bluuebunny/crossref_metadata_2025 huggingface dataset:
Efflux pump gene amplifications bypass necessity of multiple target mutations for resistance against dual-targeting antibiotic
Authors: Silva Kalinga Pavan T. , Sundar Ganesh , Khare Anupama
Published: June 2023

Antibiotics that have multiple cellular targets theoretically reduce the frequency of resistance evolution, but adaptive trajectories and resistance mechanisms against such antibiotics are understudied. Here we investigate these in methicillin resistant Staphylococcus aureus (MRSA) using experimental evolution upon exposure to delafloxacin (DLX), a novel fluoroquinolone that targets both DNA gyrase and topoisomerase IV. We show that selection for coding sequence mutations and genomic amplifications of the gene encoding a poorly characterized efflux pump, SdrM, leads to high DLX resistance, circumventing the requirement for mutations in both target enzymes. In the evolved populations, sdrM overexpression due to genomic amplifications containing sdrM and two adjacent genes encoding efflux pumps results in high DLX resistance, while the adjacent hitchhiking efflux pumps contribute to streptomycin cross-resistance. Further, lack of sdrM necessitates mutations in both target enzymes to evolve DLX resistance, and sdrM thus increases the frequency of resistance evolution. Finally, sdrM mutations and amplifications are similarly selected in two diverse clinical isolates, indicating the generality of this DLX resistance mechanism. Our study highlights that instead of reduced rates of resistance, evolution of resistance to multi-targeting antibiotics can involve alternate high-frequency evolutionary paths, that may cause unexpected alterations of the fitness landscape, including antibiotic cross-resistance.
Persistent serum protein signatures define an inflammatory subcategory of long COVID
Authors: Talla Aarthi , Vasaikar Suhas V. , Szeto Gregory Lee , Lemos Maria P. , Czartoski Julie L. , MacMillan Hugh , Moodie Zoe , Cohen Kristen W. , Fleming Lamar B. , Thomson Zachary , Okada Lauren , Becker Lynne A. , Coffey Ernest M. , De Rosa Stephen C. , Newell Evan W. , Skene Peter J. , Li Xiaojun , Bumol Thomas F. , Juliana McElrath M. , Torgerson Troy R.
Published: June 2023

Long COVID or post-acute sequelae of SARS-CoV-2 (PASC) is a clinical syndrome featuring diverse symptoms that can persist for months following acute SARS-CoV-2 infection. The aetiologies may include persistent inflammation, unresolved tissue damage or delayed clearance of viral protein or RNA, but the biological differences they represent are not fully understood. Here we evaluate the serum proteome in samples, longitudinally collected from 55 PASC individuals with symptoms lasting ≥60 days after onset of acute infection, in comparison to samples from symptomatically recovered SARS-CoV-2 infected and uninfected individuals. Our analysis indicates heterogeneity in PASC and identified subsets with distinct signatures of persistent inflammation. Type II interferon signaling and canonical NF-κB signaling (particularly associated with TNF), appear to be the most differentially enriched signaling pathways, distinguishing a group of patients characterized also by a persistent neutrophil activation signature. These findings help to clarify biological diversity within PASC, identify participants with molecular evidence of persistent inflammation, and highlight dominant pathways that may have diagnostic or therapeutic relevance, including a protein panel that we propose as having diagnostic utility for differentiating inflammatory and non-inflammatory PASC.
A village in a dish model system for population-scale hiPSC studies
Authors: Neavin Drew R. , Steinmann Angela M. , Farbehi Nona , Chiu Han Sheng , Daniszewski Maciej S. , Arora Himanshi , Bermudez Yasmin , Moutinho Cátia , Chan Chia-Ling , Bax Monique , Tyebally Mubarika , Gnanasambandapillai Vikkitharan , Lam Chuan E. , Nguyen Uyen , Hernández Damián , Lidgerwood Grace E. , Graham Robert M. , Hewitt Alex W. , Pébay Alice , Palpant Nathan J. , Powell Joseph E.
Published: June 2023

The mechanisms by which DNA alleles contribute to disease risk, drug response, and other human phenotypes are highly context-specific, varying across cell types and different conditions. Human induced pluripotent stem cells are uniquely suited to study these context-dependent effects but cell lines from hundreds or thousands of individuals are required. Village cultures, where multiple induced pluripotent stem lines are cultured and differentiated in a single dish, provide an elegant solution for scaling induced pluripotent stem experiments to the necessary sample sizes required for population-scale studies. Here, we show the utility of village models, demonstrating how cells can be assigned to an induced pluripotent stem line using single-cell sequencing and illustrating that the genetic, epigenetic or induced pluripotent stem line-specific effects explain a large percentage of gene expression variation for many genes. We demonstrate that village methods can effectively detect induced pluripotent stem line-specific effects, including sensitive dynamics of cell states.
Breakdown of self-incompatibility due to genetic interaction between a specific S-allele and an unlinked modifier
Authors: Li Yan , Mamonova Ekaterina , Köhler Nadja , van Kleunen Mark , Stift Marc
Published: June 2023

