bluuebunny/crossref_metadata_2025_split huggingface dataset:
UDP-glucuronate metabolism controls RIPK1-driven liver damage in nonalcoholic steatohepatitis
Authors: Zhang Tao , Zhang Na , Xing Jing , Zhang Shuhua , Chen Yulu , Xu Daichao , Gu Jinyang 
Published: May 2023

AbstractHepatocyte apoptosis plays an essential role in the progression of nonalcoholic steatohepatitis (NASH). However, the molecular mechanisms underlying hepatocyte apoptosis remain unclear. Here, we identify UDP-glucose 6-dehydrogenase (UGDH) as a suppressor of NASH-associated liver damage by inhibiting RIPK1 kinase-dependent hepatocyte apoptosis. UGDH is progressively reduced in proportion to NASH severity. UGDH absence from hepatocytes hastens the development of liver damage in male mice with NASH, which is suppressed by RIPK1 kinase-dead knockin mutation. Mechanistically, UGDH suppresses RIPK1 by converting UDP-glucose to UDP-glucuronate, the latter directly binds to the kinase domain of RIPK1 and inhibits its activation. Recovering UDP-glucuronate levels, even after the onset of NASH, improved liver damage. Our findings reveal a role for UGDH and UDP-glucuronate in NASH pathogenesis and uncover a mechanism by which UDP-glucuronate controls hepatocyte apoptosis by targeting RIPK1 kinase, and suggest UDP-glucuronate metabolism as a feasible target for more specific treatment of NASH-associated liver damage.
Recovery of homogeneous photocatalysts by covalent organic framework membranes
Authors: Yang Hao , Xu Jinhui , Cao Hui , Wu Jie , Zhao Dan 
Published: May 2023

AbstractTransition metal-based homogeneous photocatalysts offer a wealth of opportunities for organic synthesis. The most versatile ruthenium(II) and iridium(III) polypyridyl complexes, however, are among the rarest metal complexes. Moreover, immobilizing these precious catalysts for recycling is challenging as their opacity may obstruct light transmission. Recovery of homogeneous catalysts by conventional polymeric membranes is promising but limited, as the modulation of their pore structure and tolerance of polar organic solvents are challenging. Here, we report the effective recovery of homogeneous photocatalysts using covalent organic framework (COF) membranes. An array of COF membranes with tunable pore sizes and superior organic solvent resistance were prepared. Ruthenium and iridium photoredox catalysts were recycled for 10 cycles in various types of photochemical reactions, constantly achieving high catalytical performance, high recovery rates, and high permeance. We successfully recovered the photocatalysts at gram-scale. Furthermore, we demonstrated a cascade isolation of an iridium photocatalyst and purification of a small organic molecule product with COF membranes possessing different pore sizes. Our results indicate an intriguing potential to shift the paradigm of the pharmaceutical and fine chemical synthesis campaign.
Monoterpenoid aryl hydrocarbon receptor allosteric antagonists protect against ultraviolet skin damage in female mice
Authors: Ondrová Karolína , Zůvalová Iveta , Vyhlídalová Barbora , Krasulová Kristýna , Miková Eva , Vrzal Radim , Nádvorník Petr , Nepal Binod , Kortagere Sandhya , Kopečná Martina , Kopečný David , Šebela Marek , Rastinejad Fraydoon , Pu Hua , Soural Miroslav , Rolfes Katharina Maria , Haarmann-Stemmann Thomas , Li Hao , Mani Sridhar , Dvořák Zdeněk 
Published: May 2023

AbstractThe human aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is a pivotal regulator of human physiology and pathophysiology. Allosteric inhibition of AhR was previously thought to be untenable. Here, we identify carvones as noncompetitive, insurmountable antagonists of AhR and characterize the structural and functional consequences of their binding. Carvones do not displace radiolabeled ligands from binding to AhR but instead bind allosterically within the bHLH/PAS-A region of AhR. Carvones do not influence the translocation of ligand-activated AhR into the nucleus but inhibit the heterodimerization of AhR with its canonical partner ARNT and subsequent binding of AhR to the promoter of CYP1A1. As a proof of concept, we demonstrate physiologically relevant Ahr-antagonism by carvones in vivo in female mice. These substances establish the molecular basis for selective targeting of AhR regardless of the type of ligand(s) present and provide opportunities for the treatment of disease processes modified by AhR.
Comprehensive insights from composition to functional microbe-based biodiversity of the infant human gut microbiota
Authors: Lugli Gabriele Andrea , Mancabelli Leonardo , Milani Christian , Fontana Federico , Tarracchini Chiara , Alessandri Giulia , van Sinderen Douwe , Turroni Francesca , Ventura Marco 
Published: May 2023

