bluuebunny/crossref_metadata_2025 huggingface dataset:
On the mode of anti-C. albicansactivity of a bis(benzoxaborole) analogue of Tavaborole
Authors: Gadakh Sachin , Szczepińska Teresa , Potoczna Małgorzata , Okitsu-Sakurayama Shiho , Podlasz Piotr , Rogalska Marta , Kaczorowska Ewa , Adamczyk-Woźniak Agnieszka , Staniszewska Monika
Published: July 2024

We presented the pharmacodynamic relationship between benzoxaborole concentrations andCandida albiansblastoconidial population dynamics. Bis(benzoxaborole) analogue (2) andTavaborole(ref.) showed comparable moderate effects againstC. albicans(time-kill kinetic assays). Benzoxaboroles inhibited theC. albicansgrowth during 72 h (fungicidal after 2 h of that time) with metabolic reduction (%R=64). Biofilm-inhibiting concentration (BIC50=2 μg/mL) is the lowest concentration of bezoxaboroles that presented 50% inhibition of biofilm metabolic activity vs non-treated control.2displayed poor ability to inhibit morphogenesis ofC. albicans. Safety and fungicidal activity are still in high demand against biofilm grown on fibroblasts and the zebrafish modelin vivo. This biofilm model was used to study the interactions between theC. albicansmorphogenesis and benzoxaboroles. Benzoxaboroles displayed selectivity in cytotoxic effects.2exhibited significantly lower embryotoxicity vs ref. IC50>128 μg/mL for2. Ref. at 256 μg/mL showed approximately 80% viability of VERO E6 cells. A higher selectivity of the ref—drug to the pathogen than to the mammalian cells was observed. Contrariwise, ref. and2showed IC50=2 μg/mL against PBMCs. Benzoxaborole antifungal development targets ergosterol binding. RNAseq data indicated that efflux pumps (MDR) inC. albicanswere upregulated. Inositol-1-phosphate synthase was repressed under the benzoxaborole treatment.MDR1upregulation by2was accompanied by theIFD6(aldo-keto reductase) increase and the coordination of multiple coactivators (IFD6, TNA1encoding putative nicotinic acid transporter). Benzoxaboroles represent a similar resistance mechanism to azoles due to the subsequent expression ofMDR1andIDF6. Docking studies confirmed the proposed interactions of benzoxaborole adenosinemonophosphate adduct with LeuRS. Moreover,C5_04480C_A(cell wall biogenesis, protein folding, modification, and destination) was negatively regulated in response to the benzoxaborole stress. Benzoxaborole-altering efflux inhibitors are important for the development of combination strategies in candidiasis. Our findings present an innovative concept that can inspire further studies for designing and building new antifungal benzoxaborole.
Explicit description of viral capsid subunit shapes by unfolding dihedrons
Authors: Toyooka Ryuya , Nishimoto Seri , Tendo Tomoya , Horiyama Takashi , Tachi Tomohiro , Matsunaga Yasuhiro
Published: July 2024

Viral capsid assembly and the design of capsid-based nanocontainers critically depend on understanding the shapes and interfaces of constituent protein subunits. However, a comprehensive framework for characterizing these features is still lacking. Here, we introduce a novel approach based on spherical tiling theory that explicitly describes the 2D shapes and interfaces of subunits in icosahedral capsids. Our method unfolds spherical dihedrons defined by icosahedral symmetry axes, enabling systematic characterization of all possible subunit geometries. Applying this framework to realT= 1 capsid structures reveals distinct interface groups within this single classification, with variations in interaction patterns around 3-fold and 5-fold symmetry axes. We validate our classification through molecular docking simulations, demonstrating its consistency with physical subunit interactions. This analysis suggests different assembly pathways for capsid nucleation. Our general framework is applicable to other triangular numbers, paving the way for broader studies in structural virology and nanomaterial design.
Resolving the Structure of a Guanine Quadruplex in TMPRSS2 Messenger RNA by Circular Dichroism and Molecular Modeling
Authors: D’Anna Luisa , Froux Aurane , Rainot Aurianne , Spinello Angelo , Perricone Ugo , Barbault Florent , Grandemange Stéphanie , Barone Giampaolo , Terenzi Alessio , Monari Antonio
Published: July 2024

The presence of a guanine quadruplex in the opening reading frame of the messenger RNA coding for the transmembrane serine protease 2 (TMPRSS2) may pave the way to original anticancer and host-oriented antiviral strategy. Indeed, TMPRSS2 in addition to being overexpressed in different cancer types, is also related to the infection of respiratory viruses, including SARS-CoV-2, by promoting the cellular and viral membrane fusion through its proteolytic activity. The design of selective ligands targeting TMPRSS2 messenger RNA requires a detailed knowledge, at atomic level, of its structure. Therefore, we have used an original experimental-computational protocol to predict the first resolved structure of the parallel guanine quadruplex secondary structure in the RNA of TMPRSS2, which shows a rigid core flanked by a flexible loop. This represents the first atomic scale structure of the guanine quadruplex structure present in TMPRSS2 messenger RNA.
Collective flow of circadian clock information in honeybee colonies
Authors: Mellert Julia , Kłos Weronika , Dormagen David M. , Wild Benjamin , Zachariae Adrian , Smith Michael L. , Galizia C. Giovanni , Landgraf Tim
Published: July 2024

