bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nuclear transport at full amino-acid resolution
Authors: Dekker Maurice , de Vries Hendrik W. , Wortelboer Koen A. , Beekhuis Harm Jan , Van der Giessen Erik , Onck Patrick R. 
Published: June 2024

AbstractRecent studies of nuclear pore complexes (NPCs) have provided detailed descriptions of the core scaffold structures, yet fall short in resolving the dynamic FG-meshwork with similar pre-cision. Here, we present a novel modeling framework that enables the simulation of nuclear transport at full amino-acid resolution. We describe the distributions of the different FG-Nups in the central transporter and highlight the dynamic nature of the FG-meshwork, with FG–FG interaction lifetimes on the order of nanoseconds. Our findings reveal that Nsp1, the most abundant FG-Nup in the NPC, creates a central meshwork due to its unique bimodal structure, that is essential for controlling both passive and active transport. By introducing nuclear transport receptors (NTRs)—in the form of Kap95—to the pore, we demonstrate that NTRs play a key role in increasing the energy barrier for translocation of inert particles. We observe a dynamic interplay between high affinity binding to FG-motifs and the temporal fluctuations of the FG-meshwork, leading to local low-density pockets, so-called voids, through which Kaps move. Furthermore, we show that the introduction of Kaps to the FG-meshwork results in a clear “dirty velcro” mechanism with slower Kaps decorating the sticky surface of the high-density GLFG-assembly, thus enabling fast translocation of Kaps through the center of the pore.
Evidence of lesions from Epstein-Barr virus infection in human breast cancer genomes
Authors: Friedenson Bernard 
Published: June 2024

AbstractEpstein-Barr virus (EBV) infects essentially all humans and provides no benefit. EBV can cause nasopharyngeal cancer (NPC), Burkitt’s lymphoma (BL), and perhaps breast cancer. Breast tissues from patients with breast cancer are more likely to be EBV-positive than tissues from healthy controls. However, EBV is not a proven cause of breast cancer because the tissues are not consistently EBV-positive. If EBV causes breast cancer, it would have to do it without an active infection. Other cancers with known viral origins do not require continuing presence of the virus. However, the "hit and run" theory is difficult to test for breast cancer without a proven EBV connection.Here, I test this theory with multiple independent bioinformatic analyses. First, hundreds of breast cancer genomes contained characteristic methylation scars that indicate a cleared EBV infection. The genomes had further differential hypermethylation near positions where EBV reprograms normal cells into malignancy. Second, genomes from EBV cancers and breast cancers inactivated the same tumor-suppressive mechanisms. Third, deletions were identified on chromosome 3p in EBV cancers that shift cells to oxidative glycolysis, a prominent breast cancer phenotype known as the Warburg effect. Similar 3p deletions were found in breast cancer genomes. Fourth, somatic hypermutation clusters in EBV-cancers marked genome positions in breast cancers near translocations and focal oncogene amplification. EBV deregulation of deaminase and estrogen-induced topoisomerase explain these translocation breakpoints. Fifth, several alternate explanations for these results were ruled out. Finally, only limited segments of EBV DNA matched the human genome, making it possible that a childhood vaccine would end breast cancer.
Modular Fluorescent Cholesterol Naphthalimide Probes And Their Application For Cholesterol Trafficking Studies In Cells
Authors: Rubio Vicente , McInchak Nicholas , Fernandez Genesis , Benavides Dana , Herrera Diana , Jimenez Catherine , Mesa Haylee , Meade Jonathan , Zhang Qi , Stawikowski Maciej J. 
Published: June 2024

