment of macrophages and downregulates the production of chemokine KC that recruits neutrophils to the lung. Moreover, we found that IL-10 deletion in B cells leads to alterations in the cGMP–PKG signaling pathway. In addition, an exogenous supply of IL-10 promotes recovery from LPS-induced ALI, and IL-10-secreting B cells are present in sepsis-related ARDS. This study highlights that B cell-derived IL-10 is critical for the resolution of LPS-induced ALI and may serve as a potential therapeutic target.
The Road from AKI to CKD: Molecular Mechanisms and Therapeutic Targets of Ferroptosis
Authors: Guo Runzhi , Duan Jiayu , Pan Shaokang , Cheng Fei , Qiao Yingjin , Feng Qi , Liu Dongwei , Liu Zhangsuo 
Published: July 2023

AbstractAcute kidney injury (AKI) is a prevalent pathological condition that is characterized by a precipitous decline in renal function. In recent years, a growing body of studies have demonstrated that renal maladaptation following AKI results in chronic kidney disease (CKD). Therefore, targeting the transition of AKI to CKD displays excellent therapeutic potential. However, the mechanism of AKI to CKD is mediated by multifactor, and there is still a lack of effective treatments. Ferroptosis, a novel nonapoptotic form of cell death, is believed to have a role in the AKI to CKD progression. In this study, we retrospectively examined the history and characteristics of ferroptosis, summarized ferroptosis’s research progress in AKI and CKD, and discussed how ferroptosis participates in regulating the pathological mechanism in the progression of AKI to CKD. Furthermore, we highlighted the limitations of present research and projected the future evolution of ferroptosis. We hope this work will provide clues for further studies of ferroptosis in AKI to CKD and contribute to the study of effective therapeutic targets to prevent the progression of kidney diseases.
α-myosin heavy chain lactylation maintains sarcomeric structure and function and alleviates the development of heart failure
Authors: Zhang Naijin , Zhang Ying , Xu Jiaqi , Wang Pengbo , Wu Boquan , Lu Saien , Lu Xinxin , You Shilong , Huang Xinyue , Li Mohan , Zou Yuanming , Liu Mengke , Zhao Yuanhui , Sun Guozhe , Wang Wenbin , Geng Danxi , Liu Jingwei , Cao Liu , Sun Yingxian 
Published: July 2023

AbstractThe sarcomeric interaction of α-myosin heavy chain (α-MHC) with Titin is vital for cardiac structure and contraction. However, the mechanism regulating this interaction in normal and failing hearts remains unknown. Lactate is a crucial energy substrate of the heart. Here, we identify that α-MHC undergoes lactylation on lysine 1897 to regulate the interaction of α-MHC with Titin. We observed a reduction of α-MHC K1897 lactylation in mice and patients with heart failure. Loss of K1897 lactylation in α-MHC K1897R knock-in mice reduces α-MHC–Titin interaction and leads to impaired cardiac structure and function. Furthermore, we identified that p300 and Sirtuin 1 act as the acyltransferase and delactylase of α-MHC, respectively. Decreasing lactate production by chemical or genetic manipulation reduces α-MHC lactylation, impairs α-MHC–Titin interaction and worsens heart failure. By contrast, upregulation of the lactate concentration by administering sodium lactate or inhibiting the pivotal lactate transporter in cardiomyocytes can promote α-MHC K1897 lactylation and α-MHC–Titin interaction, thereby alleviating heart failure. In conclusion, α-MHC lactylation is dynamically regulated and an important determinant of overall cardiac structure and function. Excessive lactate efflux and consumption by cardiomyocytes may decrease the intracellular lactate level, which is the main cause of reduced α-MHC K1897 lactylation during myocardial injury. Our study reveals that cardiac metabolism directly modulates the sarcomeric structure and function through lactate-dependent modification of α-MHC.
Deep structured learning for variant prioritization in Mendelian diseases
Authors: Danzi Matt C. , Dohrn Maike F. , Fazal Sarah , Beijer Danique , Rebelo Adriana P. , Cintra Vivian , Züchner Stephan 
Published: July 2023