Honeybee colonies exhibit a collective circadian rhythm reflecting the periodic dynamics of the environment. Thousands of workers, including those engaged in in-hive tasks, must synchronize in various processes that may be rhythmic, such as nectar inflows, or non-rhythmic, such as brood care but it remains unknown how those different rhythms are integrated into a colony-level circadian rhythm. Using an AI-driven automated tracking system, we obtained uninterrupted long-term tracking of all individuals in two honeybee colonies. We demonstrate that circadian rhythmicity is present across all age groups and that this rhythm is entrained into all individuals, however, with peak activity shifting by up to 2 hours in workers furthest from the entrance. Extensive data analysis and an agent-based model suggest that mechanical interactions between individuals facilitate the transfer of movement speed, and hence Zeitgeber information. Finally, we show that this speed transfer leads to a collective slow wave of activity that initiates at the nest entrance, spreading throughout the nest. This simple mechanism, workers bumping into each other, enables colonies to entrain their rhythm to the daily cycle of the external environment and, because of the spatial organization of the nest, activates different groups of workers sequentially. The speed transfer interactions demonstrate a tightly-tuned mechanism that underlines the elegant self-organization of the superorganism.
An IL-12 mRNA-LNP adjuvant enhances mRNA vaccine induced CD8+ T cell responses
Authors: Aunins Emily A. , Phan Anthony T. , Alameh Mohamad-Gabriel , Cruz-Morales Elisa , Christian David A. , Bunkofske Molly E. , Dwivedi Garima , Kedl Ross , Weissman Drew , Hunter Christopher A.
Published: July 2024

The design of vaccines that induce CD8+ T cell responses has historically been a challenge, but the development of viral vectors or lipid nanoparticles (LNPs) to deliver mRNA that encode for target antigens provide more effective strategies to generate protective CD8+ T cell memory. Because interleukin-12 (IL-12) supports CD8+ T cell expansion and acquisition of effector functions, studies were performed to assess its contribution to the ability of an mRNA-LNP vaccine to promote CD8+ T cell responses. In vitro and in vivo, mRNA-LNPs did not stimulate myeloid cell production of IL-12, and the CD8+ T cell response to vaccination with the model antigen ovalbumin (OVA) was IL-12 independent. However, co-administration of IL-12 mRNA-LNPs with OVA mRNA-LNPs enhanced OVA-specific CD8+ T cell expansion, improved acquisition of effector function and resulted in an expanded memory CD8+ T cell pool. These heightened responses were associated with improved protective responses against Listeria monocytogenes-OVA and B16 F0-OVA melanoma. Thus, modification of mRNA vaccine formulations by inclusion of a cytokine mRNA provides a strategy to enhance CD8+ T cell mediated protection.
Dissecting the Genetic Basis of Superior Traits in Thermosensitive Genic Male Sterile Line 1892S Through Genome-Wide Analysis
Authors: Zhang Wei , Zhang Dewen
Published: July 2024

Hybrid rice has revolutionized food security by leveraging heterosis, a phenomenon where offspring outperform their parents. Sterile lines, crucial for controlled cross-pollination in hybrid breeding, have played a central role in this success. This study delves into the superior alleles of 1892S, a two-line sterile rice line widely used as a female parent in central China. By integrating extensive hybridization data, high-throughput genome sequencing, and bioinformatic analysis (RiceNavi), we elucidate the genetic underpinnings of 1892S’s exceptional adaptability. The results reveal its remarkable compatibility as a female parent in over 114 hybrid varieties, potentially due to the influence of Japonica characteristics contributing to strong hybrid vigor. Furthermore, some favorable alleles were identified that were associated with lodging resistance, high yield potential, and improved nitrogen use efficiency etc. The comprehensive characterization of 1892S provides valuable insights for future hybrid rice breeding programs, ultimately facilitating the development of superior rice varieties.
Genetic Manipulation of Caveolin-1 in the Mouse Model of Marfan Syndrome Associated Aortic Root Aneurysm: Effects on Endothelial and Smooth Muscle Function
Authors: Curry Tala , Gusek Brikena , Potter Ross M. , Bucky Jones T. , Dickman Raechel , Johnson Nathan , Vallejo-Elias Johana , Esfandiarei Mitra
Published: July 2024

Marfan Syndrome (MFS) is a systemic connective tissue disorder caused by mutations in the gene encoding for the large glycoprotein Fibrillin-1 (Fbn1), leading to wide-spectrum clinical manifestations, with the most life-threatening being aortic root aneurysm. MFS aortic aneurysm is known to be associated with reduced endothelial nitric oxide synthase (eNOS)-mediated nitric oxide (NO) production. Previous studies have shown that caveolin-1 (Cav1), a coat protein of caveolae structure on the plasma membrane, acts as a negative regulator of eNOS activity. This suggests that Cav1 may play a role in the development of aortic root aneurysm in MFS by modulating eNOS activity. In this study, we investigated the role of Cav1 in regulating aortic smooth muscle and endothelial function, aortic wall elasticity, and wall strength by generating MFS mice (FBN1+/Cys1041Gly) lackingCav1gene expression (MFS/Cav1KO). Our data show that ablation of theCav1gene results in a significant decrease in aortic smooth muscle contraction in response to the vasoconstricting agent phenylephrine seemingly due to a marked increase in NO production within the aortic wall. We also showed that acetylcholine-induced vasorelaxation was increased in MFS/Cav1KO mice potentially through the endothelial nitric oxide-dependent mechanism, further confirming inhibitory role of Cav1 on endothelial NO production. In addition, aortic wall elastin fiber structure and strength were markedly improved in male MFS/Cav1KO mice. This study demonstrates the regulatory role of Cav1 during the development of aortic root aneurysm in MFS mice through its effects on smooth muscle and endothelial functions in an NO-dependent manner.
Three Dimensional Multiscalar Neurovascular Nephron Connectivity Map of the Human Kidney Across the Lifespan
Authors: McLaughlin Liam , Zhang Bo , Sharma Siddharth , Knoten Amanda L. , Kaushal Madhurima , Purkerson Jeffrey M. , Huyck Heidy , Pryhuber Gloria S. , Gaut Joseph P. , Jain Sanjay
Published: July 2024