AbstractDevelopment of fluorescent cholesterol analogs to better understand subcellular cholesterol trafficking is of great interest for cell biology and medicine. Our approach utilizes a bifunctional 1,8-naphthalimide scaffold with a push-pull character, modified on one side with a head group and a linker on the other side connecting it to cholesterolviaan ester bond. Through structure-function studies, we’ve explored how different substituents—linkers and head groups—affect the ability of these fluorescent cholesterol naphthalimide analogs (CNDs) to mimic natural cholesterol behavior at both molecular and cellular levels.We categorized the resulting analogs into three groups: neutral, charged, and those featuring a hydroxyl group. Each compound was assessed for its solvatochromic behavior in organic solvents and model membranes. Extensive all-atom molecular dynamics simulations helped us examine how these analogs perform in model membranes compared to cholesterol. Additionally, we investigated the partitioning of these fluorescent probes in phase-separated giant unilamellar vesicles. We evaluated the uptake and distribution of these probes within mouse fibroblast cells and astrocytes, for their subcellular distributions in lysosomes and compared that to BODIPY-cholesterol, a well-regarded fluorescent cholesterol analog. The internalization efficiency of the fluorescent probes varies in different cell types and is affected mainly by the head groups. Our results demonstrate that the modular design significantly simplifies the creation of fluorescent cholesterol probes bearing distinct spectral, biophysical, and cellular targeting features, which makes it a valuable toolkit for the investigation of subcellular distribution and trafficking of cholesterol and its derivatives.
Mechanoreceptor Piezo1-Mediated Interleukin Expression in Conjunctival Epithelial Cells: Linking Mechanical Stress to Ocular Inflammation
Authors: Fukuoka Seiya , Adachi Naoki , Ouchi Erika , Ikemoto Hideshi , Okumo Takayuki , Onda Hidetoshi , Sunagawa Masataka 
Published: June 2024

AbstractPurposeMechanical stress on the ocular surface, such as from eye-rubbing, has been reported to lead to inflammation and various ocular conditions. We hypothesized that the mechanosensitive Piezo1 channel in the conjunctival epithelium contributes to the inflammatory response at the ocular surface after receiving mechanical stimuli.MethodsHuman conjunctival epithelial cells (HConjECs) were treated with Yoda1, a Piezo1-specific agonist, and various allergens to measure cytokine expression levels using qRT-PCR and Western blot. Piezo1 activation-induced intracellular signaling pathways were also investigated. Mechanical stretching experiments were conducted to simulate Piezo1 activation in HConjECs. Inin vivostudies, using immunohistochemistry, rats were administered Yoda1 eye drops to examine the inflammatory response in the conjunctiva and Piezo1-induced signaling activation.ResultsHConjECs expressed functional Piezo1 channel, and its activation significantly increased IL-6 and IL-8 expression through the p38 MAPK-CREB pathway. Piezo1-induced [Ca2+]ielevation was crucial for the production of IL-6. Mechanical stretching mimicked these effects.In vivo, Yoda1 administration led to enhanced immunoreactivity of phospho-p38 MAPK and phospho-CREB and increased IL-6 in the rat conjunctival epithelium. Significant neutrophil infiltration was also observed after Piezo1 channel activation without affecting eosinophil numbers.ConclusionMechanical stress-induced Piezo1 channel activation in conjunctival epithelial cells can cause ocular inflammation by upregulating pro-inflammatory cytokines via the p38 MAPK-CREB pathway and promoting neutrophil infiltration. These findings suggest that mechanical stimuli on ocular surface tissues are significant risk factors for ocular inflammation.HighlightsPiezo1 channel activation increased IL-6 via p38 MAPK-CREB pathway in Human conjunctival epithelial cells (HConjECs).Piezo1 activation mimicked fungal extract but not pollen or dust mite.Mechanical stretching mimicked Piezo1 effects, boosting IL-6 production in HConjECs.Piezo1 activation elevated p-p38 MAPK, p-CREB, and IL-6 in the rat conjunctiva.Piezo1 activation leads to neutrophil infiltration in the rat conjunctival epithelium.Graphical abstractMechanosensitive Piezo1 channel activation induces IL-6 expression in the conjunctival epithelial cells via elevation of [Ca2+]iand activation of p38 MAPK and transcription factor CREB.Mechanical stress stimulates Piezo1 channel and Ca2+influx through it, which induces activation of p38 MAPK. A transcription factor CREB is phosphorylated after p38 MAPK activation, then promotesIL-6transcription.
Aromatase in adipose tissue exerts an osteoprotective function in male mice via phosphate regulation
Authors: Ikedo Aoi , Yamashita Michiko , Hoshino Maiko , Okuno Yosuke , Koike Megumi , Uga Minori , Tanifuji Kazuya , Segawa Hiroko , Fukumoto Seiji , Imai Yuuki 
Published: June 2024