AbstractEffective computer-aided or automated variant evaluations for monogenic diseases will expedite clinical diagnostic and research efforts of known and novel disease-causing genes. Here we introduce MAVERICK: a Mendelian Approach to Variant Effect pRedICtion built in Keras. MAVERICK is an ensemble of transformer-based neural networks that can classify a wide range of protein-altering single nucleotide variants (SNVs) and indels and assesses whether a variant would be pathogenic in the context of dominant or recessive inheritance. We demonstrate that MAVERICK outperforms all other major programs that assess pathogenicity in a Mendelian context. In a cohort of 644 previously solved patients with Mendelian diseases, MAVERICK ranks the causative pathogenic variant within the top five variants in over 95% of cases. Seventy-six percent of cases were solved by the top-ranked variant. MAVERICK ranks the causative pathogenic variant in hitherto novel disease genes within the first five candidate variants in 70% of cases. MAVERICK has already facilitated the identification of a novel disease gene causing a degenerative motor neuron disease. These results represent a significant step towards automated identification of causal variants in patients with Mendelian diseases.
Hidden modes of DNA binding by human nuclear receptors
Authors: Bhimsaria Devesh , Rodríguez-Martínez José A. , Mendez-Johnson Jacqui L. , Ghoshdastidar Debostuti , Varadarajan Ashwin , Bansal Manju , Daniels Danette L. , Ramanathan Parameswaran , Ansari Aseem Z. 
Published: July 2023

AbstractHuman nuclear receptors (NRs) are a superfamily of ligand-responsive transcription factors that have central roles in cellular function. Their malfunction is linked to numerous diseases, and the ability to modulate their activity with synthetic ligands has yielded 16% of all FDA-approved drugs. NRs regulate distinct gene networks, however they often function from genomic sites that lack known binding motifs. Here, to annotate genomic binding sites of known and unexamined NRs more accurately, we use high-throughput SELEX to comprehensively map DNA binding site preferences of all full-length human NRs, in complex with their ligands. Furthermore, to identify non-obvious binding sites buried in DNA–protein interactomes, we develop MinSeq Find, a search algorithm based on the MinTerm concept from electrical engineering and digital systems design. The resulting MinTerm sequence set (MinSeqs) reveal a constellation of binding sites that more effectively annotate NR-binding profiles in cells. MinSeqs also unmask binding sites created or disrupted by 52,106 single-nucleotide polymorphisms associated with human diseases. By implicating druggable NRs as hidden drivers of multiple human diseases, our results not only reveal new biological roles of NRs, but they also provide a resource for drug-repurposing and precision medicine.
Threat gates visual aversion via theta activity in Tachykinergic neurons
Authors: Tsuji Masato , Nishizuka Yuto , Emoto Kazuo 
Published: July 2023

AbstractAnimals must adapt sensory responses to an ever-changing environment for survival. Such sensory modulation is especially critical in a threatening situation, in which animals often promote aversive responses to, among others, visual stimuli. Recently, threatened Drosophila has been shown to exhibit a defensive internal state. Whether and how threatened Drosophila promotes visual aversion, however, remains elusive. Here we report that mechanical threats to Drosophila transiently gate aversion from an otherwise neutral visual object. We further identified the neuropeptide tachykinin, and a single cluster of neurons expressing it (“Tk-GAL42 ∩ Vglut neurons”), that are responsible for gating visual aversion. Calcium imaging analysis revealed that mechanical threats are encoded in Tk-GAL42 ∩ Vglut neurons as elevated activity. Remarkably, we also discovered that a visual object is encoded in Tk-GAL42 ∩ Vglut neurons as θ oscillation, which is causally linked to visual aversion. Our data reveal how a single cluster of neurons adapt organismal sensory response to a threatening situation through a neuropeptide and a combination of rate/temporal coding schemes.
Inhibition of AXL receptor tyrosine kinase enhances brown adipose tissue functionality in mice
Authors: Efthymiou Vissarion , Ding Lianggong , Balaz Miroslav , Sun Wenfei , Balazova Lucia , Straub Leon G. , Dong Hua , Simon Eric , Ghosh Adhideb , Perdikari Aliki , Keller Svenja , Ghoshdastider Umesh , Horvath Carla , Moser Caroline , Hamilton Bradford , Neubauer Heike , Wolfrum Christian 
Published: July 2023