Breakdown of self-incompatibility has frequently been attributed to loss-of-function mutations of alleles at the locus responsible for recognition of self-pollen (i.e. the S-locus). However, other potential causes have rarely been tested. Here, we show that self-compatibility of S1S1-homozygotes in selfing populations of the otherwise self-incompatible Arabidopsis lyrata is not due to S-locus mutation. Between-breeding-system cross-progeny are self-compatible if they combine S1 from the self-compatible cross-partner with recessive S1 from the self-incompatible cross-partner, but self-incompatible with dominant S-alleles. Because S1S1 homozygotes in outcrossing populations are self-incompatible, mutation of S1 cannot explain self-compatibility in S1S1 cross-progeny. This supports the hypothesis that an S1-specific modifier unlinked to the S-locus causes self-compatibility by functionally disrupting S1. Self-compatibility in S19S19 homozygotes may also be caused by an S19-specific modifier, but we cannot rule out a loss-of-function mutation of S19. Taken together, our findings indicate that breakdown of self-incompatibility is possible without disruptive mutations at the S-locus.
An approach to MOFaxanes by threading ultralong polymers through metal–organic framework microcrystals
Authors: Iizuka Tomoya , Sano Hiroyuki , Le Ouay Benjamin , Hosono Nobuhiko , Uemura Takashi
Published: June 2023

Mechanically interlocked architecture has inspired the fabrication of numerous molecular systems, such as rotaxanes, catenanes, molecular knots, and their polymeric analogues. However, to date, the studies in this field have only focused on the molecular-scale integrity and topology of its unique penetrating structure. Thus, the topological material design of such architectures has not been fully explored from the nano- to the macroscopic scale. Here, we propose a supramolecular interlocked system, MOFaxane, comprised of long chain molecules penetrating a microcrystal of metal–organic framework (MOF). In this study, we describe the synthesis of polypseudoMOFaxane that is one of the MOFaxane family. This has a polythreaded structure in which multiple polymer chains thread a single MOF microcrystal, forming a topological network in the bulk state. The topological crosslinking architecture is obtained by simply mixing polymers and MOFs, and displays characteristics distinct from those of conventional polyrotaxane materials, including suppression of unthreading reactions.
Muscleblind-like proteins use modular domains to localize RNAs by riding kinesins and docking to membranes
Authors: Hildebrandt Ryan P. , Moss Kathryn R. , Janusz-Kaminska Aleksandra , Knudson Luke A. , Denes Lance T. , Saxena Tanvi , Boggupalli Devi Prasad , Li Zhuangyue , Lin Kun , Bassell Gary J. , Wang Eric T.
Published: June 2023

RNA binding proteins (RBPs) act as critical facilitators of spatially regulated gene expression. Muscleblind-like (MBNL) proteins, implicated in myotonic dystrophy and cancer, localize RNAs to myoblast membranes and neurites through unknown mechanisms. We find that MBNL forms motile and anchored granules in neurons and myoblasts, and selectively associates with kinesins Kif1bα and Kif1c through its zinc finger (ZnF) domains. Other RBPs with similar ZnFs associate with these kinesins, implicating a motor-RBP specificity code. MBNL and kinesin perturbation leads to widespread mRNA mis-localization, including depletion of Nucleolin transcripts from neurites. Live cell imaging and fractionation reveal that the unstructured carboxy-terminal tail of MBNL1 allows for anchoring at membranes. An approach, termed RBP Module Recruitment and Imaging (RBP-MRI), reconstitutes kinesin- and membrane-recruitment functions using MBNL-MS2 coat protein fusions. Our findings decouple kinesin association, RNA binding, and membrane anchoring functions of MBNL while establishing general strategies for studying multi-functional, modular domains of RBPs.
Reversible conversion between skyrmions and skyrmioniums
Authors: Yang Sheng , Zhao Yuelei , Wu Kai , Chu Zhiqin , Xu Xiaohong , Li Xiaoguang , Åkerman Johan , Zhou Yan
Published: June 2023

Skyrmions and skyrmioniums are topologically non-trivial spin textures found in chiral magnetic systems. Understanding the dynamics of these particle-like excitations is crucial for leveraging their diverse functionalities in spintronic devices. This study investigates the dynamics and evolution of chiral spin textures in [Pt/Co]3/Ru/[Co/Pt]3 multilayers with ferromagnetic interlayer exchange coupling. By precisely controlling the excitation and relaxation processes through combined magnetic field and electric current manipulation, reversible conversion between skyrmions and skyrmioniums is achieved. Additionally, we observe the topological conversion from a skyrmionium to a skyrmion, characterized by the sudden emergence of the skyrmion Hall effect. The experimental realization of reversible conversion between distinct magnetic topological spin textures represents a significant development that promises to expedite the advancement of the next generation of spintronic devices.
Structural mechanism of intracellular autoregulation of zinc uptake in ZIP transporters
Authors: Pang Changxu , Chai Jin , Zhu Ping , Shanklin John , Liu Qun
Published: June 2023

Zinc is an essential micronutrient that supports all living organisms through regulating numerous biological processes. However, the mechanism of uptake regulation by intracellular Zn2+ status remains unclear. Here we report a cryo-electron microscopy structure of a ZIP-family transporter from Bordetella bronchiseptica at 3.05 Å resolution in an inward-facing, inhibited conformation. The transporter forms a homodimer, each protomer containing nine transmembrane helices and three metal ions. Two metal ions form a binuclear pore structure, and the third ion is located at an egress site facing the cytoplasm. The egress site is covered by a loop, and two histidine residues on the loop interact with the egress-site ion and regulate its release. Cell-based Zn2+ uptake and cell growth viability assays reveal a negative regulation of Zn2+ uptake through sensing intracellular Zn2+ status using a built-in sensor. These structural and biochemical analyses provide mechanistic insight into the autoregulation of zinc uptake across membranes.
Intracranial electrophysiological and structural basis of BOLD functional connectivity in human brain white matter
Authors: Huang Yali , Wei Peng-Hu , Xu Longzhou , Chen Desheng , Yang Yanfeng , Song Wenkai , Yi Yangyang , Jia Xiaoli , Wu Guowei , Fan Qingchen , Cui Zaixu , Zhao Guoguang
Published: June 2023