The human kidney is a vital organ with a remarkable ability to coordinate the activity of up to a million nephrons, its main functional tissue unit (FTU), and maintain homeostasis. We developed tissue processing and analytical methods to construct a 3D map of neurovascular nephron connectivity of the human kidney and glean insights into how this structural organization enables coordination of various functions of the nephron, such as glomerular filtration, solute and water absorption, secretion by the tubules, and regulation of blood flow and pressure by the juxtaglomerular apparatus, in addition to how these functions change across disease and lifespans. Using light sheet fluorescence microscopy (LSFM) and morphometric analysis we discovered changes in anatomical orientation of the vascular pole, glomerular density, volume, and innervation through postnatal development and ageing. The extensive nerve network exists from cortex FTUs to medullary loop of Henle, providing connectivity within segments of the same nephron, and between separate nephrons. The nerves organize glomeruli into discreet communities (in the same network of nerves). Adjacent glomerular communities are connected to intercommunal “mother glomeruli” by nerves, a pattern repeating throughout the cortex. These neuro-nephron networks are not developed in postnatal kidneys and are disrupted in diseased kidneys (diabetic or hydronephrosis). This structural organization likely poises the entire glomerular and juxtaglomerular FTUs to synchronize responses to perturbations in fluid homeostasis, utilizing mother glomeruli as network control centers.
Genome structural variants shape adaptive success of an invasive urban malaria vectorAnopheles stephensi
Authors: Samano Alejandra , Kumar Naveen , Liao Yi , Ishtiaq Farah , Chakraborty Mahul
Published: July 2024

Global changes are associated with the emergence of several invasive species. However, the genomic determinants of the adaptive success of an invasive species in a new environment remain poorly understood. Genomic structural variants (SVs), consisting of copy number variants, play an important role in adaptation. SVs often cause large adaptive shifts in ecologically important traits, which makes SVs compelling candidates for driving rapid adaptations to environmental changes, which is critical to invasive success. To address this problem, we investigated the role SVs play in the adaptive success ofAnopheles stephensi, a primary vector of urban malaria in South Asia and an invasive malaria vector in several South Asian islands and Africa. We collected whole genome sequencing data from 115 mosquitoes from invasive island populations and four locations from mainland India, an ancestral range for the species. We identified 2,988 duplication copy number variants and 16,038 deletions in these strains, with ∼50% overlapping genes. SVs are enriched in genomic regions with signatures of selective sweeps in the mainland and invasive island populations, implying a putative adaptive role of SVs. Nearly all high-frequency SVs, including the candidate adaptive variants, in the invasive island populations are present on the mainland, suggesting a major contribution of existing variation to the success of the island populations. Among the candidate adaptive SVs, three duplications involving toxin-resistance genes evolved, likely due to the widespread application of insecticides in India since the 1950s. We also identify two SVs associated with the adaptation ofAn. stephensilarvae to brackish water in the island and two coastal mainland populations, where the mutations likely originated. Our results suggest that existing SVs play a vital role in the evolutionary success ofAn. stephensiin new environmental conditions.
A structural and mechanistic model for BSEP dysfunction in PFIC2 cholestatic disease
Authors: Gruget Clémence , Reddy Bharat , Moore Jonathan
Published: July 2024

BSEP (ABCB11) transports bile salts across the canalicular membrane of hepatocytes, where they are incorporated into bile. Biallelic mutations in BSEP can cause Progressive Familial Intrahepatic Cholestasis Type 2 (PFIC2), a rare pediatric disease characterized by hepatic bile acid accumulation leading to hepatotoxicity and, ultimately, liver failure. The most frequently occurring PFIC2 disease-causing mutations are missense mutations, which often display a phenotype with decreased protein expression and impaired maturation and trafficking to the canalicular membrane. To characterize the mutational effects on protein thermodynamic stability, we carried out biophysical characterization of 13 distinct PFIC2-associated variants using in-cell thermal shift (CETSA) measurements. These experiments reveal a cluster of residues localized to the NBD2-ICL2 interface, which exhibit severe destabilization relative to wild-type BSEP. A high-resolution (2.8 Å) cryo-EM structure provides a framework for rationalizing the CETSA results, revealing a novel, NBD2-localized mechanism through which the most severe missense patient mutations drive cholestatic disease.
Pulsed blue light and phage therapy: A novel synergistic bactericide
Authors: Rimon Amit , Belin Jonathan , Yerushalmy Ortal , Alkalay-Oren Sivan , Eavri Yonatan , Shapochnikov Anatoly , Coppenhagen-Glazer Shunit , Hazan Ronen , Gavish Lilach
Published: July 2024