AbstractDuring infancy, gut microbiota development is a crucial process involved in the establishment of microbe–host interactions which may persist throughout adulthood, and which are believed to influence host health. To fully understand the complexities of such interactions, it is essential to assess gut microbiota diversity of newborns and its associated microbial dynamics and relationships pertaining to health and disease. To explore microbial biodiversity during the first 3 years of human life, 10,935 shotgun metagenomic datasets were taxonomically and functionally classified. Microbial species distribution between infants revealed the presence of eight major Infant Community State Types (ICSTs), being dominated by 17 bacterial taxa, whose distribution was shown to correspond to the geographical origin and infant health status. In total, 2390 chromosomal sequences of the predominant taxa were reconstructed from metagenomic data and used in combination with 44,987 publicly available genomes to trace the distribution of microbial Population Subspecies (PS) within the different infant groups, revealing patterns of multistrain coexistence among ICSTs. Finally, implementation of a metagenomic- and metatranscriptomic-based metabolic profiling highlighted different enzymatic expression patterns of the gut microbiota that allowed us to acquire insights into mechanistic aspects of health-gut microbiota interplay in newborns. Comparison between metagenomic and metatranscriptomic data highlights how a complex environment like the human gut must be investigated by employing both sequencing methodologies and possibly supplemented with metabolomics approaches. While metagenomic analyses are very useful for microbial classification aimed at unveiling key players driving microbiota balances, using these data to explain functionalities of the microbiota is not always warranted.
The cell wall lipoprotein CD1687 acts as a DNA binding protein during deoxycholate-induced biofilm formation in Clostridioides difficile
Authors: Auria Emile , Hunault Lise , England Patrick , Monot Marc , Pipoli Da Fonseca Juliana , Matondo Mariette , Duchateau Magalie , Tremblay Yannick D. N. , Dupuy Bruno 
Published: May 2023

AbstractThe ability of bacterial pathogens to establish recurrent and persistent infections is frequently associated with their ability to form biofilms. Clostridioides difficile infections have a high rate of recurrence and relapses and it is hypothesized that biofilms are involved in its pathogenicity and persistence. Biofilm formation by C. difficile is still poorly understood. It has been shown that specific molecules such as deoxycholate (DCA) or metronidazole induce biofilm formation, but the mechanisms involved remain elusive. In this study, we describe the role of the C. difficile lipoprotein CD1687 during DCA-induced biofilm formation. We showed that the expression of CD1687, which is part of an operon within the CD1685-CD1689 gene cluster, is controlled by multiple transcription starting sites and some are induced in response to DCA. Only CD1687 is required for biofilm formation and the overexpression of CD1687 is sufficient to induce biofilm formation. Using RNAseq analysis, we showed that CD1687 affects the expression of transporters and metabolic pathways and we identified several potential binding partners by pull-down assay, including transport-associated extracellular proteins. We then demonstrated that CD1687 is surface exposed in C. difficile, and that this localization is required for DCA-induced biofilm formation. Given this localization and the fact that C. difficile forms eDNA-rich biofilms, we confirmed that CD1687 binds DNA in a non-specific manner. We thus hypothesize that CD1687 is a component of the downstream response to DCA leading to biofilm formation by promoting interaction between the cells and the biofilm matrix by binding eDNA.
Glucocerebrosidase activity and lipid levels are related to protein pathologies in Parkinson’s disease
Authors: Leyns Cheryl E. G. , Prigent Alice , Beezhold Brenna , Yao Lihang , Hatcher Nathan G. , Tao Peining , Kang John , Suh EunRan , Van Deerlin Vivianna M. , Trojanowski John Q. , Lee Virginia M. Y. , Kennedy Matthew E. , Fell Matthew J. , Henderson Michael X. 
Published: May 2023