While functional MRI (fMRI) studies have mainly focused on gray matter, recent studies have consistently found that blood-oxygenation-level-dependent (BOLD) signals can be reliably detected in white matter, and functional connectivity (FC) has been organized into distributed networks in white matter. Nevertheless, it remains unclear whether this white matter FC reflects underlying electrophysiological synchronization. To address this question, we employ intracranial stereotactic-electroencephalography (SEEG) and resting-state fMRI data from a group of 16 patients with drug-resistant epilepsy. We find that BOLD FC is correlated with SEEG FC in white matter, and this result is consistent across a wide range of frequency bands for each participant. By including diffusion spectrum imaging data, we also find that white matter FC from both SEEG and fMRI are correlated with white matter structural connectivity, suggesting that anatomical fiber tracts underlie the functional synchronization in white matter. These results provide evidence for the electrophysiological and structural basis of white matter BOLD FC, which could be a potential biomarker for psychiatric and neurological disorders.
A viral pan-end RNA element and host complex define a SARS-CoV-2 regulon
Authors: Khan Debjit , Terenzi Fulvia , Liu GuanQun , Ghosh Prabar K. , Ye Fengchun , Nguyen Kien , China Arnab , Ramachandiran Iyappan , Chakraborty Shruti , Stefan Jennifer , Khan Krishnendu , Vasu Kommireddy , Dong Franklin , Willard Belinda , Karn Jonathan , Gack Michaela U. , Fox Paul L.
Published: June 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, generates multiple protein-coding, subgenomic RNAs (sgRNAs) from a longer genomic RNA, all bearing identical termini with poorly understood roles in regulating viral gene expression. Insulin and interferon-gamma, two host-derived, stress-related agents, and virus spike protein, induce binding of glutamyl-prolyl-tRNA synthetase (EPRS1), within an unconventional, tetra-aminoacyl-tRNA synthetase complex, to the sgRNA 3′-end thereby enhancing sgRNA expression. We identify an EPRS1-binding sarbecoviral pan-end activating RNA (SPEAR) element in the 3′-end of viral RNAs driving agonist-induction. Translation of another co-terminal 3′-end feature, ORF10, is necessary for SPEAR-mediated induction, independent of Orf10 protein expression. The SPEAR element enhances viral programmed ribosomal frameshifting, thereby expanding its functionality. By co-opting noncanonical activities of a family of essential host proteins, the virus establishes a post-transcriptional regulon stimulating global viral RNA translation. A SPEAR-targeting strategy markedly reduces SARS-CoV-2 titer, suggesting a pan-sarbecoviral therapeutic modality.
Chirality selective magnon-phonon hybridization and magnon-induced chiral phonons in a layered zigzag antiferromagnet
Authors: Cui Jun , Boström Emil Viñas , Ozerov Mykhaylo , Wu Fangliang , Jiang Qianni , Chu Jiun-Haw , Li Changcun , Liu Fucai , Xu Xiaodong , Rubio Angel , Zhang Qi
Published: June 2023

Two-dimensional (2D) magnetic systems possess versatile magnetic order and can host tunable magnons carrying spin angular momenta. Recent advances show angular momentum can also be carried by lattice vibrations in the form of chiral phonons. However, the interplay between magnons and chiral phonons as well as the details of chiral phonon formation in a magnetic system are yet to be explored. Here, we report the observation of magnon-induced chiral phonons and chirality selective magnon-phonon hybridization in a layered zigzag antiferromagnet (AFM) FePSe3. With a combination of magneto-infrared and magneto-Raman spectroscopy, we observe chiral magnon polarons (chiMP), the new hybridized quasiparticles, at zero magnetic field. The hybridization gap reaches 0.25 meV and survives down to the quadrilayer limit. Via first principle calculations, we uncover a coherent coupling between AFM magnons and chiral phonons with parallel angular momenta, which arises from the underlying phonon and space group symmetries. This coupling lifts the chiral phonon degeneracy and gives rise to an unusual Raman circular polarization of the chiMP branches. The observation of coherent chiral spin-lattice excitations at zero magnetic field paves the way for angular momentum-based hybrid phononic and magnonic devices.
Energy conversion and storage via photoinduced polarization change in non-ferroelectric molecular [CoGa] crystals
Authors: Sadhukhan Pritam , Wu Shu-Qi , Kanegawa Shinji , Su Sheng-Qun , Zhang Xiaopeng , Nakanishi Takumi , Long Jeremy Ian , Gao Kaige , Shimada Rintaro , Okajima Hajime , Sakamoto Akira , Chiappella Joy G. , Huzan Myron S. , Kroll Thomas , Sokaras Dimosthenis , Baker Michael L. , Sato Osamu
Published: June 2023

To alleviate the energy and environmental crisis, in the last decades, energy harvesting by utilizing optical control has emerged as a promising solution. Here we report a polar crystal that exhibits photoenergy conversion and energy storage upon light irradiation. The polar crystal consists of dinuclear [CoGa] molecules, which are oriented in a uniform direction inside the crystal lattice. Irradiation with green light induces a directional intramolecular electron transfer from the ligand to a low-spin CoIIIcentre, and the resultant light-induced high-spin CoIIexcited state is trapped at low temperature, realizing energy storage. Additionally, electric current release is observed during relaxation from the trapped light-induced metastable state to the ground state, because the intramolecular electron transfer in the relaxation process is accompanied with macroscopic polarization switching at the single-crystal level. It demonstrates that energy storage and conversion to electrical energy is realized in the [CoGa] crystals, which is different from typical polar pyroelectric compounds that exhibit the conversion of thermal energy into electricity.
Language network lateralization is reflected throughout the macroscale functional organization of cortex
Authors: Labache Loïc , Ge Tian , Yeo B. T. Thomas , Holmes Avram J.
Published: June 2023