Antibiotic-resistantPseudomonas aeruginosa(PA) is a critical health threat. Novel treatment approaches are urgently required in this post-antibiotic era. In the current study, we investigated the bactericidal combinatorial potential of two non-antibiotic alternative approaches: phage therapy and pulsed blue light (PBL). Bacteriophages (phages), are viruses that specifically infect and lyse bacteria without harming eukaryotic cells. Pulsed blue light (PBL) alters bacterial membranes and was clinically shown to be innocuous to the skin in low doses. Here, using a low dose 457nm, 33KHz PBL combined with specific PA targeting phages, we demonstrated a synergistic effect that achieved complete inhibition of planktonic bacteria and a 40% reduction in formed biofilms. As part of this study, we also developed a user-friendly python-based tool for extraction of growth curve outcomes.In vivostudies are warranted for further validation of this combinatorial treatment. This approach may lead to a novel, antibiotic complementary modality to help patients suffering from difficult-to-treat antibiotic-resistant infections.

One Sentence Summary

Low-dose pulsed blue light and phage therapy have a synergistic bactericidal effect onPseudomonas aeruginosaplanktonic cultures and formed biofilm
Accelerated Simulation of Multi-Electrode Arrays Using Sparse and Low-Rank Matrix Techniques
Authors: Jensen Nathan , Chen Zhijie Charles , Kochnev Goldstein Anna , Palanker Daniel
Published: July 2024

Objective

Modeling of Multi-Electrode Arrays used in neural stimulation can be computationally challenging since it may involve incredibly dense circuits with millions of intercon-nected resistors, representing current pathways in an electrolyte (resistance matrix), coupled to nonlinear circuits of the stimulating pixels themselves. Here, we present a method for accelerating the modeling of such circuits with minimal error by using a sparse plus low-rank approximation of the resistance matrix.

Methods

We prove that thresholding of the resistance matrix elements enables its sparsification with minimized error. This is accomplished with a sorting algorithm, implying efficient O (N log (N)) complexity. The eigenvalue-based low-rank compensation then helps achieve greater accuracy without significantly increasing the problem size.Results:Utilizing these matrix techniques, we reduced the computation time of the simulation of multi-electrode arrays by about 10-fold, while maintaining an average error of less than 0.3% in the current injected from each electrode. We also show a case where acceleration reaches at least 133 times with additional error in the range of 4%, demonstrating the ability of this algorithm to perform under extreme conditions.

Conclusion

Critical improvements in the efficiency of simulations of the electric field generated by multi-electrode arrays presented here enable the computational modeling of high-fidelity neural implants with thousands of pixels, previously impossible.Significance:Computational acceleration techniques described in this manuscript were developed for simulation of high-resolution photovoltaic retinal prostheses, but they are also immediately applicable to any circuits involving dense connections between nodes, and, with modifications, more generally to any systems involving non-sparse matrices.
On branch lengths assignment methods for trees with fixed topology and related biological applications
Authors: Wei Wei , Koslicki David
Published: July 2024

Distance-guided tree construction with unknown tree topology and branch lengths has been a long studied problem. In contrast, distance-guided branch lengths assignment with fixed tree topology has not yet been systematically investigated, despite having significant applications. In this paper, we provide a formal mathematical formulation of this problem and propose two representative methods for solving this problem, each with its own strength. We evaluate the performance of these two methods under various settings using simulated data, providing guidance for the choice of methods in respective cases. We demonstrate a practical application of this operation through an extension we termed FunUniFrac, which quantifies the differences in functional units between metagenomic samples over a functional tree with assigned branch lengths, allowing clustering of metagenomic samples by functional similarity instead of taxonomic similarity in traditional methods, thus expanding the realm of comparative studies in metagenomics.
Deciphering Reductive Dehalogenase Specificity Through Targeted Mutagenesis of Chloroalkane Reductases
Authors: Picott Katherine , Bowers Connor , Edwards Elizabeth A.
Published: July 2024

Reductive dehalogenases (RDases) are essential in the anaerobic degradation of various organohalide contaminants. This family of enzymes has broad sequence diversity, but high structural conservation. There have been few studies assessing how RDase peptide sequences affect their substrate selectivity. Here we focus on two chloroalkane RDases, CfrA and DcrA, which have 95% protein sequence identity but have diverged to hold distinct substrate preferences. CfrA will dechlorinate chloroform and 1,1,1-trichloroethane, whilst DcrA will dechlorinate 1,1-dichloroethane. We mutated several residues in the active site of CfrA to investigate a change in substrate preference and to identify which wild-type residues contribute the most to substrate specialization. We determined that no individual residue solely dictates substrate discrimination, but both Y80W and F125W mutations were needed to force CfrA to prefer 1,1-dichloroethane as a substrate. This double mutation also altered the transformation pathway of 1,1,2-trichloroethane from hydrogenolysis (forms 1,2-dichloroethane) to dihaloelimination (forms vinyl chloride). We use predictive protein models and substrate docking to predict what interactions are made between the enzyme and substrate to aid in selection. The residues of significance identified in this study are consistent with those identified from chloroethene RDases, suggesting residue locations with a particularly high impact on activity.