AbstractAromatase contributes to maintenance of bone mass because male patients with loss-of-function mutations ofCYP19A1exhibit bone loss. Treatment with aromatase inhibitor also causes bone loss in men and post-menopausal women, suggesting that part of the anabolic effect of testosterone in men is dependent on estradiol (E2) biosynthesized by aromatase in non-gonadal tissues. It remains unclear how locally biosynthesized E2 contributes to maintenance of bone mass. We examined the function of aromatase in local tissues rather than gonads using cell-type specific aromatase knockout (KO) mice. Because osteoblast-specific aromatase KO mice exhibited no bone phenotype, we focused on adipose tissue, known as a reservoir of steroid hormones and analyzed the bone phenotypes of adipose tissue-specific aromatase KO (AroΔaP2) mice. Sixteen-week-old maleAroΔaP2mice exhibited significantly lower bone mineral density in tibia and femur, especially in trabecular bone, than controls. Bone histomorphometry showed thatAroΔaP2mice exhibited an insufficient calcification bone phenotype with increased osteoid volume and width, and decreased osteoclast area and numbers. Moreover, serum phosphate, renal phosphate reabsorption and FGF23 were significantly lower inAroΔaP2, suggesting that the insufficient calcification phenotype inAroΔaP2was not caused by excessive FGF23 activities. Finally, we analyzed NaPi2a and NaPi2c, phosphate transporters localized in the kidney, and found that protein levels in renal brush border membrane vesicles were lower inAroΔaP2. These results indicate that estrogens locally biosynthesized by aromatase in adipocytes can play a significant role in bone mass maintenance via regulation of phosphate reabsorption in the kidney by NaPi2.Impact StatementMale adipocyte-specific aromatase KO mice (AroΔaP2) exhibited bone loss and increased osteoid due to decreased serum phosphate and urinary phosphate reabsorption as a result of reduced NaPi2 proteins expression in the kidney.
Control of epiblast cell fate by mechanical cues
Authors: Guillot Charlène , Djeffal Yannis , Serra Mattia , Pourquié Olivier 
Published: June 2024

SummaryIn amniotes, embryonic tissues originate from multipotent epiblast cells, arranged in a mosaic of presumptive territories. How these domains fated to specific lineages become segregated during body formation remains poorly understood. Using single cell RNA sequencing analysis and lineage tracing in the chicken embryo, we identify epiblast cells contributing descendants to the neural tube, somites and lateral plate after completion of gastrulation. We show that intercalation after cell division generates important movements of epiblast cells which lead to their relocation to different presumptive territories, explaining this broad spectrum of fates. This tissue remodeling phase is transient, being soon followed by the establishment of boundaries restricting cell movements therefore defining the presumptive territories of the epiblast. Finally, we find that the epiblast faces distinct mechanical constraints along the antero-posterior axis, leading to cell fate alterations when challenged. Together, we demonstrate the critical role of mechanical cues in epiblast fate determination.
Integrating episodic and spatial context signals in the hippocampus
Authors: Nitsch Alexander , de Haas Naomi , Garvert Mona M. , Doeller Christian F. 
Published: June 2024

AbstractEpisodic and spatial memory are the two key components of the mnemonic system in humans. Episodic memory enables us to remember events from the past whereas spatial memory enables us to form a map-like representation of the environment. Interestingly, these seemingly different functions rely on the same brain structure: the hippocampus. Yet, how the hippocampus supports both at the same time remains unclear. Here, we tested the hypotheses that the hippocampus supports these two systems either via a common coding mechanism or via a parallel processing mechanism. To this end, we combined functional magnetic resonance imaging (fMRI) with an episodic life-simulation task and a spatial virtual reality task to manipulate episodic and spatial context associations of objects. We then investigated fMRI adaptation effects between these objects as a result of shared contexts. We found that the fMRI signal in the anterior hippocampus scaled with the combined prediction of shared episodic and spatial contexts, in line with the idea of a common coding mechanism. We found no evidence for a parallel processing mechanism, as there were no differences between episodic and spatial effects. The common coding effect for episodic and spatial memory dovetails with the broader notion of domain-general hippocampal cognitive maps.
Pseudomonas aeruginosaimpairs mitochondrial function and metabolism during infection of corneal epithelial cells
Authors: Ramachandran Rajalakshmy Ayilam , Abdallah Joelle T. , Rehman Mahad , Baniasadi Hamid , Blanton Abigail M. , Vizcaino Santiago , Robertson Danielle M. 
Published: June 2024