Hemispheric specialization is a fundamental feature of human brain organization. However, it is not yet clear to what extent the lateralization of specific cognitive processes may be evident throughout the broad functional architecture of cortex. While the majority of people exhibit left-hemispheric language dominance, a substantial minority of the population shows reverse lateralization. Using twin and family data from the Human Connectome Project, we provide evidence that atypical language dominance is associated with global shifts in cortical organization. Individuals with atypical language organization exhibit corresponding hemispheric differences in the macroscale functional gradients that situate discrete large-scale networks along a continuous spectrum, extending from unimodal through association territories. Analyses reveal that both language lateralization and gradient asymmetries are, in part, driven by genetic factors. These findings pave the way for a deeper understanding of the origins and relationships linking population-level variability in hemispheric specialization and global properties of cortical organization.
In vivo PAR-CLIP (viP-CLIP) of liver TIAL1 unveils targets regulating cholesterol synthesis and secretion
Authors: Vatandaslar Hasan , Garzia Aitor , Meyer Cindy , Godbersen Svenja , Brandt Laura T. L. , Griesbach Esther , Chao Jeffrey A. , Tuschl Thomas , Stoffel Markus
Published: June 2023

System-wide cross-linking and immunoprecipitation (CLIP) approaches have unveiled regulatory mechanisms of RNA-binding proteins (RBPs) mainly in cultured cells due to limitations in the cross-linking efficiency of tissues. Here, we describe viP-CLIP (in vivo PAR-CLIP), a method capable of identifying RBP targets in mammalian tissues, thereby facilitating the functional analysis of RBP-regulatory networks in vivo. We applied viP-CLIP to mouse livers and identified Insig2 and ApoB as prominent TIAL1 target transcripts, indicating an important role of TIAL1 in cholesterol synthesis and secretion. The functional relevance of these targets was confirmed by showing that TIAL1 influences their translation in hepatocytes. Mutant Tial1 mice exhibit altered cholesterol synthesis, APOB secretion and plasma cholesterol levels. Our results demonstrate that viP-CLIP can identify physiologically relevant RBP targets by finding a factor implicated in the negative feedback regulation of cholesterol biosynthesis.
A 2.2 Å cryoEM structure of a quinol-dependent NO Reductase shows close similarity to respiratory oxidases
Authors: Flynn Alex J. , Antonyuk Svetlana V. , Eady Robert R. , Muench Stephen P. , Hasnain S. Samar
Published: June 2023

Quinol-dependent nitric oxide reductases (qNORs) are considered members of the respiratory heme-copper oxidase superfamily, are unique to bacteria, and are commonly found in pathogenic bacteria where they play a role in combating the host immune response. qNORs are also essential enzymes in the denitrification pathway, catalysing the reduction of nitric oxide to nitrous oxide. Here, we determine a 2.2 Å cryoEM structure of qNOR from Alcaligenes xylosoxidans, an opportunistic pathogen and a denitrifying bacterium of importance in the nitrogen cycle. This high-resolution structure provides insight into electron, substrate, and proton pathways, and provides evidence that the quinol binding site not only contains the conserved His and Asp residues but also possesses a critical Arg (Arg720) observed in cytochrome bo3, a respiratory quinol oxidase.
In-situ spectroscopic probe of the intrinsic structure feature of single-atom center in electrochemical CO/CO2 reduction to methanol
Authors: Ren Xinyi , Zhao Jian , Li Xuning , Shao Junming , Pan Binbin , Salamé Aude , Boutin Etienne , Groizard Thomas , Wang Shifu , Ding Jie , Zhang Xiong , Huang Wen-Yang , Zeng Wen-Jing , Liu Chengyu , Li Yanguang , Hung Sung-Fu , Huang Yanqiang , Robert Marc , Liu Bin
Published: June 2023

While exploring the process of CO/CO2 electroreduction (COxRR) is of great significance to achieve carbon recycling, deciphering reaction mechanisms so as to further design catalytic systems able to overcome sluggish kinetics remains challenging. In this work, a model single-Co-atom catalyst with well-defined coordination structure is developed and employed as a platform to unravel the underlying reaction mechanism of COxRR. The as-prepared single-Co-atom catalyst exhibits a maximum methanol Faradaic efficiency as high as 65% at 30 mA/cm2 in a membrane electrode assembly electrolyzer, while on the contrary, the reduction pathway of CO2 to methanol is strongly decreased in CO2RR. In-situ X-ray absorption and Fourier-transform infrared spectroscopies point to a different adsorption configuration of *CO intermediate in CORR as compared to that in CO2RR, with a weaker stretching vibration of the C–O bond in the former case. Theoretical calculations further evidence the low energy barrier for the formation of a H-CoPc-CO– species, which is a critical factor in promoting the electrochemical reduction of CO to methanol.
Revealing core-valence interactions in solution with femtosecond X-ray pump X-ray probe spectroscopy
Authors: Weakly Robert B. , Liekhus-Schmaltz Chelsea E. , Poulter Benjamin I. , Biasin Elisa , Alonso-Mori Roberto , Aquila Andrew , Boutet Sébastien , Fuller Franklin D. , Ho Phay J. , Kroll Thomas , Loe Caroline M. , Lutman Alberto , Zhu Diling , Bergmann Uwe , Schoenlein Robert W. , Govind Niranjan , Khalil Munira
Published: June 2023