Importance

Reductive dehalogenases play an integral role in the removal of chlorinated solvents from the environment. These enzymes have specificity towards different chlorinated compounds, and it is known that small natural changes in their peptide sequence can change their activity drastically. How these specific sequence variations influence activity is largely unknown. In this study, we demonstrate that mutating a few residues within the active site of CfrA—a chloroform and trichloroethane-specific dehalogenase—changes its substrate preference to dichloroethane. We determine that only two mutations are needed to disrupt the native activity, underscoring the nuances in substrate-structure relationships in reductive dehalogenases. Though we are still far from predicting function from the sequence, this knowledge can give some insight into engineering reductive dehalogenases for new target contaminants.
Low-side and multitone suppression in the base of the gerbil cochlea
Authors: Strimbu C. Elliott , Olson Elizabeth S.
Published: July 2024

The cochlea’s mechanical response to sound stimulation is nonlinear, likely due to saturation of the mechano-electric transduction current that is part of an electromechanical feedback loop. The ability of a second tone or tones to reduce the response to a probe tone is one manifestation of nonlinearity, termed suppression. Using optical coherence tomography to measure motion within the organ of Corti, regional motion variations have been observed. Here, we report on the suppression that occurs within the organ of Corti when a high sound level, low frequency suppressor tone was delivered along with a sweep of discreet single-tones. Responses were measured in the base of the gerbil cochlea at two characteristic frequency locations, with two different directions of observation relative to the sensory tissue’s anatomical axes. Suppression extended over a wide frequency range in the outer hair cell region, whereas it was typically limited to the characteristic frequency peak in the reticular lamina region and at the basilar membrane. Aspects of the observed suppression were consistent with the effect of a saturating nonlinearity. Recent measurements have noted the three-dimensional nature of organ of Corti motion. The effects of suppression observed here could be due to a combination of reduced motion amplitude and altered vibration axis.

Significance Statement

The mammalian auditory organ, the cochlea, relies on a nonlinear active process to achieve sensitivity to low-level sounds and sharp frequency selectivity. Recent work using novel interferometric techniques has revealed complex and nonlinear vibration patterns within the cochlea’s sensory tissue. In this study, the motion response to a pure tone was reduced by additional ”suppressor” tones. The observed motion reduction was consistent with the effect of a saturating nonlinearity, possibly compounded by alterations in the axis of cellular vibration, and thus underscoring the 3-dimensional character of cell-based cochlear mechanical activity.
Gustatory Thalamic Neurons Mediate Aversive Behaviors
Authors: Cao Feng , Park Sekun , Pauli Jordan L. , Seo Eden Y. , Palmiter Richard D.
Published: July 2024

The parvicellular part of the ventral posteromedial nucleus (VPMpc) of the thalamus, also known as the gustatory thalamus, receives input from the parabrachial nucleus and relays taste sensation to the gustatory (or insular) cortex. Prior research has focussed on the role of the VPMpc in relaying taste signals. Here we provide evidence showing that VPMpc also mediates aversive behaviors. By recording calcium transientsin vivofrom single neurons in mice, we show that neurons expressing cholecystokinin and the mu-opioid receptor in the VPMpc respond to various noxious stimuli and fear memory. Chemogenetic and optogenetic activation of these neurons enhances the response to aversive stimuli, whereas silencing them attenuates aversive behaviors. The VPMpc neurons directly innervate neurons in the insular cortex and rostral lateral amygdala. This study expands the role of the VPMpc to include mediating aversive and threating signals to the insular cortex and lateral amygdala.
Unravelling the neurocognitive mechanisms underlying counterconditioning in humans
Authors: Wirz Lisa , Houtekamer Maxime C. , de Vos Jette , Dunsmoor Joseph E. , Homberg Judith R. , Henckens Marloes J.A.G. , Hermans Erno J.
Published: July 2024

Counterconditioning (CC) aims to enhance extinction of threat memories by establishing new associations of opposite valence. While its underlying neurocognitive mechanisms remain largely unexplored, previous studies suggest qualitatively different mechanisms from regular extinction. In this functional MRI study, participants underwent categorical threat conditioning (CS+/CS-: images of animals/tools), followed by either CC (CS+ images reinforced with monetary rewards, n=24) or regular extinction (n=24). The following day, we assessed spontaneous recovery of threat responses and episodic memory for CS+ and CS-category exemplars. While the ventromedial prefrontal cortex (vmPFC) was activated during regular extinction, participants undergoing CC showed persistent CS+-specific deactivation of the vmPFC and hippocampus, and CS+-specific activation of the nucleus accumbens (NAcc). The following day, physiological threat responses returned in the regular extinction group, but not in the CC group. Counterconditioning furthermore strengthened episodic memory for CS+ exemplars presented during CC, and retroactively also for CS+ exemplars presented during the threat conditioning phase. Our findings confirm that CC leads to more persistent extinction of threat memories, as well as altered consolidation of the threat conditioning episode. Crucially, we show a qualitatively different activation pattern during CC versus regular extinction, with a shift away from the vmPFC and towards the NAcc.
Deletion of Setd7 protects against cardiac hypertrophy via inhibiting lipid oxidation
Authors: Su Haibi , Wang Jinghuan , Zhang Yuyu , Xu Jie , Liu Jiayao , Li Yuhui , Xiao Chenxi , Wang Caiyun , Chang Jun , Liu Xinhua
Published: July 2024