AbstractThe current obesity epidemic and high prevalence of metabolic diseases necessitate efficacious and safe treatments. Brown adipose tissue in this context is a promising target with the potential to increase energy expenditure, however no pharmacological treatments activating brown adipose tissue are currently available. Here, we identify AXL receptor tyrosine kinase as a regulator of adipose function. Pharmacological and genetic inhibition of AXL enhance thermogenic capacity of brown and white adipocytes, in vitro and in vivo. Mechanistically, these effects are mediated through inhibition of PI3K/AKT/PDE signaling pathway, resulting in induction of nuclear FOXO1 localization and increased intracellular cAMP levels via PDE3/4 inhibition and subsequent stimulation of the PKA-ATF2 pathway. In line with this, both constitutive Axl deletion as well as inducible adipocyte-specific Axl deletion protect animals from diet-induced obesity concomitant with increases in energy expenditure. Based on these data, we propose AXL receptor as a target for the treatment of obesity.
Atomic structure of a nudivirus occlusion body protein determined from a 70-year-old crystal sample
Authors: Keown Jeremy R. , Crawshaw Adam D. , Trincao Jose , Carrique Loïc , Gildea Richard J. , Horrell Sam , Warren Anna J. , Axford Danny , Owen Robin , Evans Gwyndaf , Bézier Annie , Metcalf Peter , Grimes Jonathan M. 
Published: July 2023

AbstractInfectious protein crystals are an essential part of the viral lifecycle for double-stranded DNA Baculoviridae and double-stranded RNA cypoviruses. These viral protein crystals, termed occlusion bodies or polyhedra, are dense protein assemblies that form a crystalline array, encasing newly formed virions. Here, using X-ray crystallography we determine the structure of a polyhedrin from Nudiviridae. This double-stranded DNA virus family is a sister-group to the baculoviruses, whose members were thought to lack occlusion bodies. The 70-year-old sample contains a well-ordered lattice formed by a predominantly α-helical building block that assembles into a dense, highly interconnected protein crystal. The lattice is maintained by extensive hydrophobic and electrostatic interactions, disulfide bonds, and domain switching. The resulting lattice is resistant to most environmental stresses. Comparison of this structure to baculovirus or cypovirus polyhedra shows a distinct protein structure, crystal space group, and unit cell dimensions, however, all polyhedra utilise common principles of occlusion body assembly.
Dynamic imaging of interfacial electrochemistry on single Ag nanowires by azimuth-modulated plasmonic scattering interferometry
Authors: Wu Gang , Qian Chen , Lv Wen-Li , Zhao Xiaona , Liu Xian-Wei 
Published: July 2023

AbstractDirect visualization of surface chemical dynamics in solution is essential for understanding the mechanisms involved in nanocatalysis and electrochemistry; however, it is challenging to achieve high spatial and temporal resolution. Here, we present an azimuth-modulated plasmonic imaging technique capable of imaging dynamic interfacial changes. The method avoids strong interference from reflected light and consequently eliminates the parabolic-like interferometric patterns in the images, allowing for a 67-fold increase in the spatial resolution of plasmonic imaging. We demonstrate that this optical imaging approach enables comprehensive analyses of surface chemical dynamics and identification of previously unknown surface reaction heterogeneity by investigating electrochemical redox reactions over single silver nanowires as an example. This work provides a general strategy for high-resolution plasmonic imaging of surface electrochemical dynamics and other interfacial chemical reactions, complementing existing surface characterization methods.
Discovering functionally important sites in proteins
Authors: Cagiada Matteo , Bottaro Sandro , Lindemose Søren , Schenstrøm Signe M. , Stein Amelie , Hartmann-Petersen Rasmus , Lindorff-Larsen Kresten 
Published: July 2023

AbstractProteins play important roles in biology, biotechnology and pharmacology, and missense variants are a common cause of disease. Discovering functionally important sites in proteins is a central but difficult problem because of the lack of large, systematic data sets. Sequence conservation can highlight residues that are functionally important but is often convoluted with a signal for preserving structural stability. We here present a machine learning method to predict functional sites by combining statistical models for protein sequences with biophysical models of stability. We train the model using multiplexed experimental data on variant effects and validate it broadly. We show how the model can be used to discover active sites, as well as regulatory and binding sites. We illustrate the utility of the model by prospective prediction and subsequent experimental validation on the functional consequences of missense variants in HPRT1 which may cause Lesch-Nyhan syndrome, and pinpoint the molecular mechanisms by which they cause disease.
Conductance stable and mechanically durable bi-layer EGaIn composite-coated stretchable fiber for 1D bioelectronics
Authors: Lee Gun-Hee , Lee Do Hoon , Jeon Woojin , Yoon Jihwan , Ahn Kwangguk , Nam Kum Seok , Kim Min , Kim Jun Kyu , Koo Yong Hoe , Joo Jinmyoung , Jung WooChul , Lee Jaehong , Nam Jaewook , Park Seongjun , Jeong Jae-Woong , Park Steve 
Published: July 2023