Femtosecond pump-probe spectroscopy using ultrafast optical and infrared pulses has become an essential tool to discover and understand complex electronic and structural dynamics in solvated molecular, biological, and material systems. Here we report the experimental realization of an ultrafast two-color X-ray pump X-ray probe transient absorption experiment performed in solution. A 10 fs X-ray pump pulse creates a localized excitation by removing a 1s electron from an Fe atom in solvated ferro- and ferricyanide complexes. Following the ensuing Auger–Meitner cascade, the second X-ray pulse probes the Fe 1s → 3p transitions in resultant novel core-excited electronic states. Careful comparison of the experimental spectra with theory, extracts +2 eV shifts in transition energies per valence hole, providing insight into correlated interactions of valence 3d with 3p and deeper-lying electrons. Such information is essential for accurate modeling and predictive synthesis of transition metal complexes relevant for applications ranging from catalysis to information storage technology. This study demonstrates the experimental realization of the scientific opportunities possible with the continued development of multicolor multi-pulse X-ray spectroscopy to study electronic correlations in complex condensed phase systems.
Local cation-tuned reversible single-molecule switch in electric double layer
Authors: Tong Ling , Yu Zhou , Gao Yi-Jing , Li Xiao-Chong , Zheng Ju-Fang , Shao Yong , Wang Ya-Hao , Zhou Xiao-Shun
Published: June 2023

The nature of molecule-electrode interface is critical for the integration of atomically precise molecules as functional components into circuits. Herein, we demonstrate that the electric field localized metal cations in outer Helmholtz plane can modulate interfacial Au-carboxyl contacts, realizing a reversible single-molecule switch. STM break junction and I-V measurements show the electrochemical gating of aliphatic and aromatic carboxylic acids have a conductance ON/OFF behavior in electrolyte solution containing metal cations (i.e., Na+, K+, Mg2+ and Ca2+), compared to almost no change in conductance without metal cations. In situ Raman spectra reveal strong molecular carboxyl-metal cation coordination at the negatively charged electrode surface, hindering the formation of molecular junctions for electron tunnelling. This work validates the critical role of localized cations in the electric double layer to regulate electron transport at the single-molecule level.
Unlocking the potentials of cyanobacterial photosynthesis for directly converting carbon dioxide into glucose
Authors: Zhang Shanshan , Sun Jiahui , Feng Dandan , Sun Huili , Cui Jinyu , Zeng Xuexia , Wu Yannan , Luan Guodong , Lu Xuefeng
Published: June 2023

Glucose is the most abundant monosaccharide, serving as an essential energy source for cells in all domains of life and as an important feedstock for the biorefinery industry. The plant-biomass-sugar route dominates the current glucose supply, while the direct conversion of carbon dioxide into glucose through photosynthesis is not well studied. Here, we show that the potential ofSynechococcus elongatusPCC 7942 for photosynthetic glucose production can be unlocked by preventing native glucokinase activity. Knocking out two glucokinase genes causes intracellular accumulation of glucose and promotes the formation of a spontaneous mutation in the genome, which eventually leads to glucose secretion. Without heterologous catalysis or transportation genes, glucokinase deficiency and spontaneous genomic mutation lead to a glucose secretion of 1.5 g/L, which is further increased to 5 g/L through metabolic and cultivation engineering. These findings underline the cyanobacterial metabolism plasticities and demonstrate their applications for supporting the direct photosynthetic production of glucose.
ddRAD sequencing based genotyping of six indigenous dairy cattle breeds of India to infer existing genetic diversity and population structure
Authors: Masharing Nampher , Sodhi Monika , Chanda Divya , Singh Inderpal , Vivek Prince , Tiwari Manish , Kumari Parvesh , Mukesh Manishi
Published: June 2023

The present investigation aimed to identify genome wide SNPs and to carry out diversity and population structure study using ddRAD-seq based genotyping of 58 individuals of six indigenous milch cattle breeds (Bos indicus) such as Sahiwal, Gir, Rathi, Tharparkar, Red Sindhi and Kankrej of India. A high percentage of reads (94.53%) were mapped to theBos taurus(ARS-UCD1.2) reference genome assembly. Following filtration criteria, a total of 84,027 high quality SNPs were identified across the genome of 6 cattle breeds with the highest number of SNPs observed in Gir (34,743), followed by Red Sindhi (13,092), Kankrej (12,812), Sahiwal (8956), Tharparkar (7356) and Rathi (7068). Most of these SNPs were distributed in the intronic regions (53.87%) followed by intergenic regions (34.94%) while only 1.23% were located in the exonic regions. Together with analysis of nucleotide diversity (π = 0.373), Tajima’s D (D value ranging from − 0.295 to 0.214), observed heterozygosity (HOranging from 0.464 to 0.551), inbreeding coefficient (FISranging from − 0.253 to 0.0513) suggested for the presence of sufficient within breed diversity in the 6 major milch breeds of India. The phylogenetic based structuring, principal component and admixture analysis revealed genetic distinctness as well as purity of almost all of the 6 cattle breeds. Overall, our strategy has successfully identified thousands of high-quality genome wide SNPs that will further enrich theBos indicusrepresentation basic information about genetic diversity and structure of 6 major Indian milch cattle breeds which should have implications for better management and conservation of valuable indicine cattle diversity.
Strategy inference during learning via cognitive activity-based credit assignment models
Authors: James Ashwin , Reynaud-Bouret Patricia , Mezzadri Giulia , Sargolini Francesca , Bethus Ingrid , Muzy Alexandre
Published: June 2023