Setd7, a catalytic enzyme responsible for histone H3K4 methylation, is implicated in various cardiac diseases. However, the role of Setd7 in pathological cardiac hypertrophy remains unclear. In this study, we observed that Setd7 is significantly elevated in pathological hypertrophy stimuli cardiomyocytes and mouse failing hearts. Subsequently, we found that mice lacking Setd7 remarkably preserved cardiac function after transverse aortic constriction, as demonstrated by improving myocardial hypertrophy and fibrosis, whereas Setd7 overexpression in cardiomyocytes deteriorated hypertrophy phenotype. Further in vitro analyses revealed that Setd7 mediated-E2F1 activation induces E3 ubiquitin protein ligases WWP2 expression to catalyze the lipid-peroxide-reducing enzyme GPx4 ubiquitination degradation, ultimately causing widespread lipid peroxidation and boosting pathological cardiac hypertrophy. Remarkably, loss of activity of GPx4 blunted the Setd7 knockdown exerts antihypertrophic effect in pathological cardiomyocytes hypertrophy, further confirming an important role of lipid peroxidation in Setd7-mediated failing hearts. In summary, the role of Setd7 in pressure overload-induced cardiac hypertrophy is regulated by the Setd7-E2F1-WWP2-GPx4 signaling pathway, suggesting that targeting Setd7 is a promising therapeutic strategy to attenuate pathological cardiac hypertrophy and heart failure.
Nutrition induced changes in the microbiota can cause dysbiosis and disease development
Authors: Lachnit Tim , Ulrich Laura , Willmer Fiete M. , Hasenbein Tim , Steiner Leon X. , Wolters Maria , Herbst Eva M. , Deines Peter
Published: July 2024

The increasing global prevalence of inflammatory and autoimmune diseases highlights the need to understand their origins. The overfeeding hypothesis suggests that disturbances in the microbiota due to diet may initiate these diseases. Using the model organismHydra, we established a causal link between environmental alterations in the microbiota and disease development. Relocating Hydra to natural lakes caused significant microbial shifts due to new colonizers and nutrients. Nutrient manipulation removed the competitive advantage of the well-adapted resident microbiota, disrupted its nutrient-blocking capacity and triggered specific microbiota changes leading to disease. L-arginine supplementation alone transformedPseudomonasfrom a commensal microbe into a pathogen, showing pathogenicity as context-dependent. Our findings support the overfeeding hypothesis, highlighting the role of microbial and nutrient dynamics in disease development.
2,2-Di-Fluoro-Derivatives of Fucose Can Inhibit Cell Surface Fucosylation Without Causing Slow Transfer to Acceptors
Authors: Liu Yanyan , Sweet Igor , Boons Geert-Jan
Published: July 2024

Fucosyltransferases (FUTs) are enzymes that transfer fucose (Fuc) from GDP-Fuc to acceptor substrates resulting in fucosylated glycoconjugates that are involved in myriad of physiological and disease processes. Previously, it has been shown that per-O-acetylated 2-F-Fuc can be taken up by cells and converted into GDP-2-F-Fuc which is a competitive inhibitor of FUTs. Furthermore, it can act as a feedback inhibitor ofde-novobiosynthesis of GDP-Fuc resulting in reduced glycoconjugate fucosylation. GDP-2-F-Fuc and several other reported analogs are slow substrates, which can result in unintended incorporation of unnatural fucosides. Here, we describe the design, synthesis, and biological evaluation of GDP-2,2-di-F-Fuc and corresponding prodrugs as inhibitor of FUTs. This compound lacks the slow transfer activity observed for the mono-fluorinated counterpart. Furthermore, it was found that GDP-2-F-Fuc and GDP-2,2-di-F-Fuc have similar Kivalues for the various human fucosyl transferases while the corresponding phosphate prodrugs exhibit substantial differences in inhibition of cell surface fucosylation. Quantitative sugar nucleotides analysis by LC-MS indicates that the 2,2-di-F-Fuc prodrug has substantial greater feedback inhibitory activity. It was also found that by controlling the concentration of the inhibitor, varying degrees of inhibition of the biosynthesis of different types of fucosylatedN-glycan structures can be achieved. These findings open new avenues for the modulation of fucosylation of cell surface glycoconjugates.
ADAM17 regulates hepatic DNA damage repair and tumour formation
Authors: Reichert Manuel , Halwachs Birgit , Bolik Julia , Senftleben Anke , Krause Freia , Conrady Luisa , Bauer Renate , Rachmilewitz Jacob , Horejs-Hoeck Jutta , Rose-John Stefan , Schmidt-Arras Dirk
Published: July 2024

Background

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide. Still, therapy options for this tumour entity are limited and novel therapeutic options are highly sought after. Genomic instability of hepatocytes promotes oncogenic transformation and underlies the regulation of micro-environmental signalling cues. The membrane-bound a disintegrin and metalloprotease (ADAM) 17 is a major regulator of micro-environmental signals through the proteolytic release of paracrine factors. However, its role in hepatic DNA damage repair and its contribution to hepatic tumourigenesis is still unclear.