AbstractParkinson’s disease (PD) and dementia with Lewy bodies (DLB) are progressive neurodegenerative diseases characterized by the accumulation of misfolded α-synuclein in the form of Lewy pathology. While most cases are sporadic, there are rare genetic mutations that cause disease and more common variants that increase incidence of disease. The most prominent genetic mutations for PD and DLB are in the GBA1 and LRRK2 genes. GBA1 mutations are associated with decreased glucocerebrosidase activity and lysosomal accumulation of its lipid substrates, glucosylceramide and glucosylsphingosine. Previous studies have shown a link between this enzyme and lipids even in sporadic PD. However, it is unclear how the protein pathologies of disease are related to enzyme activity and glycosphingolipid levels. To address this gap in knowledge, we examined quantitative protein pathology, glucocerebrosidase activity and lipid substrates in parallel from 4 regions of 91 brains with no neurological disease, idiopathic, GBA1-linked, or LRRK2-linked PD and DLB. We find that several biomarkers are altered with respect to mutation and progression to dementia. We found mild association of glucocerebrosidase activity with disease, but a strong association of glucosylsphingosine with α-synuclein pathology, irrespective of genetic mutation. This association suggests that Lewy pathology precipitates changes in lipid levels related to progression to dementia.
Commensurate-to-incommensurate transition of charge-density-wave order and a possible quantum critical point in pressurized kagome metal CsV3Sb5
Authors: Feng X. Y. , Zhao Z. , Luo J. , Yang J. , Fang A. F. , Yang H. T. , Gao H. J. , Zhou R. , Zheng Guo-qing 
Published: May 2023

AbstractClarifying the interplay between charge-density waves (CDWs) and superconductivity is important in the kagome metal CsV3Sb5, and pressure (P) can play a crucial role. Here, we present121/123Sb nuclear quadrupole resonance (NQR) measurements under hydrostatic pressures up to 2.43 GPa in CsV3Sb5single crystals. We demonstrate that the CDW gradually changes from a commensurate modulation with a star-of-David (SoD) pattern to an incommensurate one with a superimposed SoD and Tri-hexagonal (TrH) pattern stacking along thec-axis. Moreover, the linewidthδνof121/123Sb-NQR spectra increases with cooling down toTCDW, indicating the appearance of a short-range CDW order due to CDW fluctuations pinned by quenched disorders. Theδνshows a Curie–Weiss temperature dependence and tends to diverge atPc ~ 1.9 GPa, suggesting that a CDW quantum critical point (QCP) exists atPcwhereTcshows the maximum. ForP > Pc, spin fluctuations are enhanced when the CDW is suppressed. Our results suggest that the maximalTcatPc ~ 1.9 GPa is related to the CDW QCP, and the presence of spin fluctuations prevents theTcfrom a rapid decrease otherwise, after the CDW is completely suppressed.
Picophotonic localization metrology beyond thermal fluctuations
Authors: Liu Tongjun , Chi Cheng-Hung , Ou Jun-Yu , Xu Jie , Chan Eng Aik , MacDonald Kevin F. , Zheludev Nikolay I. 
Published: May 2023

AbstractDespite recent tremendous progress in optical imaging and metrology1–6, there remains a substantial resolution gap between atomic-scale transmission electron microscopy and optical techniques. Is optical imaging and metrology of nanostructures exhibiting Brownian motion possible with such resolution, beyond thermal fluctuations? Here we report on an experiment in which the average position of a nanowire with a thermal oscillation amplitude of ∼150 pm is resolved in single-shot measurements with subatomic precision of 92 pm, using light at a wavelength of λ = 488 nm, providing an example of such sub-Brownian metrology with ∼λ/5,300 precision. To localize the nanowire, we employ a deep-learning analysis of the scattering of topologically structured light, which is highly sensitive to the nanowire’s position. This non-invasive metrology with absolute errors down to a fraction of the typical size of an atom, opens a range of opportunities to study picometre-scale phenomena with light.
Chloroquine resistance evolution in Plasmodium falciparum is mediated by the putative amino acid transporter AAT1
Authors: Amambua-Ngwa Alfred , Button-Simons Katrina A. , Li Xue , Kumar Sudhir , Brenneman Katelyn Vendrely , Ferrari Marco , Checkley Lisa A. , Haile Meseret T. , Shoue Douglas A. , McDew-White Marina , Tindall Sarah M. , Reyes Ann , Delgado Elizabeth , Dalhoff Haley , Larbalestier James K. , Amato Roberto , Pearson Richard D. , Taylor Alexander B. , Nosten François H. , D’Alessandro Umberto , Kwiatkowski Dominic , Cheeseman Ian H. , Kappe Stefan H. I. , Avery Simon V. , Conway David J. , Vaughan Ashley M. , Ferdig Michael T. , Anderson Timothy J. C. 
Published: May 2023