We develop a method for selecting meaningful learning strategies based solely on the behavioral data of a single individual in a learning experiment. We use simple Activity-Credit Assignment algorithms to model the different strategies and couple them with a novel hold-out statistical selection method. Application on rat behavioral data in a continuous T-maze task reveals a particular learning strategy that consists in chunking the paths used by the animal. Neuronal data collected in the dorsomedial striatum confirm this strategy.
Epidemiology of rhegmatogenous retinal detachment in commercially insured myopes in the United States
Authors: Ludwig Cassie A. , Vail Daniel , Al-Moujahed Ahmad , Callaway Natalia F. , Saroj Namrata , Moshfeghi Andrew , Moshfeghi Darius M.
Published: June 2023

Myopia is a known risk factor for rhegmatogenous retinal detachment (RRD). Given global trends of increasing myopia, we aimed to determine the absolute risk (incidence rate) of RRD in non-myopes, myopes and high myopes in the United States over ten years. We performed a retrospective cohort study of 85,476,781 commercially insured patients enrolled in the Merative™ Marketscan® Research Database. The incidence rate of RRD in phakic patients in the United States was 39-fold higher in high myopes than non-myopes (868.83 per 100,000 person-years versus 22.44 per 100,000 person-years) and three-fold higher in myopes than non-myopes (67.51 per 100,000 person-years versus 22.44 per 100,000 person-years). The incidence rate was significantly higher in males in each category (P < 0.01). Combined, the incidence rate of RRD in phakic patients in the United States from 2007 to 2016 was 25.27 RRDs per 100,000 person-years, a rate higher than those in prior published studies in North America, South America, Europe, Asia, and Australia. The absolute risk of myopia and high myopia increased from 2007 to 2016. The risk of RRD in phakic high myopes rose with increasing age. Notably, the magnitude of increased risk of RRD in myopes varied substantially according to the minimum follow-up period in our models and should be accounted for when interpreting data analyses.
RNA binding by the glucocorticoid receptor attenuates dexamethasone-induced gene activation
Authors: Lammer Nickolaus C. , Ashraf Humza M. , Ugay Daniella A. , Spencer Sabrina L. , Allen Mary A. , Batey Robert T. , Wuttke Deborah S.
Published: June 2023

The glucocorticoid receptor (GR) is a ligand-activated transcription factor that regulates a suite of genes through direct binding of GR to specific DNA promoter elements. GR also interacts with RNA, but the function of this RNA-binding activity remains elusive. Current models speculate that RNA could repress the transcriptional activity of GR. To investigate the function of the GR-RNA interaction on GR’s transcriptional activity, we generated cells that stably express a mutant of GR with reduced RNA binding affinity and treated the cells with the GR agonist dexamethasone. Changes in the dexamethasone-driven transcriptome were quantified using 4-thiouridine labeling of RNAs followed by high-throughput sequencing. We find that while many genes are unaffected, GR-RNA binding is repressive for specific subsets of genes in both dexamethasone-dependent and independent contexts. Genes that are dexamethasone-dependent are activated directly by chromatin-bound GR, suggesting a competition-based repression mechanism in which increasing local concentrations of RNA may compete with DNA for binding to GR at sites of transcription. Unexpectedly, genes that are dexamethasone-independent instead display a localization to specific chromosomal regions, which points to changes in chromatin accessibility or architecture. These results show that RNA binding plays a fundamental role in regulating GR function and highlights potential functions for transcription factor-RNA interactions.
The role of acute changes in mBDNF, cortisol and pro-BDNF in predicting cognitive performance in old age
Authors: Nilsson Jonna , Ekblom Maria , Moberg Marcus , Lövdén Martin
Published: June 2023

The interplay between biomarkers of relevance to neuroplasticity and its association with learning and cognitive ability in old age remains poorly understood. The present study investigated acute changes in plasma concentrations of mature brain-derived neurotrophic factor (mBDNF), its precursor protein (pro-BDNF), and cortisol, in response to acute physical exercise and cognitive training interventions, their covariation and role in predicting cognitive performance. Confirmatory results provided no support for mBDNF, pro-BDNF and cortisol co-varying over time, as the acute interventions unfolded, but did confirm a positive association between mBDNF and pro-BDNF at rest. The confirmatory results did not support the hypothesis that mBDNF change following physical exercise were counteracted by temporally coupled changes in cortisol or pro-BDNF, or by cortisol at rest, in its previously demonstrated faciliatory effect on cognitive training outcome. Exploratory results instead provided indications of a general and trait-like cognitive benefit of exhibiting greater mBDNF responsiveness to acute interventions when coupled with lesser cortisol responsiveness, greater pro-BDNF responsiveness, and lower cortisol at rest. As such, the results call for future work to test whether certain biomarker profiles are associated with preserved cognition in old age.
Detailed analysis of an enriched deep intronic ABCA4 variant in Irish Stargardt disease patients
Authors: Whelan Laura , Dockery Adrian , Stephenson Kirk A. J. , Zhu Julia , Kopčić Ella , Post Iris J. M. , Khan Mubeen , Corradi Zelia , Wynne Niamh , O’ Byrne James J. , Duignan Emma , Silvestri Giuliana , Roosing Susanne , Cremers Frans P. M. , Keegan David J. , Kenna Paul F. , Farrar G. Jane
Published: June 2023