Methods

We investigated the effect of ADAM17 on diethylnitrosamine (DEN)-induced acute DNA damage and subsequent DNA damage repair by utilizing mice with ubiquitous or myeloid-specific genetic deficiency in ADAM17. DNA double strand breaks and inflammation were investigated by immunofluorescence of liver tissue sections. tumourigenesis in mice with myeloid-specific ADAM17-deficiency was investigated in a chemically induced hepatocarcinogenesis model.

Results

ADAM17 on myeloid cells, in particular Kupffer cells is essentially involved in the non-cell autonomous regulation of DNA damage repair in hepatocytes. Parenchymal ADAM17 regulates hepatocyte fate and recruitment of infiltrating myeloid cells. Furthermore, myeloid ADAM17 promotes hepatic tumour initiation and correlates with poor prognosis in human HCC.

Conclusions

We identified ADAM17, in particular on myeloid cells as an essential driver of hepatic tumourigenesis and as a potential novel drug target for the treatment of hepatic malignancies.
Human-likeAPOBEC3gene expression and anti-viral responses following replacement of mouseApobec3with the 7-gene humanAPOBEC3locus
Authors: Kirkwood Nerissa K , Prosser Haydn M , Yap Melvyn W , Gibson Jane , Cook Ross , Reddin Ian , Stranger Ane , Howes Emma , Zainal Nur , Periyasamy Manikandan , Conticello Silvestro G , Thomas Gareth J. , Scott James , Bishop Kate N , Ali Simak , Bradley Allan , Fenton Tim R
Published: July 2024

The seven human APOBEC3 (hA3) genes encode polynucleotide cytidine deaminases that play vital roles in restricting replication of viruses and retrotransposons. However, off-target A3 deamination of the cellular genome is a major source of somatic mutations in human cancer. The ability to study A3 biologyin vivois hindered by the fact that the solitary murineApobec3gene (mA3) encodes a cytoplasmic enzyme, with no apparent mutagenic activity. Transgenic expression of individual hA3 genes in mice has helped to confirm their oncogenic potential but important questions including which hA3 genes are active in different tissue contexts and how they function in concert when under control of their cognate promoters cannot be addressed using these models. Here we describe humanization of the mouse mA3 locus by integration of a modified BAC clone encompassing the entire 7-gene hA3 locus from human chromosome 22 replacing mA3 on mouse chromosome 15. APOBEC3 mice are viable and fertile and hA3 gene expression in cells and tissues correlates strongly with expression in corresponding human cells and tissues, indicating human-like regulation of hA3 gene expression in the mice. Splenocytes from this line display a functional human A3 response to Friend Murine Leukaemia Virus (F-MLV) infection. We propose that the Hs-APOBEC3 mouse will uniquely model the function of the complete hA3 locus in a living organism and that it will serve as a useful background upon which to model human cancer, as well as assisting drug discovery efforts.
Application of deep learning methods for beam size control during user operation at the Advanced Light Source
Authors: Hellert Thorsten , Ford Tynan , Leemann Simon C. , Nishimura Hiroshi , Venturini Marco , Pollastro Andrea
Published: July 2024

Past research at the Advanced Light Source (ALS) provided a proof-of-principle demonstration that deep learning methods could be effectively employed to compensate for the significant perturbations to the transverse electron beam size induced by user-controlled adjustments of the insertion devices. However, incorporating these methods into the ALS’ daily operations has faced notable challenges. The complexity of the system’s operational requirements and the significant upkeep demands has restricted their sustained application during user operation. Here, we introduce the development of a more robust neural network (NN)-based algorithm that utilizes a novel online fine-tuning approach and its systematic integration into the day-to-day machine operations. Our analysis emphasizes the process of NN model selection, demonstrates the superior performance of the NN-based method over traditional feedback methods, and examines the effectiveness and resilience of the new algorithm during user-operation scenarios.

Published by the American Physical Society
2024
Explaining the cosmological dark matter coincidence in asymmetric dark QCD
Authors: Ritter Alexander C. , Volkas Raymond R.
Published: July 2024

To properly solve the coincidence problem (ΩDM≃5ΩVM) in a model of asymmetric dark matter, one cannot simply relate the number densities of visible and dark matter without also relating their particle masses. Following previous work, we consider a framework where the dark matter is a confined state of a dark QCD gauge group whose confinement scale is dynamically related to the QCD confinement scale by a mechanism utilizing infrared fixed points of the two gauge couplings. In this work we present a new, “zero-coupling infrared fixed point” approach, which allows a larger proportion of models in this framework to generically relate the masses of the visible and dark matter particles. Due to the heavy mass scale required for the new field content, we introduce supersymmetry to the theory. We consider how these models may be incorporated in a full theory of asymmetric dark matter, presenting some example leptogenesis-like models. We also discuss the phenomenology of these models; in particular, there are gravitational wave signals which, while weak, may be measurable at future mHz and μHz detectors.

Published by the American Physical Society
2024
The corrosion behavior of AZ91 bulk alloy and thin films
Authors: Yang Zhenlei , Du Yuzhou , Ma Bo , Wang Qian , Yang Chao
Published: July 2024

Purpose

The purpose of this study is to campare the corrosion behavior of Az91 films and bulk sample, in the objective to provide reference for the corrosion resistance improvement of Mg alloys.