AbstractMalaria parasites break down host haemoglobin into peptides and amino acids in the digestive vacuole for export to the parasite cytoplasm for growth: interrupting this process is central to the mode of action of several antimalarial drugs. Mutations in the chloroquine (CQ) resistance transporter, pfcrt, located in the digestive vacuole membrane, confer CQ resistance in Plasmodium falciparum, and typically also affect parasite fitness. However, the role of other parasite loci in the evolution of CQ resistance is unclear. Here we use a combination of population genomics, genetic crosses and gene editing to demonstrate that a second vacuolar transporter plays a key role in both resistance and compensatory evolution. Longitudinal genomic analyses of the Gambian parasites revealed temporal signatures of selection on a putative amino acid transporter (pfaat1) variant S258L, which increased from 0% to 97% in frequency between 1984 and 2014 in parallel with the pfcrt1 K76T variant. Parasite genetic crosses then identified a chromosome 6 quantitative trait locus containing pfaat1 that is selected by CQ treatment. Gene editing demonstrated that pfaat1 S258L potentiates CQ resistance but at a cost of reduced fitness, while pfaat1 F313S, a common southeast Asian polymorphism, reduces CQ resistance while restoring fitness. Our analyses reveal hidden complexity in CQ resistance evolution, suggesting that pfaat1 may underlie regional differences in the dynamics of resistance evolution, and modulate parasite resistance or fitness by manipulating the balance between both amino acid and drug transport.
Signal peptide mimicry primes Sec61 for client-selective inhibition
Authors: Rehan Shahid , Tranter Dale , Sharp Phillip P. , Craven Gregory B. , Lowe Eric , Anderl Janet L. , Muchamuel Tony , Abrishami Vahid , Kuivanen Suvi , Wenzell Nicole A. , Jennings Andy , Kalyanaraman Chakrapani , Strandin Tomas , Javanainen Matti , Vapalahti Olli , Jacobson Matthew P. , McMinn Dustin , Kirk Christopher J. , Huiskonen Juha T. , Taunton Jack , Paavilainen Ville O. 
Published: May 2023

AbstractPreventing the biogenesis of disease-relevant proteins is an attractive therapeutic strategy, but attempts to target essential protein biogenesis factors have been hampered by excessive toxicity. Here we describe KZR-8445, a cyclic depsipeptide that targets the Sec61 translocon and selectively disrupts secretory and membrane protein biogenesis in a signal peptide-dependent manner. KZR-8445 potently inhibits the secretion of pro-inflammatory cytokines in primary immune cells and is highly efficacious in a mouse model of rheumatoid arthritis. A cryogenic electron microscopy structure reveals that KZR-8445 occupies the fully opened Se61 lateral gate and blocks access to the lumenal plug domain. KZR-8445 binding stabilizes the lateral gate helices in a manner that traps select signal peptides in the Sec61 channel and prevents their movement into the lipid bilayer. Our results establish a framework for the structure-guided discovery of novel therapeutics that selectively modulate Sec61-mediated protein biogenesis.
3DFlex: determining structure and motion of flexible proteins from cryo-EM
Authors: Punjani Ali , Fleet David J. 
Published: May 2023

AbstractModeling flexible macromolecules is one of the foremost challenges in single-particle cryogenic-electron microscopy (cryo-EM), with the potential to illuminate fundamental questions in structural biology. We introduce Three-Dimensional Flexible Refinement (3DFlex), a motion-based neural network model for continuous molecular heterogeneity for cryo-EM data. 3DFlex exploits knowledge that conformational variability of a protein is often the result of physical processes that transport density over space and tend to preserve local geometry. From two-dimensional image data, 3DFlex enables the determination of high-resolution 3D density, and provides an explicit model of a flexible protein’s motion over its conformational landscape. Experimentally, for large molecular machines (tri-snRNP spliceosome complex, translocating ribosome) and small flexible proteins (TRPV1 ion channel, αVβ8 integrin, SARS-CoV-2 spike), 3DFlex learns nonrigid molecular motions while resolving details of moving secondary structure elements. 3DFlex can improve 3D density resolution beyond the limits of existing methods because particle images contribute coherent signal over the conformational landscape.
Early detection of Solanum lycopersicum diseases from temporally-aggregated hyperspectral measurements using machine learning
Authors: Tomaszewski Michał , Nalepa Jakub , Moliszewska Ewa , Ruszczak Bogdan , Smykała Krzysztof 
Published: May 2023