Over 15% of probands in a large cohort of more than 1500 inherited retinal degeneration patients present with a clinical diagnosis of Stargardt disease (STGD1), a recessive form of macular dystrophy caused by biallelic variants in the ABCA4 gene. Participants were clinically examined and underwent either target capture sequencing of the exons and some pathogenic intronic regions of ABCA4, sequencing of the entire ABCA4 gene or whole genome sequencing. ABCA4 c.4539 + 2028C > T, p.[= ,Arg1514Leufs*36] is a pathogenic deep intronic variant that results in a retina-specific 345-nucleotide pseudoexon inclusion. Through analysis of the Irish STGD1 cohort, 25 individuals across 18 pedigrees harbour ABCA4 c.4539 + 2028C > T and another pathogenic variant. This includes, to the best of our knowledge, the only two homozygous patients identified to date. This provides important evidence of variant pathogenicity for this deep intronic variant, highlighting the value of homozygotes for variant interpretation. 15 other heterozygous incidents of this variant in patients have been reported globally, indicating significant enrichment in the Irish population. We provide detailed genetic and clinical characterization of these patients, illustrating that ABCA4 c.4539 + 2028C > T is a variant of mild to intermediate severity. These results have important implications for unresolved STGD1 patients globally with approximately 10% of the population in some western countries claiming Irish heritage. This study exemplifies that detection and characterization of founder variants is a diagnostic imperative.
Screening of reference genes for microRNA analysis in the study of solider caste differentiation of Formosan subterranean termite Coptotermes formosanus Shiraki
Authors: Du He , Huang Runmei , Chen Dasong , Huang Chaofu , Zhang Huan , Lia Zhiqiang
Published: June 2023

The soldier caste differentiation is a complex process that is governed by the transcriptional regulation and post-transcriptional regulation. microRNAs (miRNAs) are noncoding RNAs that control a wide range of activities. However, their roles in solider caste differentiation are barely studied. RT-qPCR is a powerful tool to study the function of genes. A reference gene is required for normalization for the the relative quantification method. However, no reference gene is available for miRNA quantification in the study of solider caste differentiation ofCoptotermes formosanusShiraki. In this research, in order to screen the suitable reference genes for the study of the roles of miRNAs in solider caste differentiation, the expression levels of 8 candidate miRNA genes were quantified in the head and thorax + abdomen during soldier differentiation. The qPCR data were analyzed using geNorm, NormFinder, BestKeeper, ΔCtmethod and RefFinder. The normalization effect of the reference genes was evaluated using thelet-7-3p. Our study showed thatnovel-m0649-3pwas the most stable reference gene, whileU6was the least stable reference gene. Our study has selected the most stable reference gene, and has paved the way for functional analysis of miRNAs in solider caste differentiation.
The evolutionary history of Brachyury genes in Hydrozoa involves duplications, divergence, and neofunctionalization
Authors: Vetrova Alexandra A. , Kupaeva Daria M. , Kizenko Alena , Lebedeva Tatiana S. , Walentek Peter , Tsikolia Nikoloz , Kremnyov Stanislav V.
Published: June 2023

Brachyury, a member of T-box gene family, is widely known for its major role in mesoderm specification in bilaterians. It is also present in non-bilaterian metazoans, such as cnidarians, where it acts as a component of an axial patterning system. In this study, we present a phylogenetic analysis of Brachyury genes within phylum Cnidaria, investigate differential expression and address a functional framework of Brachyury paralogs in hydrozoan Dynamena pumila. Our analysis indicates two duplication events of Brachyury within the cnidarian lineage. The first duplication likely appeared in the medusozoan ancestor, resulting in two copies in medusozoans, while the second duplication arose in the hydrozoan ancestor, resulting in three copies in hydrozoans. Brachyury1 and 2 display a conservative expression pattern marking the oral pole of the body axis in D. pumila. On the contrary, Brachyury3 expression was detected in scattered presumably nerve cells of the D. pumila larva. Pharmacological modulations indicated that Brachyury3 is not under regulation of cWnt signaling in contrast to the other two Brachyury genes. Divergence in expression patterns and regulation suggest neofunctionalization of Brachyury3 in hydrozoans.
The accuracy of non-contrast brain CT scan in predicting the presence of a vascular etiology in patients with primary intracranial hemorrhage
Authors: Abbasi Bita , Ganjali Raheleh , Akhavan Reza , Tavassoli Ahmadreza , Khojasteh Fatemeh
Published: June 2023

Spontaneous intraparenchymal cerebral hemorrhages (SIPH) account for 10–15% of acute strokes. Sorting these patients according to the risk of harboring an underlying vascular etiology may help selecting the patients who would mostly benefit from Multidetector CT Angiography (MDCTA). The aim of this study was to evaluate the accuracy of Non-Contrast brain CT (NCCT) in predicting possible vascular etiologies in patients with SIPH. In this retrospective study, we evaluated the NCCT of 334 patients who presented with SIPH from March 2017 to March 2021 and we looked for vascular etiologies in the CTA which was performed for these patients. We used NCCT criteria to predict the presence of any vascular etiologies in SIPH patients and proposed a scoring system based on these criteria which might predict the risk of vascular ICH (VICH score). Out of 334 evaluated patients, 9.3% had an underlying vascular etiology. Independent predictors of the vascular etiology included: age < 46 years, no history of hypertension and coagulation disorders, lobar hemorrhages, and presence of significant perilesional edema. We used these criteria and NCCT classification to create a practical scoring system to predict the risk of vascular ICH (VICH). In our study, VICH score ≥ 4 had 51.6% sensitivity and 96.4% specificity for predicting a positive MDCTA as the maximum optimal cut-off point. The VICH score seemed to be successful in predicting vascular etiologies in this retrospective cohort of 334 patients. This scoring system can be used to select patients if there are limited resources to perform CT angiography.
A perfusion-based three-dimensional cell culture system to model alveolar rhabdomyosarcoma pathological features
Authors: Saggioro Mattia , D’Agostino Stefania , Veltri Giulia , Bacchiega Maira , Tombolan Lucia , Zanon Carlo , Gamba Piergiorgio , Serafin Valentina , Muraro Manuele Giuseppe , Martin Ivan , Pozzobon Michela
Published: June 2023