AbstractDeformable semi-solid liquid metal particles (LMP) have emerged as a promising substitute for rigid conductive fillers due to their excellent electrical properties and stable conductance under strain. However, achieving a compact and robust coating of LMP on fibers remains a persistent challenge, mainly due to the incompatibility of conventional coating techniques with LMP. Additionally, the limited durability and absence of initial electrical conductivity of LMP restrict their widespread application. In this study, we propose a solution process that robustly and compactly assembles mechanically durable and initially conductive LMP on fibers. Specifically, we present a shearing-based deposition of polymer-attached LMP followed by additional coating with CNT-attached LMP to create bi-layer LMP composite with exceptional durability, electrical conductivity, stretchability, and biocompatibility on various fibers. The versatility and reliability of this manufacturing strategy for 1D electronics are demonstrated through the development of sewn electrical circuits, smart clothes, stretchable biointerfaced fiber, and multifunctional fiber probes.
Colloidal transport by light induced gradients of active pressure
Authors: Pellicciotta Nicola , Paoluzzi Matteo , Buonomo Dario , Frangipane Giacomo , Angelani Luca , Di Leonardo Roberto 
Published: July 2023

AbstractActive fluids, like all other fluids, exert mechanical pressure on confining walls. Unlike equilibrium, this pressure is generally not a function of the fluid state in the bulk and displays some peculiar properties. For example, when activity is not uniform, fluid regions with different activity may exert different pressures on the container walls but they can coexist side by side in mechanical equilibrium. Here we show that by spatially modulating bacterial motility with light, we can generate active pressure gradients capable of transporting passive probe particles in controlled directions. Although bacteria swim faster in the brighter side, we find that bacteria in the dark side apply a stronger pressure resulting in a net drift motion that points away from the low activity region. Using a combination of experiments and numerical simulations, we show that this drift originates mainly from an interaction pressure term that builds up due to the compression exerted by a layer of polarized cells surrounding the slow region. In addition to providing new insights into the generalization of pressure for interacting systems with non-uniform activity, our results demonstrate the possibility of exploiting active pressure for the controlled transport of microscopic objects.
Clinicopathologic and genomic features of lobular like invasive mammary carcinoma: is it a distinct entity?
Authors: Yu Jing , da Silva Edaise M. , La Hae-Sun , Clark Beth Z. , Fine Jeffrey L. , Carter Gloria J. , Villatoro Tatiana M. , Soong T. Rinda , Lee Adrian V. , Oesterreich Steffi , Basili Thais , Blanco-Heredia Juan , Selenica Pier , Ye Qiqi , Da Cruz Paula Arnaud , Dopeso Higinio , Gazzo Andrea , Marra Antonio , Pareja Fresia , Reis-Filho Jorge S. , Bhargava Rohit 
Published: July 2023