AbstractSome plant diseases can significantly reduce harvest, but their early detection in cultivation may prevent those consequential losses. Conventional methods of diagnosing plant diseases are based on visual observation of crops, but the symptoms of various diseases may be similar. It increases the difficulty of this task even for an experienced farmer and requires detailed examination based on invasive methods conducted in laboratory settings by qualified personnel. Therefore, modern agronomy requires the development of non-destructive crop diagnosis methods to accelerate the process of detecting plant infections with various pathogens. This research pathway is followed in this paper, and an approach for classifying selected Solanum lycopersicum diseases (anthracnose, bacterial speck, early blight, late blight and septoria leaf) from hyperspectral data captured on consecutive days post inoculation (DPI) is presented. The objective of that approach was to develop a technique for detecting infection in less than seven days after inoculation. The dataset used in this study included hyperspectral measurements of plants of two cultivars of S. lycopersicum: Benito and Polfast, which were infected with five different pathogens. Hyperspectral reflectance measurements were performed using a high-spectral-resolution field spectroradiometer (350–2500 nm range) and they were acquired for 63 days after inoculation, with particular emphasis put on the first 17 day-by-day measurements. Due to a significant data imbalance and low representation of measurements on some days, the collective datasets were elaborated by combining measurements from several days. The experimental results showed that machine learning techniques can offer accurate classification, and they indicated the practical utility of our approaches.
Evaluation of microbial communities of Chinese Feng-flavor Daqu with effects of environmental factors using traceability analysis
Authors: Zhang Yongli , Xu Chen , Xing Gang , Yan Zongke , Chen Yaodong 
Published: May 2023

AbstractAnalysis of the changes of microorganisms during Chinese Feng-flavor Daqu fermentation, and the specific contribution of different environmental factors to Daqu microorganisms. High throughput sequencing technology and SourceTracker software were used to analyze the microbial diversity of Feng-flavor Daqu before and after fermentation. 85 fungal and 105 bacterial were detected in the newly pressed Feng-flavor Daqu, while 33 fungal and 50 bacterial in the mature Daqu, and 202 fungal and 555 bacterial in the environmental samples. After fermentation, the microbial community structure of Daqu changed and decreased significantly. 94.7% of fungi come from raw materials and 1.8% from outdoor ground, 60.95% of bacteria come from indoor ground, 20.44% from raw materials, and 8.98% from tools. By comparing the changes of microorganisms in Daqu before and after fermentation, the microorganisms in mature Daqu may mainly come from not only the enhanced strains but also the environment.The source of main microorganisms in Feng-flavor Daqu and the influence of environmental factors on the quality of Daqu were clarified, which provided a basis for improving the quality of Feng-flavor Daqu.
Distinct histopathological features are associated with molecular subtypes and outcome in low grade serous ovarian carcinoma
Authors: Hollis Robert L. , Thomson John P. , van Baal Juliette , Ilenkovan Narthana , Churchman Michael , van de Vijver Koen , Dijk Frederike , Meynert Alison M. , Bartos Clare , Rye Tzyvia , Croy Ian , Diana Patricia , van Gent Mignon , Creedon Helen , Nirsimloo Rachel , Lok Christianne , Gourley Charlie , Herrington C. Simon 
Published: May 2023

AbstractLow grade serous ovarian carcinoma (LGSOC) demonstrates unique clinical and molecular features compared to other ovarian cancer types. The relationship between common histological features of LGSOC and molecular events, such as hormone receptor expression patterns and MAPK gene mutation status, remains poorly understood. Recent data suggest some of these molecular features may be biomarkers of response to recently introduced biologically-targeted therapies, namely endocrine therapy and MEK inhibitors. We utilize a cohort of 63 pathologically-confirmed LGSOC cases with whole exome sequencing and hormone receptor expression data to investigate these relationships. LGSOC cases demonstrated uniformly high oestrogen receptor (ER) expression, but variable progesterone receptor (PR) expression intensity. 60% and 37% of cases demonstrated micropapillary and macropapillary patterns of stromal invasion, respectively. 63% of cases demonstrated desmoplasia, which was significantly associated with advanced disease stage and visible residual disease after cytoreductive surgery. MAPK-mutant cases (KRAS,BRAF,NRAS) more frequently demonstrated macropapillary stromal invasion, while Chr1p loss was associated with desmoplasia and low PR expression. Presence of micropapillary stromal invasion and low PR expression were associated with significantly poorer survival after accounting for stage and residual disease status. Together, these data identify novel relationships between histopathological features and molecularly-defined subgroups in LGSOC.