AbstractPseudomonas aeruginosa(PA) is a gram-negative opportunistic pathogen that can infect the cornea as a result of trauma or contact lens wear. In addition to their known energy producing role, mitochondria are important mediators of immune signaling and host defense. While certain pathogens have developed strategies to evade host defenses by modulating host mitochondrial dynamics and metabolism, the ability of PA to harness host cell mitochondria during corneal infection is unknown. Using a combination of biochemical and imaging techniques, we show that PA infection of corneal epithelial cells induced mitochondrial fission in a DRP1-dependent manner that preceded PINK1/Parkin and FUNDC1-mediated mitophagy. PA also impaired NADH-linked respiration through a reduction in complex 1. This corresponded to a decrease in metabolic pathways related to glycolysis and the TCA cycle. Metabolomics analysis further demonstrated an upregulation of the pentose phosphate pathway, arginine, purine, and pyrimidine metabolism in PA infected cells. These pathways may provide a key source of nucleotides, amino acids, and nitrogen for both the host cell and PA, in addition to antioxidant functions. Following treatment with gentamicin to kill all extracellular bacteria, metabolic flux analysis showed that corneal epithelial cells were able to restore mitochondrial function despite the continued presence of intracellular PA. Taken together, these data demonstrate that mitochondrial dysfunction and metabolic rewiring in host cells is triggered by extracellular PA, but once inside, PA requires healthy mitochondria to ensure host cell survival.
Separating sensory from timing processes: a cognitive encoding and neural decoding approach
Authors: Jin Christina Yi , Razafindrahaba Anna , Bordas Raphaël , van Wassenhove Virginie 
Published: June 2024

AbstractThe internal clock is a psychological model for timing behavior. According to information theory, psychological time might be a manifestation of information flow during sensory processing. Herein, we tested three hypotheses: (1) whether sensory adaptation reduces (or novelty increases) the rate of the internal clock (2) whether the speed of the clock reflects the amount of cortical sensory processing? (3) whether motion tunes clock speed.The current study used an oddball paradigm in which participants detected duration changes while being recorded with electroencephalography (EEG). For data analysis, we combined cognitive modeling with neural decoding techniques. Specifically, we designed Adaptive-Thought-of-Control (ACT-R) models to explain human data and linked them to the sensory EEG features discovered through machine learning.Our results indicate that timing performance is influenced by both timing and non-timing factors. The internal clock may reflect the amount of sensory processing, thereby clarifying a long-standing sensory timing mystery.
Structural and mechanistic studies on human LONP1 redefine the hand-over-hand translocation mechanism
Authors: Mindrebo Jeffrey T. , Lander Gabriel C. 
Published: June 2024

AbstractAAA+ enzymes use energy from ATP hydrolysis to remodel diverse cellular targets. Structures of substrate-bound AAA+ complexes suggest that these enzymes employ a conserved hand-over-hand mechanism to thread substrates through their central pore. However, the fundamental aspects of the mechanisms governing motor function and substrate processing within specific AAA+ families remain unresolved. We used cryo-electron microscopy to structurally interrogate reaction intermediates from in vitro biochemical assays to inform the underlying regulatory mechanisms of the human mitochondrial AAA+ protease, LONP1. Our results demonstrate that substrate binding allosterically regulates proteolytic activity, and that LONP1 can adopt a configuration conducive to substrate translocation even when the ATPases are bound to ADP. These results challenge the conventional understanding of the hand-over-hand translocation mechanism, giving rise to an alternative model that aligns more closely with biochemical and biophysical data on related enzymes like ClpX, ClpA, the 26S proteasome, and Lon protease.
Long term follow-up in anti-contactin-1 autoimmune nodopathy
Authors: Caballero-Ávila Marta , Martín-Aguilar Lorena , Pascual-Goñi Elba , Michael Milou R. , Koel-Simmelink Marleen J.A. , Höftberger Romana , Wanschitz Julia , Alonso-Jiménez Alicia , Armangué Thais , Baars Adája Elisabeth , Carbayo Álvaro , Castek Barbara , Collet-Vidiella Roger , Winter Jonathan De , del Real Maria Angeles , Delmont Emilien , Diamanti Luca , Doneddu Pietro Emiliano , Hiew Fu Liong , Gallardo Eduard , Gonzalez Amaia , Grinzinger Susanne , Horga Alejandro , Iglseder Stephan , Jacobs Bart C. , Jauregui Amaia , Killestein Joep , Pozza Elisabeth Lindeck , Martínez-Martínez Laura , Nobile-Orazio Eduardo , Ortiz Nicolau , Pérez-Pérez Helena , Poppert Kai-Nicolas , Ripellino Paolo , Roche Jose Carlos , Rodriguez de Rivera Franscisco Javier , Rostasy Kevin , Sparasci Davide , Tejada-Illa Clara , Teunissen Charlotte C.E. , Vegezzi Elisa , Xuclà-Ferrarons Tomàs , Zach Fabian , Wieske Luuk , Eftimov Filip , Lleixà Cinta , Querol Luis 
Published: June 2024