Although a rare disease, rhabdomyosarcoma (RMS) is one of the most common cancers in children the more aggressive and metastatic subtype is the alveolar RMS (ARMS). Survival outcomes with metastatic disease remain dismal and the need for new models that recapitulate key pathological features, including cell-extracellular matrix (ECM) interactions, is warranted. Here, we report an organotypic model that captures cellular and molecular determinants of invasive ARMS. We cultured the ARMS cell line RH30 on a collagen sponge in a perfusion-based bioreactor (U-CUP), obtaining after 7 days a 3D construct with homogeneous cell distribution. Compared to static culture, perfusion flow induced higher cell proliferation rates (20% vs. 5%), enhanced secretion of active MMP-2, and upregulation of the Rho pathway, associated with cancer cell dissemination. Consistently, the ECM genes LAMA1 and LAMA2, the antiapoptotic gene HSP90, identified in patient databases as hallmarks of invasive ARMS, were higher under perfusion flow at mRNA and protein level. Our advanced ARMS organotypic model mimics (1) the interactions cells-ECM, (2) the cell growth maintenance, and (3) the expression of proteins that characterize tumor expansion and aggressiveness. In the future, the perfusion-based model could be used with primary patient-derived cell subtypes to create a personalized ARMS chemotherapy screening system.
Six-year trajectories and associated factors of positive and negative symptoms in schizophrenia patients, siblings, and controls: Genetic Risk and Outcome of Psychosis (GROUP) study
Authors: Habtewold Tesfa Dejenie , Tiles-Sar Natalia , Liemburg Edith J. , Sandhu Amrit Kaur , Islam Md Atiqul , Boezen H. Marike ,   GROUP Investigators, Alizadeh Behrooz Z. , van Amelsvoort Therese , Bartels-Velthuis Agna A. , de Haan Lieuwe , Schirmbeck Frederike , Simons Claudia J. P. , van Os Jim , Bruggeman Richard , Alizadeh Behrooz Z.
Published: June 2023

Positive and negative symptoms are prominent but heterogeneous characteristics of schizophrenia spectrum disorder (SSD). Within the framework of the Genetic Risk and Outcome of Psychosis (GROUP) longitudinal cohort study, we aimed to distinguish and identify the genetic and non-genetics predictors of homogenous subgroups of the long-term course of positive and negative symptoms in SSD patients (n = 1119) and their unaffected siblings (n = 1059) in comparison to controls (n = 586). Data were collected at baseline, and after 3- and 6-year follow-ups. Group-based trajectory modeling was applied to identify latent subgroups using positive and negative symptoms or schizotypy scores. A multinomial random-effects logistic regression model was used to identify predictors of latent subgroups. Patients had decreasing, increasing, and relapsing symptoms course. Unaffected siblings and healthy controls had three to four subgroups characterized by stable, decreasing, or increasing schizotypy. PRSSCZ did not predict the latent subgroups. Baseline symptoms severity in patients, premorbid adjustment, depressive symptoms, and quality of life in siblings predicted long-term trajectories while were nonsignificant in controls. In conclusion, up to four homogenous latent subgroups of symptom course can be distinguished within patients, siblings, and controls, while non-genetic factors are the main factors associated with the latent subgroups.
Kombucha electronics: electronic circuits on kombucha mats
Authors: Adamatzky Andrew , Tarabella Giuseppe , Phillips Neil , Chiolerio Alessandro , D’Angelo Pasquale , Nikolaidou Anna , Sirakoulis Georgios Ch.
Published: June 2023

A kombucha is a tea and sugar fermented by over sixty kinds of yeasts and bacteria. This symbiotic community produces kombucha mats, which are cellulose-based hydrogels. The kombucha mats can be used as an alternative to animal leather in industry and fashion once they have been dried and cured. Prior to this study, we demonstrated that living kombucha mats display dynamic electrical activity and distinct stimulating responses. For use in organic textiles, cured mats of kombucha are inert. To make kombucha wearables functional, it is necessary to incorporate electrical circuits. We demonstrate that creating electrical conductors on kombucha mats is possible. After repeated bending and stretching, the circuits maintain their functionality. In addition, the abilities and electronic properties of the proposed kombucha, such as being lighter, less expensive, and more flexible than conventional electronic systems, pave the way for their use in a diverse range of applications.
Validation of CT-based ventilation and perfusion biomarkers with histopathology confirms radiation-induced pulmonary changes in a porcine model
Authors: Flakus Mattison J. , Wuschner Antonia E. , Wallat Eric M. , Graham Melissa , Shao Wei , Shanmuganayagam Dhanansayan , Christensen Gary E. , Reinhardt Joseph M. , Bayouth John E.
Published: June 2023

Imaging biomarkers can assess disease progression or prognoses and are valuable tools to help guide interventions. Particularly in lung imaging, biomarkers present an opportunity to extract regional information that is more robust to the patient’s condition prior to intervention than current gold standard pulmonary function tests (PFTs). This regional aspect has particular use in functional avoidance radiation therapy (RT) in which treatment planning is optimized to avoid regions of high function with the goal of sparing functional lung and improving patient quality of life post-RT. To execute functional avoidance, detailed dose–response models need to be developed to identify regions which should be protected. Previous studies have begun to do this, but for these models to be clinically translated, they need to be validated. This work validates two metrics that encompass the main components of lung function (ventilation and perfusion) through post-mortem histopathology performed in a novel porcine model. With these methods validated, we can use them to study the nuanced radiation-induced changes in lung function and develop more advanced models.