AbstractThis study describes “lobular-like invasive mammary carcinomas” (LLIMCas), a group of low- to intermediate-grade invasive mammary carcinomas with discohesive, diffusely infiltrative cells showing retained circumferential membranous immunoreactivity for both E-cadherin and p120. We analyzed the clinical-pathologic features of 166 LLIMCas compared to 104 classical invasive lobular carcinomas (ILCs) and 100 grade 1 and 2 invasive ductal carcinomas (IDCs). Tumor size and pT stage of LLIMCas were intermediate between IDCs and ILCs, and yet often underestimated on imaging and showed frequent positive margins on the first resection. Despite histomorphologic similarities to classical ILC, the discohesion in LLIMCa was independent of E-cadherin/p120 immunophenotypic alteration. An exploratory, hypothesis-generating analysis of the genomic features of 14 randomly selected LLIMCas and classical ILCs (7 from each category) was performed utilizing an FDA-authorized targeted capture sequencing assay (MSK-IMPACT). None of the seven LLIMCas harbored CDH1 loss-of-function mutations, and none of the CDH1 alterations detected in two of the LLIMCas was pathogenic. In contrast, all seven ILCs harbored CDH1 loss-of-function mutations coupled with the loss of heterozygosity of the CDH1 wild-type allele. Four of the six evaluable LLIMCas were positive for CDH1 promoter methylation, which may partially explain the single-cell infiltrative morphology seen in LLIMCa. Further studies are warranted to better define the molecular basis of the discohesive cellular morphology in LLIMCa. Until more data becomes available, identifying LLIMCas and distinguishing them from typical IDCs and ILCs would be justified. In patients with LLIMCas, preoperative MRI should be entertained to guide surgical management.
The Troyer syndrome protein spartin mediates selective autophagy of lipid droplets
Authors: Chung Jeeyun , Park Joongkyu , Lai Zon Weng , Lambert Talley J. , Richards Ruth C. , Zhang Jiuchun , Walther Tobias C. , Farese Robert V. 
Published: July 2023

AbstractLipid droplets (LDs) are crucial organelles for energy storage and lipid homeostasis. Autophagy of LDs is an important pathway for their catabolism, but the molecular mechanisms mediating LD degradation by selective autophagy (lipophagy) are unknown. Here we identify spartin as a receptor localizing to LDs and interacting with core autophagy machinery, and we show that spartin is required to deliver LDs to lysosomes for triglyceride mobilization. Mutations in SPART (encoding spartin) lead to Troyer syndrome, a form of complex hereditary spastic paraplegia1. Interfering with spartin function in cultured human neurons or murine brain neurons leads to LD and triglyceride accumulation. Our identification of spartin as a lipophagy receptor, thus, suggests that impaired LD turnover contributes to Troyer syndrome development.
Real-time microscopy of the relaxation of a glass
Authors: Ruiz-Ruiz Marta , Vila-Costa Ana , Bar Tapas , Rodríguez-Tinoco Cristian , Gonzalez-Silveira Marta , Plaza Jose Antonio , Alcalá Jorge , Fraxedas Jordi , Rodriguez-Viejo Javier 
Published: July 2023

AbstractThe understanding of the dynamics of a glass above its devitrification temperature remains incomplete. Here, we build a spatio-temporal map of the relaxation dynamics of a highly stable glass into its supercooled liquid using real-time atomic force microscopy imaging. This methodology enables direct visualization of the progression of the liquid phase and clarifies and quantifies the presence of localized fast mobility regions separated by giant length scales. Our data establish a clear correlation between dynamic length and time scales in glasses. This approach may also be applicable to unveil the microscopic structure and dynamics of other glass-forming systems with much shorter length and time scales, including liquid-cooled glasses.
Molecular basis for ubiquitin/Fubi cross-reactivity in USP16 and USP36
Authors: O’Dea Rachel , Kazi Nafizul , Hoffmann-Benito Alicia , Zhao Zhou , Recknagel Sarah , Wendrich Kim , Janning Petra , Gersch Malte 
Published: July 2023

AbstractUbiquitin and ubiquitin-like proteins typically use distinct machineries to facilitate diverse functions. The immunosuppressive ubiquitin-like protein Fubi is synthesized as an N-terminal fusion to a ribosomal protein (Fubi-S30). Its proteolytic maturation by the nucleolar deubiquitinase USP36 is strictly required for translationally competent ribosomes. What endows USP36 with this activity, how Fubi is recognized and whether other Fubi proteases exist are unclear. Here, we report a chemical tool kit that facilitated the discovery of dual ubiquitin/Fubi cleavage activity in USP16 in addition to USP36 by chemoproteomics. Crystal structures of USP36 complexed with Fubi and ubiquitin uncover its substrate recognition mechanism and explain how other deubiquitinases are restricted from Fubi. Furthermore, we introduce Fubi C-terminal hydrolase measurements and reveal a synergistic role of USP16 in Fubi-S30 maturation. Our data highlight how ubiquitin/Fubi specificity is achieved in a subset of human deubiquitinases and open the door to a systematic investigation of the Fubi system.