Design/methodology/approach

AZ91 films with various thickness values are produced by magnetron sputtering technique, and the corrosion behavior was characterized by immersion tests and electrochemical measurements.

Findings

The AZ91 films exhibited a preferred orientation with basal planes parallel to the surface and increased densification with the increase of thickness, and a superior corrosion resistance for the AZ91 films compared with the bulk sample.

Originality/value

The preferred (0002) basal planes in AZ91 films benefited the corrosion resistance and the nanoscale AZ91 films facilitated the development of a dense passivation film. Consequently, AZ91 film exhibited a superior corrosion resistance.
De-othering: indigenous perspectives on diversity, equity and inclusion
Authors: Henry Ella , Leroy-Dyer Sharlene
Published: July 2024

Purpose

The purpose of this paper is to share two Indigenous perspectives on diversity, equity and inclusion (DEI). It is grounded in aspirations for de-othering and de-colonisation. De-othering is the unpicking of the status of “other” bestowed upon us by the dominant culture, and de-colonisation involves the deconstruction of the ways the settler states in which we live have defined and oppressed us.

Design/methodology/approach

The methodology is a critical self-reflection, drawing on the lived experience of two Indigenous scholars in business fields outside of the international business discipline.

Findings

The findings explore policies, like affirmative action emerging in the 1960s, to the pantheon of DEI theory and strategies developed, as tools of the dominant culture, albeit well-meaning, that perpetuate the dependency of the “other” on the largesse of the “dominant”, which ultimately maintain relations of oppression.

Research limitations/implications

The limitations of the paper include, that we cannot speak for all Indigenous peoples. This paper is a personal viewpoint and is not a meta-analysis of theory and literature. The authors draw on the personal, which for Indigenous peoples is also the political, perspectives, that are steeped in their cultural histories and identities, and underpinned by their aspirations for social change and social justice for their peoples.

Practical implications

The authors offer practical implications for those Indigenous Peoples and allies looking to develop empowering strategies for de-othering individuals and communities defined by dominant cultures as “others”, which in turn has social implications for engagement in truly empowering work in social justice at the borderlands of power, particularly in terms of international business guided by ethics and social responsibility.

Social implications

In this paper, the authors use the following terms: Maori, Aboriginal and Torres Strait Islander, First Peoples and Indigenous Peoples. They use the term Peoples to denote that they are not one homogenous People but a collective society that consists of many distinct communities, peoples and nations.

Originality/value

The authors offer practical implications for those Indigenous Peoples and allies looking to develop empowering strategies for de-othering those defined by dominant cultures as “others”, which in turn has social implications for those engaged in truly empowering work for social justice at the borderlands of power, particularly in terms of international business guided by ethics and social responsibility. They make no apologies for this paper, as it is entirely based on personal viewpoints.
Optimization of semi-supervised generative adversarial network models: a survey
Authors: Ma Yongqing , Zheng Yifeng , Zhang Wenjie , Wei Baoya , Lin Ziqiong , Liu Weiqiang , Li Zhehan
Published: July 2024

Purpose

With the development of intelligent technology, deep learning has made significant progress and has been widely used in various fields. Deep learning is data-driven, and its training process requires a large amount of data to improve model performance. However, labeled data is expensive and not readily available.

Design/methodology/approach

To address the above problem, researchers have integrated semi-supervised and deep learning, using a limited number of labeled data and many unlabeled data to train models. In this paper, Generative Adversarial Networks (GANs) are analyzed as an entry point. Firstly, we discuss the current research on GANs in image super-resolution applications, including supervised, unsupervised, and semi-supervised learning approaches. Secondly, based on semi-supervised learning, different optimization methods are introduced as an example of image classification. Eventually, experimental comparisons and analyses of existing semi-supervised optimization methods based on GANs will be performed.

Findings

Following the analysis of the selected studies, we summarize the problems that existed during the research process and propose future research directions.

Originality/value

This paper reviews and analyzes research on generative adversarial networks for image super-resolution and classification from various learning approaches. The comparative analysis of experimental results on current semi-supervised GAN optimizations is performed to provide a reference for further research.
Children’s sensemaking of algorithms and data flows across YouTube and social media
Authors: Starks Allison , Reich Stephanie Michelle
Published: July 2024

Purpose

This study aims to explore children’s cognitions about data flows online and their understandings of algorithms, often referred to as algorithmic literacy or algorithmic folk theories, in their everyday uses of social media and YouTube. The authors focused on children ages 8 to 11, as these are the ages when most youth acquire their own device and use social media and YouTube, despite platform age requirements.

Design/methodology/approach

Nine focus groups with 34 socioeconomically, racially and ethnically diverse children (8–11 years) were conducted in California. Groups discussed data flows online, digital privacy, algorithms and personalization across platforms.

Findings

Children had several misconceptions about privacy risks, privacy policies, what kinds of data are collected about them online and how algorithms work. Older children had more complex and partially accurate theories about how algorithms determine the content they see online, compared to younger children. All children were using YouTube and/or social media despite age gates and children used few strategies to manage the flow of their personal information online.

Practical implications

The paper includes implications for digital and algorithmic literacy efforts, improving the design of privacy consent practices and user controls, and regulation for protecting children’s privacy online.

Originality/value

Research has yet to explore what socioeconomically, racially and ethnically diverse children understand about datafication and algorithms online, especially in middle childhood.