AbstractObjectiveTo analyze long-term clinical and biomarker features of anti-contactin-1 (CNTN1) autoimmune nodopathy (AN).MethodsPatients with anti-CNTN1+ AN detected in our laboratory from which clinical information was available were included. Clinical features and treatment response were retrospectively collected. Autoantibody, serum neurofilament light (sNfL) and serum CNTN1 levels (sCNTN1) were analyzed at baseline and follow-up.ResultsThirty-one patients were included. Patients presented with progressive motor-sensory neuropathy (76.7%) with proximal (74.2%) and distal involvement (87.1%), ataxia (71.4%) and severe disability (median INCAT at nadir of 8)). Eleven patients (35%) showed kidney involvement. Most patients (97%) received IVIg but only one achieved remission with IVIg. Twenty-two patients (71%) received corticosteroids, and three of them (14%) did not need further treatments. Rituximab was effective in 21/22 patients (95.5%), with most of them (72%) receiving a single course. Four patients (12.9%) relapsed after a median follow-up of 25 months after effective treatment [12-48]. Anti-CNTN1 titers correlated with clinical scales at sampling and were negative after treatment in all patients but one (20/21). sNfL levels were significantly higher and sCNTN1 significantly lower in anti-CNTN1+ patients than in healthy controls (sNfL: 135.9 pg/mL vs 7.48 pg/mL, sCNTN1: 25.03 pg/mL vs 22186 pg/mL, p< 0.0001). Both sNfL and sCNTN1 returned to normal levels after successful treatment.InterpretationPatients with anti-CNTN1+ AN have a characteristic clinical profile. Clinical and immunological relapses are infrequent after successful treatment, suggesting that continuous treatment is unnecessary. Anti-CNTN1 antibodies, sNfL and aCNTN1 levels are useful to monitor disease status and treatment efficacy in these patients.
Disentangling the effects of nicotine versus non-nicotine constituents of tobacco smoke on major depressive disorder: A multivariable Mendelian randomization study
Authors: Burke Chloe , Taylor Gemma , Freeman Tom P , Sallis Hannah , Wootton Robyn E , Munafò Marcus R , Dardani Christina , Khouja Jasmine 
Published: June 2024

ABSTRACTBackground and aimsThere is growing evidence that tobacco smoking causes depression, but it is unclear which constituents of tobacco smoke (e.g., nicotine, carbon monoxide) may be responsible. We used Mendelian randomisation (MR) to examine the independent effect of nicotine on depression, by adjusting the effect of nicotine exposure (via nicotine metabolite ratio [NMR]) for the overall effect of smoking heaviness (via cigarettes per day [CPD]) to account for the non-nicotine constituents of tobacco smoke.DesignUnivariable MR and multivariable MR (MVMR) were used to explore the total and independent effects of genetic liability to NMR and CPD on major depressive disorder (MDD). Our primary method was inverse variance weighted (IVW) regression, with other methods as sensitivity analyses.Setting and participantsFor the exposures, we used genome-wide association study (GWAS) summary statistics among European ancestry individuals for CPD (n=143,210) and NMR (n=5,185). For the outcome, a GWAS of MDD stratified by smoking status was conducted using individual-level data from UK Biobank (n=35,871-194,881).MeasurementsGenetic variants robustly associated with NMR and CPD.FindingsUnivariable MR indicated a causal effect of CPD on MDD (odds ratio [OR]IVW=1.13, 95% confidence interval [CI]=1.04-1.23,P=0.003) but no clear evidence for an effect of NMR on MDD (ORIVW=0.98, 95% CI=0.97-1.00,P=0.134). MVMR indicated a causal effect of CPD on MDD when accounting for NMR (ORMVMR-IVW=1.19, 95% CI=1.03-1.37,P=0.017; ORMVMR-EGGER=1.13, 95% CI=0.89-1.43,P=0.300) and weak evidence of a small effect of NMR on MDD when accounting for CPD (ORMVMR-IVW=0.98, 95% CI=0.96-1.00,P=0.056; ORMVMR-EGGER=0.98, 95% CI=0.96-1.00,P=0.038).ConclusionsThe causal effect of tobacco smoking on depression appears to be largely independent of nicotine exposure, which implies the role of alternative causal pathways.